CA2484282A1 - Pyrimidine derivatives intermediates for producing aminopyrimidines as sorbitol dehydrogenase inhibitors - Google Patents
Pyrimidine derivatives intermediates for producing aminopyrimidines as sorbitol dehydrogenase inhibitors Download PDFInfo
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Abstract
Disclosed are pyrimidine compounds of formula Z:
(see formula I) formula ZZ:
(see formula II) formula III:
(see formula III) wherein R100 is (C1-C8) alkyl, benzyl or phenyl, said benzyl or phenyl being unsubstituted or substituted, as well as a process for preparing the compound of formula Z. Those compounds are useful as intermediates for producing aminepyridine compounds of the formula:
(see formula IV) in which R1 is formyl, acetyl, etc.; R2 is H, alkyl or alkoxy; and R3 is a substituted amino group such as (see formula V) in which R9 is pyrimidyl or triazinyl, useful as sorbitol dehydrogenase inhibitors.
(see formula I) formula ZZ:
(see formula II) formula III:
(see formula III) wherein R100 is (C1-C8) alkyl, benzyl or phenyl, said benzyl or phenyl being unsubstituted or substituted, as well as a process for preparing the compound of formula Z. Those compounds are useful as intermediates for producing aminepyridine compounds of the formula:
(see formula IV) in which R1 is formyl, acetyl, etc.; R2 is H, alkyl or alkoxy; and R3 is a substituted amino group such as (see formula V) in which R9 is pyrimidyl or triazinyl, useful as sorbitol dehydrogenase inhibitors.
Description
PYRIMIDINE DERIVATIVES INTERMEDIATES FOR PRODUCING
AMINOPYRIMIDINES AS SORBITOL DEHYDROGENASE INHIBITORS , This is a divisional application of Canadian Patent Application No. 2,366,858 filed September 27, 2001.
The parent application describes novel aminopyrimidine derivatives and to the use of such derivatives and related compounds to inhibit sorbitol dehydrogenase (SDH), lower fructose levels, or treat or prevent diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy in mammals. The parent also describes pharmaceutical compositions containing such pyrimidine derivatives and related compounds. The parent also describes pharmaceutical compositions comprising a combination of a sorbitol dehydrogenase inhibitor of formula I and an aldose reductase inhibitor and to the use of such compositions to treat or prevent diabetic complications in mammals. The parent also describes pharmaceutical compositions comprising a combination of a sorbitol dehydrogenase inhibitor of formula I and an NHE=1 inhibitor and to the use of such compositions to reduce tissue damage resulting from ischemia, and particularly to prevent perioperative myocardial ischemic injury. The present divisional application is directed to specific novel pyrimidine derivatives of the formulae Z, ZZ and III
described hereinunder and their production processes.
Throughout the specification, it should be understood that the expression "present invention" or the like encompasses the subject matters of both the parent and divisional applications.
~ -la-S. Ao et al., Metabolism, 40, 77-87 (1991) have shown that significant functional improvement in the nerves of diabetic rats (based on nerve conduction velocity) occurs when nerve fructose levels are pharmacologically lowered, and that such improvement correlates fore closely with the lowering of nerve fructose than the lowering of nerve sorbitol. Similar results were reported by N. E. Cameron and M. A. Cotter, Diabetic Medicine, 8, Suppl. 1, 35A-36A
(1991). In both of these cases, lowering of nerve fructose was achieved using relatively high dose of aldose reductase inhibitors, which inhibit the formation of sorbitol, a precursor of fructose, from glucose via the enzyme aldose reductase.
U.S. Patent Nos. 5,138,058 and 5,215,990 each disclose compounds of the formula:
AMINOPYRIMIDINES AS SORBITOL DEHYDROGENASE INHIBITORS , This is a divisional application of Canadian Patent Application No. 2,366,858 filed September 27, 2001.
The parent application describes novel aminopyrimidine derivatives and to the use of such derivatives and related compounds to inhibit sorbitol dehydrogenase (SDH), lower fructose levels, or treat or prevent diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy in mammals. The parent also describes pharmaceutical compositions containing such pyrimidine derivatives and related compounds. The parent also describes pharmaceutical compositions comprising a combination of a sorbitol dehydrogenase inhibitor of formula I and an aldose reductase inhibitor and to the use of such compositions to treat or prevent diabetic complications in mammals. The parent also describes pharmaceutical compositions comprising a combination of a sorbitol dehydrogenase inhibitor of formula I and an NHE=1 inhibitor and to the use of such compositions to reduce tissue damage resulting from ischemia, and particularly to prevent perioperative myocardial ischemic injury. The present divisional application is directed to specific novel pyrimidine derivatives of the formulae Z, ZZ and III
described hereinunder and their production processes.
Throughout the specification, it should be understood that the expression "present invention" or the like encompasses the subject matters of both the parent and divisional applications.
~ -la-S. Ao et al., Metabolism, 40, 77-87 (1991) have shown that significant functional improvement in the nerves of diabetic rats (based on nerve conduction velocity) occurs when nerve fructose levels are pharmacologically lowered, and that such improvement correlates fore closely with the lowering of nerve fructose than the lowering of nerve sorbitol. Similar results were reported by N. E. Cameron and M. A. Cotter, Diabetic Medicine, 8, Suppl. 1, 35A-36A
(1991). In both of these cases, lowering of nerve fructose was achieved using relatively high dose of aldose reductase inhibitors, which inhibit the formation of sorbitol, a precursor of fructose, from glucose via the enzyme aldose reductase.
U.S. Patent Nos. 5,138,058 and 5,215,990 each disclose compounds of the formula:
2 3 R ~N/R
N
Ri/ \N/ 4 R
where R'. R~, R', R' and RS are as disclosed therein. Said o~mpounds are disclosed as having utility as tools in screening for aldose reductase inhibitors due to tt~e sorbitol aoarmulating activity of said compounds:
Commonly assigned U.S. Patent Nos. 5,728,704 and 5,866,578 each disclose compounds of the formula A, A
wherein R' through RS are defined as disclosed therein. Further, U.S.
5,728,704 discloses that sorbitol dehydrogenase compounds have utility in the treatment of diabetic complications.
Pyrimidine derivatives of the formula I, as defined below, and their pham~aoeutically axeptable salts, lower fiuctose levels in the tissues of mammals affected by diabetes (e.g., nerve, kidney and retina tissue) and are useful in the treatment and prevention of the diabetic complications referred to above.
These compounds, or their metabolites in vivo, are inhibitors of the enzyme sorbibot dehydrogenase, which catalyzes the oxidation of sorbitol to fructose.
SUMMARY OF THE INVENTION
The present invention is directed to a oort~potrnd of the fornxrla I
R' R~
~N
N R' a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug, wherein:
R' is fomryl, acetyl, propionyl, carbamoyl or -C(OH)R'R°;
R' and Rs are each independently hydrogen, methyl, ethyl or hydroxy-(C,-C~alkyl;
.
R' is hydrogen, (C,-C,~Ikyl or (C,-C,)alk~Oxy;
pCT/IB00700296 R' is a radical of the formula ~ ~R9 , ~ n , R23 zN ~N N
( i1 ~ G' ( _). ~G' 2e G R
N , R3a I . R3d ( , R3c ( .
R~°
.
WO 00!59510 PGT/IB00/00296 R" Raa A-N
\ 8 N /N
Ra2 ~ Raz Rao ~ ~ Ran R'z~ R'=
R~ Rs~
HO R4z N~R4o Ra, ~R"a ' R" Rsu E
N N
Rae Ras Rak I R» I
N
Rai ( Y, ~as R4~ Yt R~\NiYwRsa ss\
R ~N~Rs, N
R,\ iY (CH2)m (CHz)"
R3m I ~ Ran Rss/N\ R~
Y' Ni \ R's a~ , R \N~Y~Rsa (CHz)k or R3p I ~ N
' N J
R I _ wherein said radical of formula R'~ is additionally substituted on the ring by Re, R' and R°;
said radical of formula R~° is additionally substituted on the ring by R'°, R'° and R~°;
G, G' and G= are taken separately and are each hydrogen and R° is hydrogen, (C,-C,~Ikyl. (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,~Ikyl, hydroxy-(C,-C,~Ikyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl; (C,-C,)alkyl or (C,-C,)alkoxy, wherein said (C,-C,)alkyl in the definition of R° and said (C,-C,~Ikoxy in the defirirtion of Rare optionally and independently substituted with up to five tiuoro; R' and R° are each independently hydrogen or (C,-C,~lkyl; or G and G' are taken together and are (C,-C,~Ikylene and Re, R', R° and Gz are hydrogen; or G' and GZ are taken together and are (C,-C,)alkylene and R°, R', R° and G are hydrogen;
q~0orl;
X is a covalent bond, -(C=NR'°)-, oxycarbonyl, vinylenylcart~onyl, oxy(C,-C,~Ikylenylcarbonyl, (C, C,)alkylenylcarbonyl, (C,-C,~Ikenylcarbonyl, thio(C,_ C,~Ikylenyicarbonyl, vinylenylsulfonyl; sutfinyl-(C,-C,~Ikylenytcarbonyl, sulfonyl-(C,-C,)alkylenylcarbonyl or carbonyl(C°-C,)alkylenylcarbonyl; wherein said oxy(C,-C,)alkylenylcarbonyl, (C,-C,~Ikylenylcarbonyl, (C,-C,~Ikenylrarbonyl and thio(C,-C,)alkylenytcarbonyl in the definition of X are each optionally and independently substituted with up to two (C,-C,)alkyl, benryl o~ Ar, said vinylenylsutfortyl and said vinylenylcarbonyl in the definition of X are optionally substituted independently on one or two vinylenyl carbons with (C,-C,~Ikyl, benzyl or Ar; and said carbonyl(Co-C,)alkyienylcarbonyl in the definition of X is optionally substituted independently with up to three (C,-C,~Ikyl, benzyl or Ar;
R'° is hydrogen or (C,-C,)alkyl;
R9 is (C,-C,kydoatkyl, Ar'-(C°-C,~Ikylenyl or (C,-C°~fkyl optionally substituted with up to five fluoro; provided that when q = 0 and X is a covalent bond, oxycartrorryl or (C,-C,)alkylenylcartionyl; then R° is not (C,-Ca~lkyl:
Ar and Ar' ere independently a fully saturated, partially saturated or fully unsaturated five- to eight-membered ring optionally having up to four heteroatoms selected WO 00/59510 PCT/IB00l00396 ..6_ independently from oxygen, sulfur and nitrogen, or a bicydic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five- to seven-membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyGic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five to seven membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially saturated. fully saturated ring or fully unsaturated monocydic ring, bicyGic ring or tricydic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur, Ar and Ar' are optionally independently substituted on carbon or nitrogen, .on one ring if the moiety is monocydic, on one or both rtngs if the moiety is bicydic, or on one, two or three rings if the moiety is tricydic, with up to a total of four substituents independently selected from R", R'2, R'~ and R"; wherein R", R'Z, R" and R"
are each taken separately and are each independently halo, formyl, (C,-Cs~lkoxycarbonyl, (C,-C6)alkylenyloxycarbonyl, (C,-C,)alkoxy tC,-C,)alkyl, C(OH)R'SR'B, naphthyl, phenyl, imidazolyl, pyridyl, triazolyl, morpholinyl, (Co-C,)alkylsutfamoyl, N-(Co-C,)alkylrzrbamoyl, N,Nrdi-(C,-C,)alkylcarbamoyl, N-phenylcarbamoyl, N-(C,-C,~Ikyl-N-phenylcarbamoyl, N.,N-Biphenyl carbamoyl, (C,-C,~Ikylcarbonylamido, (C3-C,)cydoalkylcarbonytamido, phenylcartionytamido, piperidinyl, pyrrolidinyl, piperazinyl, cyano, benzimidazolyl, amino, anilino, pyrimidyl, oxazolyl, isoxazoiyl, tetrazolyl, thienyl, thiazolyl, ben~othiazolyl, pyrrolyl, pyrazoiyt;
tetrahydroquinolyl, tetrahydroisoquinolyt, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfanyi, furanyl, 8-(C,-C,~Ikyl-3,8-diaza[3.2.1]bicydoodyl, 3.5-dioxo-1,2,4-triazinyl, phenoxy, thiophenoxy, (C,-C,)alkylsulfanyl, (C,-C,~fkylsulfonyl, (C3-C~kydoalkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or tC,-C,~Ikoxy optionally substituted with up to five fluoro; said naphthyl, phenyl, pyridyl, piperidinyl, benzimidazolyl, pyrimidyl, thienyl, benzothiazolyl, pyrroiyl, tetrahydroquinolyl, tetrahydroisoquinolyl, bentoxazolyl, pyridazinyl, pyridyioxy, pyridylsulfanyl, furanyl, thiophenoxy,-anilino and phenoxy in the definition of R", R'~, R" and R" are optionally substituted with up to three substituer~ts independently sele~ed from hydroxy, halo, hydroxy-(C,-C,~Ikyl.'(C,-C,~Ikoxy-(C,-C,)alkyt. (C,-C,~Iky optimally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to flue tluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazotyl in the definition of R", R'Z, R" and R" are optionally substituted with up to two substituents independently selected from hydroxy, halo, hydroxy-(Ca-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted'with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said morphofinyl in the definition of R", R'~, R" and R" is optionally substituted with up to two substituents independently selected from (C,-C,~Ikyl; said pyrrolidinyl in the definition of R", R'Z, R"
and R" is optionally substituted with up to two substituents independently selected from hydroxy, hydroxy-(C,-C,)alkyl, (C,-C,~lkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to flue fluoro; said piperazinyl in the definition of R", R'Z, R" and R" is optionally substituted with up to three substituents independently selected from (C,-C,)alkoxy-(C,-C,~Ik~l, hydroxy-(C,-C,)alkyl, phenyl, pyridyl, (Co-C,)alkylsulfamoyl, (C,-C;)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said triazolyl in the definition of R", R'~, R" and R" is optionally substituted with hydroxy, halo, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~alkyl optionally substituted with up to flue fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said tetrazolyl in the definition of R", R'z, R" and R" is opti~afly substituted with hydroxy-(C=-Chalky! or (C,-C,~Ikyl optionally substituted with up to five fluoro;
and said phenyl and pyridyl which are optionally substituted on piperazine in the definition of R", R'2, R" and R" are optionally substituted with up to three hydroxy, halo, hydroxy-(C,-C,~Ikyl, (C,-C,~lkoxy-(C,-C,)alkyl, (C,-C.~Ikyl optionally substituted with up to 5ve fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; or R" and R'= are taken together on adjacent carbon atoms and are -CH20C(CH,)ZOCHZ- or -0-(CHZ)o-0-, and R" and R" are taken separately and are each independently hydrogen or (C,-C,~Ikyl;
pisl,2or3;
R's and R'6 are taken separately and are each independently hydrogen, (C,-C,)alkyl optionally substituted with up to five fluoro; or R'S and R'6 are taken separately and R's is hydrogen and R'° is (C,-Cskycloalkyl, hydroxy-(C,-~C,~lkyl, Phenyl.
PY~.
pyrirnidyl, thienyl, furanyl, thiazolyl, oxazolyl. imidazolyl, benzothiazotyi or benzoxazolyl; or R'S and R'6 are taken together and are (C,-Ca~lkylene;
G', G' and Gs are taken separately and are each hydrogen; r is 0; R'°
is hydrogen, (C,-C,)atkyl. (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C;-C,)alkyl, hydroxy-(C,-C,)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)atkyl or (C,-C,)atkoxy, wherein said 6 (C,-C,)alkyl in the definition of R6 and said (C,-C,)atkoxy in the definition of Raar~e optionally and independently substituted with up to five tluoro; and R'° and R~° are each independently (C,-C,)alkyl; or G', G' and GS are taken separately and are each hydrogen; r is 1; R'°
is hydrogen, (C,-C,)alkyl, (C;-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,)alkyl, hydroxy-(C,-C,)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl or (C,-C.)alkoxy, whec~;in said (C,-C,)alkyl in the definition of R6 and said (C,-C,)alkoxy in the definition of Rsare.
optionally and independently substituted with up to five fluoro; and R'° and R~° are each independently hydrogen or.(C,-C,)alkyl; or G' and G' are taken together and are (C,-C~)afkylene; r is 0 or 1; and R'°, R'°, Rm and Gs are hydrogen; or G' and GS are taken together and are (C,-C°)alkylene; r is fl or 1; and R'°, R'°, Rm and G' are hydrogen;
R" is SOzNR2'R~, CONR2'R~, (C,-Cs)alkoxycarbonyl, (C,-C6)alkylcarbonyl, Ar~-carbonyl, (C,-C°)alkylsulfonyt, (C,-C6)alkylsulfinyl, Ar? sutfonyl, Are-sufinyl and (C,-C6)allcyl;
R2' and R~ are taken separately and are each independenti)r selected from hydrogen, (C,-C°)alkyl, (C,-C,)cydoalkyl and Are-(Co-C,)atkylenyl; or R=' and R~ are taken together with the nitrogen atom to which they are attad~ed to form azetidinyl, pyrrolidinyl, piperidcnyl, pcperazinyl, motpholinyl, a~epinyl, azabicydo[3.22]nonanyl, azabicydo[22.1]heptyl, 6,7-dihydro-SH-dibenzo[c,e]azepinyl,1,2,3,4-tetrahydro-isoquinolyl or 5,6,7,&tetrahydropyrido[4,3-d]pyrimidyt; said azetidinyl in the definition of R~' and t~ is optionally substituted independently uvith one substctuent seceded from hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)altcyl, (C,-C,)alky! optionally substituted with up to flue fluoro and (C,-C,)alkoxy optionally substit<rted with up to five fluoro; said pymdidinyl, piperidinyl; azepinyi in the definition of RZ' and R~ are optionally substituted independently with up to two substituents independently selected from hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,~Ikyl. (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of RZ' and R~ is optionally substituted with up to two subsiituents independently selected from hydroxy-(C,-C,~Ikyl, (C,-C,~lkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to flue 8uo~o and (C,-C,)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definitioh of R2' and R~ is optionally substituted independently with up to three substituents independently selected from phenyl, pyridyl, pyrimidyl; (C,-C,~Ikoxy~carbonyl and (C,-C,)alkyl optionally substituted with up to five fluoro; said 1,2,3,4-tetrahydro-isoquinolyl and said 5,6,7,8-tetrahydropyrtdo[4,3-dJpyrimidyl in the definition of R~' and !~ are optionally substituted independently with up to three substituents independently selected from hydroxy, amino, halo, hydroxy-(C,-C,)alkyl, (C,-C,)atkoxy-(C,-C,)alkyl, (C,-C,)alkyl.
optionally substituted with up to five fluoro and (C,~C,)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-diben2ojc,e]azepinyl in the'definition of 7 5 R~' and R~ is optionally substituted with up to four substituents independently selected from hydroxy, amino, halo, hydroxy-(C,-C,)alkyf, (C,-C,~lkoxy-(C,-C,~alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,~Ikoxy optionally substituted with up to five fluoro; said pyrimidyt, pyridyl and phenyl which are optionally substituted on said piperazine in the definition of Rs' and R~ is optionally substituted with vp to three substituents selected from hydroxy, amino, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~Ikyf optionally substituted with up to five fluoro and (C,-C,~Ikoxy optionally substituted with up to five fluoro;
Arz is independently defined as set forth for Ar and Ar' above;
said Ar= is optionally independently substituted as set forth for Ar and Ar' above;
R~' is CONR~'R~ or S02R~R~, wherein R~ is hydrogen (C,-C,~tkyl or Ar,'-(Co-C,)alkylenyl and R~ is Ar'-(Co-C,)alkylenyl; provided that when Ar' is phenyl, naphthyl or biphenyl, then R~' cannot be CONR~R~ where Rte' is hydrogen of Ar' and R~° is Ar':
R~' is hydrogen, (C,-C,~Ikyl. (C,-C,)alkoxycarbonyl. (C,-C,~Ikoxy-(C,-C,~lkyl.
hydroxy-(C,-C,~(kyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,~Ikyl. (C,-C,~Ikoxy-(C,-Cajalkyl, (C,-Cs~tkyl or ~C,-C,j~alkoxy, wherein said (C,-C,~Ikyl in fhe definition of fZ° and said (C,-C,~Ikoxy in the definition of R° are optionally and independenfly substituted with up to five tluoro;
Ar' is independently defined as set forth for Ar and Ar' above;
said Ar' is optionally independently substituted as set forth for Ar and Ar' above;
R~' is hydrogen or (C,-C,~Ikyl;
R~ and R'° are each independently hydrogen, hydroxy, halo, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up bo fnre fluoro, (C,-C,)alkoxy optionally substituted with up to five fluoro, phenyl, pyridyl, pyrifiidyi, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, SOZNR'°R", CONR'°R" or NR'°R";
said thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of R'° and R~ are optionally substituted by up to two hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alky! optionally substrtuted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said phenyl, pyridyl, phenoxy and thiophenoxy in the definition of R~ and R~ are optionally substituted by dp to three hydroxy, halo, hydroxy-(C,-C,~Ikyi, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,~Ikyl optionally substituted with up to five fluoro or (C,-C,~lkoxy optionally substituted with up to five fluoro;
R'° and R" are each independently hydrogen, (C,-C,)alkyl, (C,-C~)cydoalkyl or phenyl, said phenyl is optionally substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)atkoxy optionally substituted with up to five fluoro; or R'° and R" are taken together with the nitrogen to which they are attad~ed to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; said pymolidinyl and pipe~dinyl in the definition of R'° and R" are optionally substituted with up to two hydroxy, amino, hydroxy-(C,-C,)alkyl, {C,-C,)alkoxy-(C,-C,~(kyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said indolinyl and piperazinyl in the definition of R'° and R" are optionally substituted with up to three hydroxy, amino, hydroxy-(C,-C,~Ikyl, (C,-C,~Ikoxy-(C,-C,~lkyi, (C,-C,~Ikoxycarbonyl. (C,~C.)alkyl oPtionaliY
substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted_with up to five tluoro; said morpholinyl in the definition of R'° and R" is optionally substituted with up to two substituents independently selected from hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,~Ikoxy optionally Substituted with up to five fiuoro;
A is N optionally substituted with hydrogen or (C,-C,)alkyl and B is carb~yl;
or A is cart~onyl and B is N optionally substituted with hydrogen or (C,-C,~Ikyl;
R'~ is hydrogen or (C,-C,)alkyl;
R" is phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolys, benzyl, quinolyl, isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl, beivzoxazoiyl, ben~ofuranyl or benzothienyl;
said phenyl, pyridyl, pyrimidyl, thiazotyl, oxazolyl, benzyl, quinolyl, isoquinolyl, phthalizinyi, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl and benzothienyl in the definition of R" are optionally substituted with up to three phenyl, phenoxy, NR"R'~, halo, hydroxy, hydroxy-(C,-C,~lkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to flue fluoro or (C,-C,)alkoxy optionatf)r substituted with up to five fluoro;
R~' and R'~ are each independently hydrogen, (C,-C, alkyl), phenyl or phenylsulfonyl;
said phenyl and phenylsulfonyl in the definition of R" and R'~ are optionally substituted with up to three halo, hydroxy, (C,-C,~Ikyl optionally substituted with up to five fluoro or (C,-C,~lkoxy optionally substituted with up to flue fluoro;
D is CO, CHOH or CH2;
EisO.NHorS;
R'~ and R" are taken separately and are each independently hydrogen, halo, cyano, hydroxy, amino. (C,-CB)alkylamino, di-(C,-C6)alkylamino. pyrroGdir~, piperidino, morpholino, (C,-C,~Ikoxy-(C,-C,)alkyl, hydroxy-(C,-C,)atkyl, Ar', (C,-C,)atkyl optionally substituted with up to five.fluoro or (C,-C,)alkoxy optionally subsfltuted with up to flue fluoro;
R'°, R'~ and R'° are each independently hydrogen or (C,-C,)-alkyl;
A~' is phenyl. furanyl, thienyl. PY~YI. PYh~dyl, PY~nyr or pyridazinyl; said Ar' being optionally substituted with up to three hydroxy, (C,-C,)alkoxy-(C,-C,)alkyl, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,~Ikoxy optionally substituted with up to five fluoro; or R'~ and R" are taken together on adjacent carbon atoms and are -O-(CH~h-O-;
tisl,2or3;
Y is (C=-Ca)atkylene;
R", R'~ and R'~ ~ar~e each independently hydrogen or (C,-C,)alkyl;
m and n are each independently 1, 2 or 3, provided that the sum of m and n is 2, 3 or k is 0,1. 2, 3 or 4;
Y' is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R" is (C3-C,)cydoalkyl, Ars-(Co-C,)alkylenyl, NR"R'° or (C,-Cs~lkyl optionally substituted with one to five fluoro; provided that when Y' is a covalent bond or oxycarbonyl, then R" is not NR"R'°;
R" and R'° are taken separately and are each independently selected from hydrogen, Ars, (C,-Ca)alkyl and Ar5-(Co-C,)alkylenyl; or R" and R'° are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicydo[32.2]nonanyl, azabicydo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl, 6,7-dihydro-SH-dibenzo[c,e]a2epinyl or 5,6,7,8-tetrahydropyrido[4,3~jpyrimidyl;
said azetidinyl in the definition of R" and R'° are optionally substituted with one hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyi optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl and azepinyl in the definition of R"
and R'° are 7 5 optionally substituted with up to two hydroxy, amino, hydroxy-{C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~Ikyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said rnorphofinyl in the definition of R" and R'° is optionally substituted with up to tviro substituents independently selected from hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl; (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and 5,6,7,&tetrahydro[4,3-d]pyrimidyl in the definition of R" and R'° are optionally substituted with up to thn:e hydroxy, amino, halo, hydroxy-(C,-C,)alkyf, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,~Ikyl optionally substituted'with up to frve fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e~azepinyl in the definition of R"
and R'° are optionally substituted with up to four hydroxy, amino, halo, hydro~cy-(C,-C,)alkyL (C,-C,~Ikoxy-(C,-C,~Ikyl, (C,-C,~Ikyl optiona8y substituted with up to five fluoro or (C,-C,~Ikoxy optionally substituted with up to five fluoro;
Ars is independently defined as set forth for Ar and Ar' above;
Ar5 is optionally-independently substituted as set forth for Ar and Ar' above;
R'2 and R'b are independently hydrogen, (C,-Crkydoalkyl, Ara-(Co-C~~tkylenyl, Ar6-(C=-C,)alkenyl, Ar°-carbonyl or (C,-Cb~alkyl optionally substituted with up to flue fluoro;
Ar' is independently defined as set forth for Ar and Ar' above;
Ar° is optionally independently substituted as set forth for Ar and Ar' above; and R" and R"' are each independently hydrogen or (C,-C4)alkyl.
A preferred group of compounds of formula I, designated Group A, are those compounds of formula 1, prodnrgs thereof a'nd pham~aceutically acceptable salts of said compounds or said prodrugs, wherein:
R' is R"
N
)r~as G~.
~,3 . N
substituted by R'°, R'9 or R~°;
G', G' and GS are taken.separately and are each hydrogen, r is 0 and R'° is hydrogen, (C,-C,)alkyl, (C,-C,~Ikoxycarbonyl or phenyl optionally substituted by up to thn:e hydroxy, halo, hydroxy-(C,-C,~lkyl, {C,-C,)alkoxy-(C,-C.)alkyl, (C,-C,~tkyl optionally . substituted with up to five fluoro or (G,-C,~Ikoxy optionally substituted with up to five fluoro; R'9 and R~° are each independently (C,-C,)alkyl;
G', G' and G5 are taken separately and are each hydrogen; r is 1; and R'° is hydrogen, (C,rC,)alkyl, (C,-C,)alkoxycarbonyl or phenyl optionally substituted by up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,)atkyl optionally substituted with up to five fluoro or {C,-C,)atkoxy optionally substituted with up to five fluoro; R'° and R~° are each independently hydrogen or (C,-C,)alkyt; or G' and G' are taken together and are (C,-C,)alkylene; r is 0 or 1; and R'°, R'°, R~° and G° are hydrogen; or G' and GS are taken together and are (C,-C,)alkylene; r is 0 or 1; and R'°, R'9, R~° and G' are hydrogen;
R" is SOzNR~'R~, CONRz'R~, (C,-Cs)alko~cycarbonyl, (C,-Cs~lkylcarbonyl, Ar?
carbonyl, (C,-C6~Ikytsulfonyl, (C,-Ce)alkylsulfinyl, Arz-sulfonyl, Are-sufinyl and (C,-C,~~Ikyi;
RZ' and R~ are taken separately and are each independently selected from hydrogen, (C,-Ce~lkyl. (C~-C~kydoalkyl and Arz-(Cro~,~alkylenyl; or wo oo~s9sio rcrnsooioo~96 RZ' and R~ are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morphoiinyi, azepinyl, azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1]heptyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl, 1,2,3,4-tetrahydro-i5oquinolyl or 6,6,7.8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of R2' and R~ is optionally substituted independently with one substituent selected from hydroxy, amino, hydronyr-(C;-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,=C,)alkoxy optronally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl, morpholinyl, azepinyl in the definition of RZ' and R~ are optionally substituted independently with up to two substituents independently selected from hydroxy, amino, hydroxy-(C; C,)alkyl, (C,-C,~ikoxy-(C,-C,)alkyl, (C,-C,~tkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally sWbstituted with up to five fluoro; said morpholinyl in the definition of Rz' and R~ is optionally substituted with up to two substituents independently selected from hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~lkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definition of RZ' and R~ is optionally substituted independently with up to three substituents independently selected from phenyl, pyridyl, pyrtimidyl, (C,-C,)alkoxycarbonyl and (C,-C,)alkyl optionally substituted with up to five fluoro; said 1,2.3,4-tetrahydro-isoquinolyl and said 5,6,7,&tetrahydropyrido[4,3-d]pyrimidyl in the definition of RZ' and R~ are optionally substituted independently with up to.
there substituents independently selected from hydroxy, amino, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to fire fluoro and (C,-C,~Ikoxy optionally substituted with up to five fluoro: said pyimidyl.
PY~yr ~
phenyl which are optionally substituted on said piperazine in the definition of R~' and R'~ is optionally substituted with up to three substituents selected from hydroxy, amino, hydroxy-(C,-C.)alkyl. (C,-C,~Ikoxy-(C,-C.~Ikyl. (C,-C,~tkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to flue fluoro; and said 6,7-dihydro-SH-dibenzo[c,e]azepinyl in the definition of Rr and R~ is optionally substituted with up to four substituents independenthr selected from hydroxy, amino, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,j~alkyl optionally substituted with up to five fluoro and (~,-C,)alkoxy opflonaiiy subst~uted with up to five fluoro.
pCT/IB00/00396 Another preferred group of compounds of formula t, designated Group B, are those compounds of formula I, prodrugs thereof and ph2rmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R' is Rz' I , N ' Rza N
~ ;
R~' is CONR~R~, SOZRnR~, wherein R~ is hydrogen (C,-C,)alkyl or Ar'-(Co-C,)alkylenyl and R~ is Ar'-(Co-C,)alkylenyl; provided that when Ar' is phenyl, naphthyl~
or biphenyl, then Rte' cannot be CONRz''R~ where Rn is hydrogen or Ar' and R~
is RZ' is hydrogen, (C,-C,)alkyl; (C,-C,)alkoxycarbonyl or phenyl optionally substituted by up to three (C,-C,)alkyl optionally substituted with up to five fluoro, (C,-C,)alkoxy optionally substituted with up to five fluoro, hydroxy, halo or hydroxy-(C,-C3)alkyl.
Another preferred group of compounds of formula !, designated Group C, are those compounds of formula I, prodnrgs thereof arid pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R' is ~~ Rze or R~' is hydrogen or (C,-C,)alkyt;
R~ and R~° are each independently hydrogen, hydroxy, halo, hydroxy-(C,-C4~tkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro, (C,-C,~Ikoxy optionally substituted with up to five fluoro, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazofyl, phenoxy, thiophenoxy, S02NR'°R", CONR'°R" or NR'°R";
said thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of R'° and R'° are optionally substituted by up to two hydroxy, halo, hydrotcy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to flue fluoro:,said phenyl, pyridyl, phenoxy and thiophenoxy in the definition of R'° and R~ are optionally substituted by up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
R'° and R" are each independently hydrogen, (C,-C,)alkyl, (C,-C,kycloalky4 or phenyl, said phenyl is optionally substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C.~tkoxy-(C,-C,jalkyl, (C,-C.~IkYI optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to flue fluoro; or R'° and R" are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyt, piperidinyt, piperaLnyl or motpholinyl; said pyrrolidinyl and piperidinyl in the definition'of R'° and R" are optionally substituted with up to two hjrdroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)atkoxy-(C,-C,)alkyl, (C,-C,~Ikyl optionally substituted with up to flue fluoro or (C,-C,~Ikoxy optionally substituted with up to five fluoro; said indolinyl and piperazinyl in the definition of R'° and R" are optionally substituted with up to three hydroxy, amino, or hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,~lkyl, (C,-C,~Ikoxycar6onyt, (C,-C,~Ikyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R'° and R" is optionally substituted with up to two substituents independently selected from hydroxy-(C,-C,)alkyt, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,)alkyi optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to flue fluoro.
Yet another preferred group of compounds of fomwla I, designated Group D, are those compounds of formula 1, prodrugs then:of and pham~aoeuticapy acceptable salts of said compounds or said prodrugs, wherein:
R' is Ru ,R~ , A_. ~ ~N
B N ~N
R3z ~ or , . Rs~.
N N
pGT/iB00/00296 A is N optionally substituted with hydrogen or (C,-C,)alkyt and B is carbonyl;
or A is carbonyl and 8 is N optionally substituted with hydrogen or (C,-C,)aikyl;
R'~ is hydrogen or (C,-C,)alkyl;
R" is phenyl, pyridyl, pyrimidyl, thiazolyl, oxazQlyl, benzyl, quinolyl, isoquinolyl, phthalizinyl, quinoxaniyl, benzothiazoyl, benzoxazolyl, benzofuranyl or benzothisnyl;
said phenyl, pyiidyl, pyrimidyl, thiazolyl, oxazotyl, benzyt, quinolyl, isoquinolyl, phthaiizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl and benzothienyl in the definition of R" are optionally substituted with up to three phenyl, phenoxy, NR~"R", halo, hydroxy, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,~lkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
R" and R" are each independently hydrogen, (C,-C, alkyl), phenyl or phenylsulfonyt;
said phenyl and phenylsulfonyl in the definition of R" and R" are optionally substituted with up to three halo, hydroxy, (C,-C,)alkyt optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro.
Still another preferred group of compounds of formula l, designated Group ~, are those compounds of formula I, prodrugs thet'eof and pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R' is pC'r/iB00~0296 -1 &
or D is CO, CHOH or CHz; ' , E is O, NH or S;
R'~ and R" are taken separately and are each independently hydrogen, halo, cyano, hydroxy, amino, (C,-C6)alkylamino, di-(C,-Ca)alkytamino, pyrrolidino;
pipe~idino, morpholino, (C,-C,)alkoxy-(C,-C,~Ikyt, hydroxy-(C,-C,~Ikyl, At', (C,-C,~Ikyl optionally substituted with up to fnre fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
R'°, R'~ and R'° are each independently hydrogen or (C,-C,ratkyt;
Ar' is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl;
said Ar being optionally substituted with up to three hydroxy, (C,-C4)alkoxy-(C,-G4)alkyl, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to fnre fluoro or (C,-C,)alkoxy optiona8y substituted with up to five fluoro; or R'~ and R" are taken together on adjacent carbon atoms and are -O-(CH2~-O-;
tis1,2or3.
Stil! another preferred group of compounds of formuta t, designated Group F, are those compounds of formula 1, prodrugs thereof and phamiaceuticatly acceptable salts of said compounds or said prodrugs, wherein:
R' is ..as , -i 9-Y2 ~ts , R'~ Y, R'\N~YwRas R's N a N
R
R~ \ iY {CH CHZ) I ' ~
R's/N\
N~Y~R's R \N~Y,~R's {CH=)k ', or J
I
Y is (C2-Ca~lkylene;
R", R'~ and R'~ are each independently hydrogen or (C,-C,)alkyl;
m and n are each independently 1, 2 or 3, provided that the sum of m and n is 2. 3 or 4;
kisOto4;
Y' is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R" is (C3-C,)cydoalkyl, Ar5-(Co-C,)alkylenyl. NR"R'° or (C,-Ca)alkyl optionally substituted with one to five fiuoro; provided that when Y' is a covalent bond or oxycarbonyl, then R" is not NR"R'°;
R" and R'° are taken separately and are each independently selected from hydrogen, Ars. (C,-C,)alkyl and Ar5-(Co-C,)alkylenyl; or R" and R'° are taken together with the nitrogen atom to which they are attadied to form azetidinyl, pyfrolidinyl, pipetidinyl, piperazinyl, morpholinyl, a~epinyl, azabicydo[3.2.2]nonanyl, azabicydo[22.1]heptyl,1,2,3,4-tetrahydroisoquindyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl or 5,fi;7,8-tetrahydropyrido[4,3-d]pyrimidyt;
said azetidinyl in the definition of R" and R'° are optionally substituted with one hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C; C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)a(koxy optionally sut;stituted with up to five fluoro; said pyrrolidinyl, piperidinyl and azepinyl in the definition of R"
and R'° are optionally substituted with up to two hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro o~ (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R" and R'° is optionally substituted with up to two substituents independently selected from hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C')alkyl optionally substituted with up to five fluoro and (C,-C,~Ikoxy optionally substituted with,up to flue fluoro; said piperaziny(,1,2,3,4-tetrahydroisoquinolyl and 5,6,7,8-tetrahydro[4,3-d]pyrimidyi in the definition of R" and R'° are optionally substituted with up to three hydroxy, amino, halo, hydroxy-(C,-C,~Ikyt, (C,-C,)alkoxy-(C,-C,)atkyl, (C,~,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R"
and R'° are optionally substituted with up to four hydroxy, amino, halo, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C;-C,~Ikyl, (C,-Ca)alkyi optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro.
A preferred group of compounds within Group F, designated Group FA, are those compounds, prodnrgs thereof and pharmaceutically acceptable salts of said compounds or said prodnrgs wherein:
R' is (R~1-hydroxy-ethyl;
RZ is hydrogen;
R' is N~YsRas (CH2)k N~
k is 0;
Y' is a covalent bond; and R" is 4-pyrimidinyl substituted at the 2-position with 1-hydroxymethyl.
A preferred group of compounds within Group .FA, designated Group FB, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, which is 1 R-(4-{1'-[2-(, R-hydroxy-ethylrpyrimidin-4-ylj-[4.4~bipiperidinyl-,-yl}-pyrimidin-2-yl)-ethanol.
Another preferred group of compounds of formula I, designated Group G, are those compounds of formula I, prodrugs thereof and phamiaceuticatty acceptable salts of said compounds or said prodrugs, wherein:
R' is HO R,T
R" Ra,. ~ Ra, R4"
N . or I
,o R"and R"' are independently hydrogen, (C,-C,kydoallcyl, Ar'-(CQ-C,)alkylenyl, Ars-(C2-C,)alkenyl, Are-carbonyl or (C,-C6)alkyl optionally substituted with up to five fluoro;
and R" and R"' are independently hydrogen or (C,-C,)alkyt.
Still another preferred group of compounds of formula I, designated Group H, are those compounds of formula I, prodnrgs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R' is C(OH)R'R5, where R' and Rs are each independently hydrogen or methyl;
RZ is hydrogen;
R' is N
T
( ~)~ G, V
N
wherein said R' is substituted by R°, R' or R°;
WO 00/59510 PGTIIB00/00~96 G, G' and GZ are taken separately and are each hydrogen and R° is hydrogen or (C,- , C,)alkyl; R' and R° are each independently hydrogen or (C,-C,)atkyl; or G and G' are taken together and are (C,-C,)alkylene and R°, R', R° and G2 are hydrogen; or G' and GZ are taken together and are (C,-C,)alkylene and R°, R', R° and G are hydrogen;
qis0orl;
X is a covalent bond, oxycarbonyl,vinytenylcarbonyt, oxy(C,-C,)alkylenylcarbonyl, thio(C,-C,~Ikylenylcarbonyl or vinylenylsulfonyt; said vinylenylcarbonyl and said vinylenylsulfonyl in the definition of X are optionally substituted on one or two vinylenyf carbons with (C,-C,)alkyl, benzyl or Ar, said oxy(C,-C,)alkylenyicarbonyl and said thio(C,-C,)alkyfenylcarbonyl in the definition of X are optionally substituted with up to two (C,-C,)alkyl, benzyl or Ar;
R' is (C3-C~)cyctoalkyl, Ar'-(Co-C,)alkylenyl or (C,-C°)alkyl optionally substituted with up to five fiuoro;
Ar' is phenyl, naphthyl; pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, quinofyl, isoquinolyl, quinazolyl, quinoxalyl, phthatazinyl, annotinyl, naphthyridinyl, pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl, pyrimidopyridazinyt, pyrimidopyrimidyl, pyridopyrimidyl, pyridopyrazinyt, pyridopyridazinyl, pyn-olyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, PY~oIYf, isoxazolyl, isothiazolyt, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzisoxazolyl, benzisothiazofyi, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazolopyridyl, oxazotopyridy(, thiazofopyridyl, pyrazolopyridyl, isoxazotopyridyl, isothiazolopyridyl, pyrrolopyrimidyl, furopyrimidyl, thienopyrimidyl, imidazolopyrimidyl, oxazotopyrimidyl, thiazolopyrimidyl, pyrazolopyrimidyl, isoxazolopyrimidyl, isothiazolopyrimidyl, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, imidazolopyrazinyl, oxazolopyrazinyl, thiazolopyrazinyl, pyrazolopyrazinyl, isoxazolopyrazinyl, isothiazolopyrazinyl, pyn-otopyridazinyl, furopyridazinyl, thienopyridazinyl, imidazolopyridazinyl, oxazoiopyridazinyl, 3b thiazolopyridazinyl, pyrazolopyridazinyl, isoxazolopyridazinyl or isothiazolopyridazinyl;
and said Ar' is optionally substituted as set forth above.
. pCTIIB00/Q0296 -23- , A preferred group of compounds within Group H, designated Group HA, are ~ , those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
X is a covalent bond, oxycarbonyl or vinylehylcarbonyl optionally substituted on one or two vinyienyl carbons with (C,-C,~Ikyl, benzyl or Ar, R° is Ar'-(Co-C,)alkylenyl; .
Ar' is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, triazinyl, quinolyl, isoquinoiyl, quinazolyl, quinoxalyl, furanyl, thienyl, indolyl, benzofuranyl; benzothienyl;
benzoxazolyl, benzothiazolyl, furopyridyl, oxazotopyridyl, thiazoiopyridyl, thienopyridyl, 1 fl furopyrimidyl, thienopyrimidyl, oxazolopyrimidyl or thiazolopyrimidyl;
and said Ar' is optionally substituted as set forth in daim 1.
A preferred group of compounds within,Group HA, designated Group H8, are those compounds, prodrugs thereof and phamnaceuticaliy acceptable salts of said compounds or said prodnrgs, wherein:
R2 is hydrogen;
R~ is hydrogen or methyl;
RS is methyl;
G, G' and GZ are hydrogen;
R° and R' are each independently hydrogen or methyl;
R° is hydrogen.
A preferred group of compounds within Group H8, designated Group HC, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R' is (R)-1-hydroxy-ethyl; and R' is O R°
N
Me ~ Me WO 00!59510 PCT/IBOO~OZ96 A preferred compound within Group HC is the compound wherein R° is faro[3.2-c]pyridyl, a prodrug thereof or a pham~aceut~ally acceptable salt of said compound or said prodrug.
Another preferred compound within Group HC as the compound wherein R9 is 2-(4-chloro-faro[3,2-cjpyridyl), a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
Another preferred compound within Group HC is the compound wherein Rs is 2-(4-pyrrolidin-1-yl-faro[3,2-cjpyridyl), a prodrug thereof or a pharmaceutically acceptable salt.of said compound or said prodnrg.
Another preferred compound within Group HC is the compound wherein R° is 2-(4-morpholin-4-yl-furo[3,2-cJpyridyt), a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
Another preferred compound within Group HC is the compound wherein R' is 2-imidazo[1,2-a]pyridyl, a prodrug thereof or a pham~aceutiraliy acceptable salt of said compound or said prodrug.
Preferred compounds within Group HC are faro[3,2-c]pyridin-2-yl-{4-i2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-methanone; (4-chloro-faro[3.2-clPYridin-2-yl]"{4-[2-(1 R-hydroxy-ethyl~pyrimidin-4-ylj-3R,5S-dimethyh piperazin-1-yI}-methanone; {4-[2-(1R-hydroxy-ethyl~pyrimidin-4-yf]-3R,5S-dimethyl-piperazin-1-yt}-(4-pyrrolidin-1-yf-faro[3,2-cJpyridin-2-y1j~methanone; ~4-[2-(1R-hydroxy-ethyl)-pyrimidin~-ytj-3R,5S-dimethyl-piperazin-1-yl}-(4-morpholin-4-yl-furo(3,2-cJpyridin-2-yl)-methanone; and {4-i2-(1R-hydroxy-ethylj~pyrimidin-4-y()-3R,5S-dimethyl-piperazin-1-YI}-imidazo[1.2-a]PYcidin-2-yl-methanone.
Another preferred group of compounds within Group HB, designated Group HD, are those compounds, prodnrgs thereof and pham~ac~eutically acceptable salts of said compounds or said prodrugs wherein:
R' is (Rr1-hydroxy-ethyl; and Ra ~
rc~rnsoo~ooZ96 O Re ' Me N Me ~N
A preferred compound within Group HO is the compound wherein R9 is 2-furo[3,2-c]pyridyl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
An espeaally prefen-ed compound within Group HD is furo[3,2-cjpyridin-2-yl-{4-[2-(1R-hydroxy-ethyl~pyrimidin-4 y~-2R,6S-dimethyl-piperazin-1-yl}-methanone.
Another preferred group of compounds within Group H8, designated Group HE, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R' is (R}-1-hydroxy-ethyl; and R~ is A preferred compound within Group HE is the compound wherein R9 is 3-pyridyl, a prodrug thereof or a phan'naceutically acceptable salt of said compound or said prodnrg.
Another preferred compound within Group HE is the compound wherein Rs is
N
Ri/ \N/ 4 R
where R'. R~, R', R' and RS are as disclosed therein. Said o~mpounds are disclosed as having utility as tools in screening for aldose reductase inhibitors due to tt~e sorbitol aoarmulating activity of said compounds:
Commonly assigned U.S. Patent Nos. 5,728,704 and 5,866,578 each disclose compounds of the formula A, A
wherein R' through RS are defined as disclosed therein. Further, U.S.
5,728,704 discloses that sorbitol dehydrogenase compounds have utility in the treatment of diabetic complications.
Pyrimidine derivatives of the formula I, as defined below, and their pham~aoeutically axeptable salts, lower fiuctose levels in the tissues of mammals affected by diabetes (e.g., nerve, kidney and retina tissue) and are useful in the treatment and prevention of the diabetic complications referred to above.
These compounds, or their metabolites in vivo, are inhibitors of the enzyme sorbibot dehydrogenase, which catalyzes the oxidation of sorbitol to fructose.
SUMMARY OF THE INVENTION
The present invention is directed to a oort~potrnd of the fornxrla I
R' R~
~N
N R' a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug, wherein:
R' is fomryl, acetyl, propionyl, carbamoyl or -C(OH)R'R°;
R' and Rs are each independently hydrogen, methyl, ethyl or hydroxy-(C,-C~alkyl;
.
R' is hydrogen, (C,-C,~Ikyl or (C,-C,)alk~Oxy;
pCT/IB00700296 R' is a radical of the formula ~ ~R9 , ~ n , R23 zN ~N N
( i1 ~ G' ( _). ~G' 2e G R
N , R3a I . R3d ( , R3c ( .
R~°
.
WO 00!59510 PGT/IB00/00296 R" Raa A-N
\ 8 N /N
Ra2 ~ Raz Rao ~ ~ Ran R'z~ R'=
R~ Rs~
HO R4z N~R4o Ra, ~R"a ' R" Rsu E
N N
Rae Ras Rak I R» I
N
Rai ( Y, ~as R4~ Yt R~\NiYwRsa ss\
R ~N~Rs, N
R,\ iY (CH2)m (CHz)"
R3m I ~ Ran Rss/N\ R~
Y' Ni \ R's a~ , R \N~Y~Rsa (CHz)k or R3p I ~ N
' N J
R I _ wherein said radical of formula R'~ is additionally substituted on the ring by Re, R' and R°;
said radical of formula R~° is additionally substituted on the ring by R'°, R'° and R~°;
G, G' and G= are taken separately and are each hydrogen and R° is hydrogen, (C,-C,~Ikyl. (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,~Ikyl, hydroxy-(C,-C,~Ikyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl; (C,-C,)alkyl or (C,-C,)alkoxy, wherein said (C,-C,)alkyl in the definition of R° and said (C,-C,~Ikoxy in the defirirtion of Rare optionally and independently substituted with up to five tiuoro; R' and R° are each independently hydrogen or (C,-C,~lkyl; or G and G' are taken together and are (C,-C,~Ikylene and Re, R', R° and Gz are hydrogen; or G' and GZ are taken together and are (C,-C,)alkylene and R°, R', R° and G are hydrogen;
q~0orl;
X is a covalent bond, -(C=NR'°)-, oxycarbonyl, vinylenylcart~onyl, oxy(C,-C,~Ikylenylcarbonyl, (C, C,)alkylenylcarbonyl, (C,-C,~Ikenylcarbonyl, thio(C,_ C,~Ikylenyicarbonyl, vinylenylsulfonyl; sutfinyl-(C,-C,~Ikylenytcarbonyl, sulfonyl-(C,-C,)alkylenylcarbonyl or carbonyl(C°-C,)alkylenylcarbonyl; wherein said oxy(C,-C,)alkylenylcarbonyl, (C,-C,~Ikylenylcarbonyl, (C,-C,~Ikenylrarbonyl and thio(C,-C,)alkylenytcarbonyl in the definition of X are each optionally and independently substituted with up to two (C,-C,)alkyl, benryl o~ Ar, said vinylenylsutfortyl and said vinylenylcarbonyl in the definition of X are optionally substituted independently on one or two vinylenyl carbons with (C,-C,~Ikyl, benzyl or Ar; and said carbonyl(Co-C,)alkyienylcarbonyl in the definition of X is optionally substituted independently with up to three (C,-C,~Ikyl, benzyl or Ar;
R'° is hydrogen or (C,-C,)alkyl;
R9 is (C,-C,kydoatkyl, Ar'-(C°-C,~Ikylenyl or (C,-C°~fkyl optionally substituted with up to five fluoro; provided that when q = 0 and X is a covalent bond, oxycartrorryl or (C,-C,)alkylenylcartionyl; then R° is not (C,-Ca~lkyl:
Ar and Ar' ere independently a fully saturated, partially saturated or fully unsaturated five- to eight-membered ring optionally having up to four heteroatoms selected WO 00/59510 PCT/IB00l00396 ..6_ independently from oxygen, sulfur and nitrogen, or a bicydic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five- to seven-membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyGic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five to seven membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially saturated. fully saturated ring or fully unsaturated monocydic ring, bicyGic ring or tricydic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur, Ar and Ar' are optionally independently substituted on carbon or nitrogen, .on one ring if the moiety is monocydic, on one or both rtngs if the moiety is bicydic, or on one, two or three rings if the moiety is tricydic, with up to a total of four substituents independently selected from R", R'2, R'~ and R"; wherein R", R'Z, R" and R"
are each taken separately and are each independently halo, formyl, (C,-Cs~lkoxycarbonyl, (C,-C6)alkylenyloxycarbonyl, (C,-C,)alkoxy tC,-C,)alkyl, C(OH)R'SR'B, naphthyl, phenyl, imidazolyl, pyridyl, triazolyl, morpholinyl, (Co-C,)alkylsutfamoyl, N-(Co-C,)alkylrzrbamoyl, N,Nrdi-(C,-C,)alkylcarbamoyl, N-phenylcarbamoyl, N-(C,-C,~Ikyl-N-phenylcarbamoyl, N.,N-Biphenyl carbamoyl, (C,-C,~Ikylcarbonylamido, (C3-C,)cydoalkylcarbonytamido, phenylcartionytamido, piperidinyl, pyrrolidinyl, piperazinyl, cyano, benzimidazolyl, amino, anilino, pyrimidyl, oxazolyl, isoxazoiyl, tetrazolyl, thienyl, thiazolyl, ben~othiazolyl, pyrrolyl, pyrazoiyt;
tetrahydroquinolyl, tetrahydroisoquinolyt, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfanyi, furanyl, 8-(C,-C,~Ikyl-3,8-diaza[3.2.1]bicydoodyl, 3.5-dioxo-1,2,4-triazinyl, phenoxy, thiophenoxy, (C,-C,)alkylsulfanyl, (C,-C,~fkylsulfonyl, (C3-C~kydoalkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or tC,-C,~Ikoxy optionally substituted with up to five fluoro; said naphthyl, phenyl, pyridyl, piperidinyl, benzimidazolyl, pyrimidyl, thienyl, benzothiazolyl, pyrroiyl, tetrahydroquinolyl, tetrahydroisoquinolyl, bentoxazolyl, pyridazinyl, pyridyioxy, pyridylsulfanyl, furanyl, thiophenoxy,-anilino and phenoxy in the definition of R", R'~, R" and R" are optionally substituted with up to three substituer~ts independently sele~ed from hydroxy, halo, hydroxy-(C,-C,~Ikyl.'(C,-C,~Ikoxy-(C,-C,)alkyt. (C,-C,~Iky optimally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to flue tluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazotyl in the definition of R", R'Z, R" and R" are optionally substituted with up to two substituents independently selected from hydroxy, halo, hydroxy-(Ca-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted'with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said morphofinyl in the definition of R", R'~, R" and R" is optionally substituted with up to two substituents independently selected from (C,-C,~Ikyl; said pyrrolidinyl in the definition of R", R'Z, R"
and R" is optionally substituted with up to two substituents independently selected from hydroxy, hydroxy-(C,-C,)alkyl, (C,-C,~lkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to flue fluoro; said piperazinyl in the definition of R", R'Z, R" and R" is optionally substituted with up to three substituents independently selected from (C,-C,)alkoxy-(C,-C,~Ik~l, hydroxy-(C,-C,)alkyl, phenyl, pyridyl, (Co-C,)alkylsulfamoyl, (C,-C;)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said triazolyl in the definition of R", R'~, R" and R" is optionally substituted with hydroxy, halo, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~alkyl optionally substituted with up to flue fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said tetrazolyl in the definition of R", R'z, R" and R" is opti~afly substituted with hydroxy-(C=-Chalky! or (C,-C,~Ikyl optionally substituted with up to five fluoro;
and said phenyl and pyridyl which are optionally substituted on piperazine in the definition of R", R'2, R" and R" are optionally substituted with up to three hydroxy, halo, hydroxy-(C,-C,~Ikyl, (C,-C,~lkoxy-(C,-C,)alkyl, (C,-C.~Ikyl optionally substituted with up to 5ve fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; or R" and R'= are taken together on adjacent carbon atoms and are -CH20C(CH,)ZOCHZ- or -0-(CHZ)o-0-, and R" and R" are taken separately and are each independently hydrogen or (C,-C,~Ikyl;
pisl,2or3;
R's and R'6 are taken separately and are each independently hydrogen, (C,-C,)alkyl optionally substituted with up to five fluoro; or R'S and R'6 are taken separately and R's is hydrogen and R'° is (C,-Cskycloalkyl, hydroxy-(C,-~C,~lkyl, Phenyl.
PY~.
pyrirnidyl, thienyl, furanyl, thiazolyl, oxazolyl. imidazolyl, benzothiazotyi or benzoxazolyl; or R'S and R'6 are taken together and are (C,-Ca~lkylene;
G', G' and Gs are taken separately and are each hydrogen; r is 0; R'°
is hydrogen, (C,-C,)atkyl. (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C;-C,)alkyl, hydroxy-(C,-C,)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)atkyl or (C,-C,)atkoxy, wherein said 6 (C,-C,)alkyl in the definition of R6 and said (C,-C,)atkoxy in the definition of Raar~e optionally and independently substituted with up to five tluoro; and R'° and R~° are each independently (C,-C,)alkyl; or G', G' and GS are taken separately and are each hydrogen; r is 1; R'°
is hydrogen, (C,-C,)alkyl, (C;-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,)alkyl, hydroxy-(C,-C,)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl or (C,-C.)alkoxy, whec~;in said (C,-C,)alkyl in the definition of R6 and said (C,-C,)alkoxy in the definition of Rsare.
optionally and independently substituted with up to five fluoro; and R'° and R~° are each independently hydrogen or.(C,-C,)alkyl; or G' and G' are taken together and are (C,-C~)afkylene; r is 0 or 1; and R'°, R'°, Rm and Gs are hydrogen; or G' and GS are taken together and are (C,-C°)alkylene; r is fl or 1; and R'°, R'°, Rm and G' are hydrogen;
R" is SOzNR2'R~, CONR2'R~, (C,-Cs)alkoxycarbonyl, (C,-C6)alkylcarbonyl, Ar~-carbonyl, (C,-C°)alkylsulfonyt, (C,-C6)alkylsulfinyl, Ar? sutfonyl, Are-sufinyl and (C,-C6)allcyl;
R2' and R~ are taken separately and are each independenti)r selected from hydrogen, (C,-C°)alkyl, (C,-C,)cydoalkyl and Are-(Co-C,)atkylenyl; or R=' and R~ are taken together with the nitrogen atom to which they are attad~ed to form azetidinyl, pyrrolidinyl, piperidcnyl, pcperazinyl, motpholinyl, a~epinyl, azabicydo[3.22]nonanyl, azabicydo[22.1]heptyl, 6,7-dihydro-SH-dibenzo[c,e]azepinyl,1,2,3,4-tetrahydro-isoquinolyl or 5,6,7,&tetrahydropyrido[4,3-d]pyrimidyt; said azetidinyl in the definition of R~' and t~ is optionally substituted independently uvith one substctuent seceded from hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)altcyl, (C,-C,)alky! optionally substituted with up to flue fluoro and (C,-C,)alkoxy optionally substit<rted with up to five fluoro; said pymdidinyl, piperidinyl; azepinyi in the definition of RZ' and R~ are optionally substituted independently with up to two substituents independently selected from hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,~Ikyl. (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of RZ' and R~ is optionally substituted with up to two subsiituents independently selected from hydroxy-(C,-C,~Ikyl, (C,-C,~lkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to flue 8uo~o and (C,-C,)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definitioh of R2' and R~ is optionally substituted independently with up to three substituents independently selected from phenyl, pyridyl, pyrimidyl; (C,-C,~Ikoxy~carbonyl and (C,-C,)alkyl optionally substituted with up to five fluoro; said 1,2,3,4-tetrahydro-isoquinolyl and said 5,6,7,8-tetrahydropyrtdo[4,3-dJpyrimidyl in the definition of R~' and !~ are optionally substituted independently with up to three substituents independently selected from hydroxy, amino, halo, hydroxy-(C,-C,)alkyl, (C,-C,)atkoxy-(C,-C,)alkyl, (C,-C,)alkyl.
optionally substituted with up to five fluoro and (C,~C,)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-diben2ojc,e]azepinyl in the'definition of 7 5 R~' and R~ is optionally substituted with up to four substituents independently selected from hydroxy, amino, halo, hydroxy-(C,-C,)alkyf, (C,-C,~lkoxy-(C,-C,~alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,~Ikoxy optionally substituted with up to five fluoro; said pyrimidyt, pyridyl and phenyl which are optionally substituted on said piperazine in the definition of Rs' and R~ is optionally substituted with vp to three substituents selected from hydroxy, amino, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~Ikyf optionally substituted with up to five fluoro and (C,-C,~Ikoxy optionally substituted with up to five fluoro;
Arz is independently defined as set forth for Ar and Ar' above;
said Ar= is optionally independently substituted as set forth for Ar and Ar' above;
R~' is CONR~'R~ or S02R~R~, wherein R~ is hydrogen (C,-C,~tkyl or Ar,'-(Co-C,)alkylenyl and R~ is Ar'-(Co-C,)alkylenyl; provided that when Ar' is phenyl, naphthyl or biphenyl, then R~' cannot be CONR~R~ where Rte' is hydrogen of Ar' and R~° is Ar':
R~' is hydrogen, (C,-C,~Ikyl. (C,-C,)alkoxycarbonyl. (C,-C,~Ikoxy-(C,-C,~lkyl.
hydroxy-(C,-C,~(kyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,~Ikyl. (C,-C,~Ikoxy-(C,-Cajalkyl, (C,-Cs~tkyl or ~C,-C,j~alkoxy, wherein said (C,-C,~Ikyl in fhe definition of fZ° and said (C,-C,~Ikoxy in the definition of R° are optionally and independenfly substituted with up to five tluoro;
Ar' is independently defined as set forth for Ar and Ar' above;
said Ar' is optionally independently substituted as set forth for Ar and Ar' above;
R~' is hydrogen or (C,-C,~Ikyl;
R~ and R'° are each independently hydrogen, hydroxy, halo, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up bo fnre fluoro, (C,-C,)alkoxy optionally substituted with up to five fluoro, phenyl, pyridyl, pyrifiidyi, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, SOZNR'°R", CONR'°R" or NR'°R";
said thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of R'° and R~ are optionally substituted by up to two hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alky! optionally substrtuted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said phenyl, pyridyl, phenoxy and thiophenoxy in the definition of R~ and R~ are optionally substituted by dp to three hydroxy, halo, hydroxy-(C,-C,~Ikyi, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,~Ikyl optionally substituted with up to five fluoro or (C,-C,~lkoxy optionally substituted with up to five fluoro;
R'° and R" are each independently hydrogen, (C,-C,)alkyl, (C,-C~)cydoalkyl or phenyl, said phenyl is optionally substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)atkoxy optionally substituted with up to five fluoro; or R'° and R" are taken together with the nitrogen to which they are attad~ed to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; said pymolidinyl and pipe~dinyl in the definition of R'° and R" are optionally substituted with up to two hydroxy, amino, hydroxy-(C,-C,)alkyl, {C,-C,)alkoxy-(C,-C,~(kyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said indolinyl and piperazinyl in the definition of R'° and R" are optionally substituted with up to three hydroxy, amino, hydroxy-(C,-C,~Ikyl, (C,-C,~Ikoxy-(C,-C,~lkyi, (C,-C,~Ikoxycarbonyl. (C,~C.)alkyl oPtionaliY
substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted_with up to five tluoro; said morpholinyl in the definition of R'° and R" is optionally substituted with up to two substituents independently selected from hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,~Ikoxy optionally Substituted with up to five fiuoro;
A is N optionally substituted with hydrogen or (C,-C,)alkyl and B is carb~yl;
or A is cart~onyl and B is N optionally substituted with hydrogen or (C,-C,~Ikyl;
R'~ is hydrogen or (C,-C,)alkyl;
R" is phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolys, benzyl, quinolyl, isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl, beivzoxazoiyl, ben~ofuranyl or benzothienyl;
said phenyl, pyridyl, pyrimidyl, thiazotyl, oxazolyl, benzyl, quinolyl, isoquinolyl, phthalizinyi, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl and benzothienyl in the definition of R" are optionally substituted with up to three phenyl, phenoxy, NR"R'~, halo, hydroxy, hydroxy-(C,-C,~lkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to flue fluoro or (C,-C,)alkoxy optionatf)r substituted with up to five fluoro;
R~' and R'~ are each independently hydrogen, (C,-C, alkyl), phenyl or phenylsulfonyl;
said phenyl and phenylsulfonyl in the definition of R" and R'~ are optionally substituted with up to three halo, hydroxy, (C,-C,~Ikyl optionally substituted with up to five fluoro or (C,-C,~lkoxy optionally substituted with up to flue fluoro;
D is CO, CHOH or CH2;
EisO.NHorS;
R'~ and R" are taken separately and are each independently hydrogen, halo, cyano, hydroxy, amino. (C,-CB)alkylamino, di-(C,-C6)alkylamino. pyrroGdir~, piperidino, morpholino, (C,-C,~Ikoxy-(C,-C,)alkyl, hydroxy-(C,-C,)atkyl, Ar', (C,-C,)atkyl optionally substituted with up to five.fluoro or (C,-C,)alkoxy optionally subsfltuted with up to flue fluoro;
R'°, R'~ and R'° are each independently hydrogen or (C,-C,)-alkyl;
A~' is phenyl. furanyl, thienyl. PY~YI. PYh~dyl, PY~nyr or pyridazinyl; said Ar' being optionally substituted with up to three hydroxy, (C,-C,)alkoxy-(C,-C,)alkyl, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,~Ikoxy optionally substituted with up to five fluoro; or R'~ and R" are taken together on adjacent carbon atoms and are -O-(CH~h-O-;
tisl,2or3;
Y is (C=-Ca)atkylene;
R", R'~ and R'~ ~ar~e each independently hydrogen or (C,-C,)alkyl;
m and n are each independently 1, 2 or 3, provided that the sum of m and n is 2, 3 or k is 0,1. 2, 3 or 4;
Y' is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R" is (C3-C,)cydoalkyl, Ars-(Co-C,)alkylenyl, NR"R'° or (C,-Cs~lkyl optionally substituted with one to five fluoro; provided that when Y' is a covalent bond or oxycarbonyl, then R" is not NR"R'°;
R" and R'° are taken separately and are each independently selected from hydrogen, Ars, (C,-Ca)alkyl and Ar5-(Co-C,)alkylenyl; or R" and R'° are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicydo[32.2]nonanyl, azabicydo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl, 6,7-dihydro-SH-dibenzo[c,e]a2epinyl or 5,6,7,8-tetrahydropyrido[4,3~jpyrimidyl;
said azetidinyl in the definition of R" and R'° are optionally substituted with one hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyi optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl and azepinyl in the definition of R"
and R'° are 7 5 optionally substituted with up to two hydroxy, amino, hydroxy-{C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~Ikyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said rnorphofinyl in the definition of R" and R'° is optionally substituted with up to tviro substituents independently selected from hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl; (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and 5,6,7,&tetrahydro[4,3-d]pyrimidyl in the definition of R" and R'° are optionally substituted with up to thn:e hydroxy, amino, halo, hydroxy-(C,-C,)alkyf, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,~Ikyl optionally substituted'with up to frve fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e~azepinyl in the definition of R"
and R'° are optionally substituted with up to four hydroxy, amino, halo, hydro~cy-(C,-C,)alkyL (C,-C,~Ikoxy-(C,-C,~Ikyl, (C,-C,~Ikyl optiona8y substituted with up to five fluoro or (C,-C,~Ikoxy optionally substituted with up to five fluoro;
Ars is independently defined as set forth for Ar and Ar' above;
Ar5 is optionally-independently substituted as set forth for Ar and Ar' above;
R'2 and R'b are independently hydrogen, (C,-Crkydoalkyl, Ara-(Co-C~~tkylenyl, Ar6-(C=-C,)alkenyl, Ar°-carbonyl or (C,-Cb~alkyl optionally substituted with up to flue fluoro;
Ar' is independently defined as set forth for Ar and Ar' above;
Ar° is optionally independently substituted as set forth for Ar and Ar' above; and R" and R"' are each independently hydrogen or (C,-C4)alkyl.
A preferred group of compounds of formula I, designated Group A, are those compounds of formula 1, prodnrgs thereof a'nd pham~aceutically acceptable salts of said compounds or said prodrugs, wherein:
R' is R"
N
)r~as G~.
~,3 . N
substituted by R'°, R'9 or R~°;
G', G' and GS are taken.separately and are each hydrogen, r is 0 and R'° is hydrogen, (C,-C,)alkyl, (C,-C,~Ikoxycarbonyl or phenyl optionally substituted by up to thn:e hydroxy, halo, hydroxy-(C,-C,~lkyl, {C,-C,)alkoxy-(C,-C.)alkyl, (C,-C,~tkyl optionally . substituted with up to five fluoro or (G,-C,~Ikoxy optionally substituted with up to five fluoro; R'9 and R~° are each independently (C,-C,)alkyl;
G', G' and G5 are taken separately and are each hydrogen; r is 1; and R'° is hydrogen, (C,rC,)alkyl, (C,-C,)alkoxycarbonyl or phenyl optionally substituted by up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,)atkyl optionally substituted with up to five fluoro or {C,-C,)atkoxy optionally substituted with up to five fluoro; R'° and R~° are each independently hydrogen or (C,-C,)alkyt; or G' and G' are taken together and are (C,-C,)alkylene; r is 0 or 1; and R'°, R'°, R~° and G° are hydrogen; or G' and GS are taken together and are (C,-C,)alkylene; r is 0 or 1; and R'°, R'9, R~° and G' are hydrogen;
R" is SOzNR~'R~, CONRz'R~, (C,-Cs)alko~cycarbonyl, (C,-Cs~lkylcarbonyl, Ar?
carbonyl, (C,-C6~Ikytsulfonyl, (C,-Ce)alkylsulfinyl, Arz-sulfonyl, Are-sufinyl and (C,-C,~~Ikyi;
RZ' and R~ are taken separately and are each independently selected from hydrogen, (C,-Ce~lkyl. (C~-C~kydoalkyl and Arz-(Cro~,~alkylenyl; or wo oo~s9sio rcrnsooioo~96 RZ' and R~ are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morphoiinyi, azepinyl, azabicyclo[3.2.2]nonanyl, azabicyclo[2.2.1]heptyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl, 1,2,3,4-tetrahydro-i5oquinolyl or 6,6,7.8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of R2' and R~ is optionally substituted independently with one substituent selected from hydroxy, amino, hydronyr-(C;-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,=C,)alkoxy optronally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl, morpholinyl, azepinyl in the definition of RZ' and R~ are optionally substituted independently with up to two substituents independently selected from hydroxy, amino, hydroxy-(C; C,)alkyl, (C,-C,~ikoxy-(C,-C,)alkyl, (C,-C,~tkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally sWbstituted with up to five fluoro; said morpholinyl in the definition of Rz' and R~ is optionally substituted with up to two substituents independently selected from hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~lkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definition of RZ' and R~ is optionally substituted independently with up to three substituents independently selected from phenyl, pyridyl, pyrtimidyl, (C,-C,)alkoxycarbonyl and (C,-C,)alkyl optionally substituted with up to five fluoro; said 1,2.3,4-tetrahydro-isoquinolyl and said 5,6,7,&tetrahydropyrido[4,3-d]pyrimidyl in the definition of RZ' and R~ are optionally substituted independently with up to.
there substituents independently selected from hydroxy, amino, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to fire fluoro and (C,-C,~Ikoxy optionally substituted with up to five fluoro: said pyimidyl.
PY~yr ~
phenyl which are optionally substituted on said piperazine in the definition of R~' and R'~ is optionally substituted with up to three substituents selected from hydroxy, amino, hydroxy-(C,-C.)alkyl. (C,-C,~Ikoxy-(C,-C.~Ikyl. (C,-C,~tkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to flue fluoro; and said 6,7-dihydro-SH-dibenzo[c,e]azepinyl in the definition of Rr and R~ is optionally substituted with up to four substituents independenthr selected from hydroxy, amino, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,j~alkyl optionally substituted with up to five fluoro and (~,-C,)alkoxy opflonaiiy subst~uted with up to five fluoro.
pCT/IB00/00396 Another preferred group of compounds of formula t, designated Group B, are those compounds of formula I, prodrugs thereof and ph2rmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R' is Rz' I , N ' Rza N
~ ;
R~' is CONR~R~, SOZRnR~, wherein R~ is hydrogen (C,-C,)alkyl or Ar'-(Co-C,)alkylenyl and R~ is Ar'-(Co-C,)alkylenyl; provided that when Ar' is phenyl, naphthyl~
or biphenyl, then Rte' cannot be CONRz''R~ where Rn is hydrogen or Ar' and R~
is RZ' is hydrogen, (C,-C,)alkyl; (C,-C,)alkoxycarbonyl or phenyl optionally substituted by up to three (C,-C,)alkyl optionally substituted with up to five fluoro, (C,-C,)alkoxy optionally substituted with up to five fluoro, hydroxy, halo or hydroxy-(C,-C3)alkyl.
Another preferred group of compounds of formula !, designated Group C, are those compounds of formula I, prodnrgs thereof arid pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R' is ~~ Rze or R~' is hydrogen or (C,-C,)alkyt;
R~ and R~° are each independently hydrogen, hydroxy, halo, hydroxy-(C,-C4~tkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro, (C,-C,~Ikoxy optionally substituted with up to five fluoro, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazofyl, phenoxy, thiophenoxy, S02NR'°R", CONR'°R" or NR'°R";
said thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of R'° and R'° are optionally substituted by up to two hydroxy, halo, hydrotcy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to flue fluoro:,said phenyl, pyridyl, phenoxy and thiophenoxy in the definition of R'° and R~ are optionally substituted by up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
R'° and R" are each independently hydrogen, (C,-C,)alkyl, (C,-C,kycloalky4 or phenyl, said phenyl is optionally substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C.~tkoxy-(C,-C,jalkyl, (C,-C.~IkYI optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to flue fluoro; or R'° and R" are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyt, piperidinyt, piperaLnyl or motpholinyl; said pyrrolidinyl and piperidinyl in the definition'of R'° and R" are optionally substituted with up to two hjrdroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)atkoxy-(C,-C,)alkyl, (C,-C,~Ikyl optionally substituted with up to flue fluoro or (C,-C,~Ikoxy optionally substituted with up to five fluoro; said indolinyl and piperazinyl in the definition of R'° and R" are optionally substituted with up to three hydroxy, amino, or hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,~lkyl, (C,-C,~Ikoxycar6onyt, (C,-C,~Ikyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R'° and R" is optionally substituted with up to two substituents independently selected from hydroxy-(C,-C,)alkyt, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,)alkyi optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to flue fluoro.
Yet another preferred group of compounds of fomwla I, designated Group D, are those compounds of formula 1, prodrugs then:of and pham~aoeuticapy acceptable salts of said compounds or said prodrugs, wherein:
R' is Ru ,R~ , A_. ~ ~N
B N ~N
R3z ~ or , . Rs~.
N N
pGT/iB00/00296 A is N optionally substituted with hydrogen or (C,-C,)alkyt and B is carbonyl;
or A is carbonyl and 8 is N optionally substituted with hydrogen or (C,-C,)aikyl;
R'~ is hydrogen or (C,-C,)alkyl;
R" is phenyl, pyridyl, pyrimidyl, thiazolyl, oxazQlyl, benzyl, quinolyl, isoquinolyl, phthalizinyl, quinoxaniyl, benzothiazoyl, benzoxazolyl, benzofuranyl or benzothisnyl;
said phenyl, pyiidyl, pyrimidyl, thiazolyl, oxazotyl, benzyt, quinolyl, isoquinolyl, phthaiizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl and benzothienyl in the definition of R" are optionally substituted with up to three phenyl, phenoxy, NR~"R", halo, hydroxy, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,~lkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
R" and R" are each independently hydrogen, (C,-C, alkyl), phenyl or phenylsulfonyt;
said phenyl and phenylsulfonyl in the definition of R" and R" are optionally substituted with up to three halo, hydroxy, (C,-C,)alkyt optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro.
Still another preferred group of compounds of formula l, designated Group ~, are those compounds of formula I, prodrugs thet'eof and pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R' is pC'r/iB00~0296 -1 &
or D is CO, CHOH or CHz; ' , E is O, NH or S;
R'~ and R" are taken separately and are each independently hydrogen, halo, cyano, hydroxy, amino, (C,-C6)alkylamino, di-(C,-Ca)alkytamino, pyrrolidino;
pipe~idino, morpholino, (C,-C,)alkoxy-(C,-C,~Ikyt, hydroxy-(C,-C,~Ikyl, At', (C,-C,~Ikyl optionally substituted with up to fnre fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
R'°, R'~ and R'° are each independently hydrogen or (C,-C,ratkyt;
Ar' is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl;
said Ar being optionally substituted with up to three hydroxy, (C,-C4)alkoxy-(C,-G4)alkyl, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to fnre fluoro or (C,-C,)alkoxy optiona8y substituted with up to five fluoro; or R'~ and R" are taken together on adjacent carbon atoms and are -O-(CH2~-O-;
tis1,2or3.
Stil! another preferred group of compounds of formuta t, designated Group F, are those compounds of formula 1, prodrugs thereof and phamiaceuticatly acceptable salts of said compounds or said prodrugs, wherein:
R' is ..as , -i 9-Y2 ~ts , R'~ Y, R'\N~YwRas R's N a N
R
R~ \ iY {CH CHZ) I ' ~
R's/N\
N~Y~R's R \N~Y,~R's {CH=)k ', or J
I
Y is (C2-Ca~lkylene;
R", R'~ and R'~ are each independently hydrogen or (C,-C,)alkyl;
m and n are each independently 1, 2 or 3, provided that the sum of m and n is 2. 3 or 4;
kisOto4;
Y' is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R" is (C3-C,)cydoalkyl, Ar5-(Co-C,)alkylenyl. NR"R'° or (C,-Ca)alkyl optionally substituted with one to five fiuoro; provided that when Y' is a covalent bond or oxycarbonyl, then R" is not NR"R'°;
R" and R'° are taken separately and are each independently selected from hydrogen, Ars. (C,-C,)alkyl and Ar5-(Co-C,)alkylenyl; or R" and R'° are taken together with the nitrogen atom to which they are attadied to form azetidinyl, pyfrolidinyl, pipetidinyl, piperazinyl, morpholinyl, a~epinyl, azabicydo[3.2.2]nonanyl, azabicydo[22.1]heptyl,1,2,3,4-tetrahydroisoquindyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl or 5,fi;7,8-tetrahydropyrido[4,3-d]pyrimidyt;
said azetidinyl in the definition of R" and R'° are optionally substituted with one hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C; C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)a(koxy optionally sut;stituted with up to five fluoro; said pyrrolidinyl, piperidinyl and azepinyl in the definition of R"
and R'° are optionally substituted with up to two hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro o~ (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R" and R'° is optionally substituted with up to two substituents independently selected from hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C')alkyl optionally substituted with up to five fluoro and (C,-C,~Ikoxy optionally substituted with,up to flue fluoro; said piperaziny(,1,2,3,4-tetrahydroisoquinolyl and 5,6,7,8-tetrahydro[4,3-d]pyrimidyi in the definition of R" and R'° are optionally substituted with up to three hydroxy, amino, halo, hydroxy-(C,-C,~Ikyt, (C,-C,)alkoxy-(C,-C,)atkyl, (C,~,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the definition of R"
and R'° are optionally substituted with up to four hydroxy, amino, halo, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C;-C,~Ikyl, (C,-Ca)alkyi optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro.
A preferred group of compounds within Group F, designated Group FA, are those compounds, prodnrgs thereof and pharmaceutically acceptable salts of said compounds or said prodnrgs wherein:
R' is (R~1-hydroxy-ethyl;
RZ is hydrogen;
R' is N~YsRas (CH2)k N~
k is 0;
Y' is a covalent bond; and R" is 4-pyrimidinyl substituted at the 2-position with 1-hydroxymethyl.
A preferred group of compounds within Group .FA, designated Group FB, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, which is 1 R-(4-{1'-[2-(, R-hydroxy-ethylrpyrimidin-4-ylj-[4.4~bipiperidinyl-,-yl}-pyrimidin-2-yl)-ethanol.
Another preferred group of compounds of formula I, designated Group G, are those compounds of formula I, prodrugs thereof and phamiaceuticatty acceptable salts of said compounds or said prodrugs, wherein:
R' is HO R,T
R" Ra,. ~ Ra, R4"
N . or I
,o R"and R"' are independently hydrogen, (C,-C,kydoallcyl, Ar'-(CQ-C,)alkylenyl, Ars-(C2-C,)alkenyl, Are-carbonyl or (C,-C6)alkyl optionally substituted with up to five fluoro;
and R" and R"' are independently hydrogen or (C,-C,)alkyt.
Still another preferred group of compounds of formula I, designated Group H, are those compounds of formula I, prodnrgs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
R' is C(OH)R'R5, where R' and Rs are each independently hydrogen or methyl;
RZ is hydrogen;
R' is N
T
( ~)~ G, V
N
wherein said R' is substituted by R°, R' or R°;
WO 00/59510 PGTIIB00/00~96 G, G' and GZ are taken separately and are each hydrogen and R° is hydrogen or (C,- , C,)alkyl; R' and R° are each independently hydrogen or (C,-C,)atkyl; or G and G' are taken together and are (C,-C,)alkylene and R°, R', R° and G2 are hydrogen; or G' and GZ are taken together and are (C,-C,)alkylene and R°, R', R° and G are hydrogen;
qis0orl;
X is a covalent bond, oxycarbonyl,vinytenylcarbonyt, oxy(C,-C,)alkylenylcarbonyl, thio(C,-C,~Ikylenylcarbonyl or vinylenylsulfonyt; said vinylenylcarbonyl and said vinylenylsulfonyl in the definition of X are optionally substituted on one or two vinylenyf carbons with (C,-C,)alkyl, benzyl or Ar, said oxy(C,-C,)alkylenyicarbonyl and said thio(C,-C,)alkyfenylcarbonyl in the definition of X are optionally substituted with up to two (C,-C,)alkyl, benzyl or Ar;
R' is (C3-C~)cyctoalkyl, Ar'-(Co-C,)alkylenyl or (C,-C°)alkyl optionally substituted with up to five fiuoro;
Ar' is phenyl, naphthyl; pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, quinofyl, isoquinolyl, quinazolyl, quinoxalyl, phthatazinyl, annotinyl, naphthyridinyl, pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl, pyrimidopyridazinyt, pyrimidopyrimidyl, pyridopyrimidyl, pyridopyrazinyt, pyridopyridazinyl, pyn-olyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, PY~oIYf, isoxazolyl, isothiazolyt, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzisoxazolyl, benzisothiazofyi, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazolopyridyl, oxazotopyridy(, thiazofopyridyl, pyrazolopyridyl, isoxazotopyridyl, isothiazolopyridyl, pyrrolopyrimidyl, furopyrimidyl, thienopyrimidyl, imidazolopyrimidyl, oxazotopyrimidyl, thiazolopyrimidyl, pyrazolopyrimidyl, isoxazolopyrimidyl, isothiazolopyrimidyl, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, imidazolopyrazinyl, oxazolopyrazinyl, thiazolopyrazinyl, pyrazolopyrazinyl, isoxazolopyrazinyl, isothiazolopyrazinyl, pyn-otopyridazinyl, furopyridazinyl, thienopyridazinyl, imidazolopyridazinyl, oxazoiopyridazinyl, 3b thiazolopyridazinyl, pyrazolopyridazinyl, isoxazolopyridazinyl or isothiazolopyridazinyl;
and said Ar' is optionally substituted as set forth above.
. pCTIIB00/Q0296 -23- , A preferred group of compounds within Group H, designated Group HA, are ~ , those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs, wherein:
X is a covalent bond, oxycarbonyl or vinylehylcarbonyl optionally substituted on one or two vinyienyl carbons with (C,-C,~Ikyl, benzyl or Ar, R° is Ar'-(Co-C,)alkylenyl; .
Ar' is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, triazinyl, quinolyl, isoquinoiyl, quinazolyl, quinoxalyl, furanyl, thienyl, indolyl, benzofuranyl; benzothienyl;
benzoxazolyl, benzothiazolyl, furopyridyl, oxazotopyridyl, thiazoiopyridyl, thienopyridyl, 1 fl furopyrimidyl, thienopyrimidyl, oxazolopyrimidyl or thiazolopyrimidyl;
and said Ar' is optionally substituted as set forth in daim 1.
A preferred group of compounds within,Group HA, designated Group H8, are those compounds, prodrugs thereof and phamnaceuticaliy acceptable salts of said compounds or said prodnrgs, wherein:
R2 is hydrogen;
R~ is hydrogen or methyl;
RS is methyl;
G, G' and GZ are hydrogen;
R° and R' are each independently hydrogen or methyl;
R° is hydrogen.
A preferred group of compounds within Group H8, designated Group HC, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R' is (R)-1-hydroxy-ethyl; and R' is O R°
N
Me ~ Me WO 00!59510 PCT/IBOO~OZ96 A preferred compound within Group HC is the compound wherein R° is faro[3.2-c]pyridyl, a prodrug thereof or a pham~aceut~ally acceptable salt of said compound or said prodrug.
Another preferred compound within Group HC as the compound wherein R9 is 2-(4-chloro-faro[3,2-cjpyridyl), a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
Another preferred compound within Group HC is the compound wherein Rs is 2-(4-pyrrolidin-1-yl-faro[3,2-cjpyridyl), a prodrug thereof or a pharmaceutically acceptable salt.of said compound or said prodnrg.
Another preferred compound within Group HC is the compound wherein R° is 2-(4-morpholin-4-yl-furo[3,2-cJpyridyt), a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
Another preferred compound within Group HC is the compound wherein R' is 2-imidazo[1,2-a]pyridyl, a prodrug thereof or a pham~aceutiraliy acceptable salt of said compound or said prodrug.
Preferred compounds within Group HC are faro[3,2-c]pyridin-2-yl-{4-i2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-methanone; (4-chloro-faro[3.2-clPYridin-2-yl]"{4-[2-(1 R-hydroxy-ethyl~pyrimidin-4-ylj-3R,5S-dimethyh piperazin-1-yI}-methanone; {4-[2-(1R-hydroxy-ethyl~pyrimidin-4-yf]-3R,5S-dimethyl-piperazin-1-yt}-(4-pyrrolidin-1-yf-faro[3,2-cJpyridin-2-y1j~methanone; ~4-[2-(1R-hydroxy-ethyl)-pyrimidin~-ytj-3R,5S-dimethyl-piperazin-1-yl}-(4-morpholin-4-yl-furo(3,2-cJpyridin-2-yl)-methanone; and {4-i2-(1R-hydroxy-ethylj~pyrimidin-4-y()-3R,5S-dimethyl-piperazin-1-YI}-imidazo[1.2-a]PYcidin-2-yl-methanone.
Another preferred group of compounds within Group HB, designated Group HD, are those compounds, prodnrgs thereof and pham~ac~eutically acceptable salts of said compounds or said prodrugs wherein:
R' is (Rr1-hydroxy-ethyl; and Ra ~
rc~rnsoo~ooZ96 O Re ' Me N Me ~N
A preferred compound within Group HO is the compound wherein R9 is 2-furo[3,2-c]pyridyl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
An espeaally prefen-ed compound within Group HD is furo[3,2-cjpyridin-2-yl-{4-[2-(1R-hydroxy-ethyl~pyrimidin-4 y~-2R,6S-dimethyl-piperazin-1-yl}-methanone.
Another preferred group of compounds within Group H8, designated Group HE, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R' is (R}-1-hydroxy-ethyl; and R~ is A preferred compound within Group HE is the compound wherein R9 is 3-pyridyl, a prodrug thereof or a phan'naceutically acceptable salt of said compound or said prodnrg.
Another preferred compound within Group HE is the compound wherein Rs is
3-(2-methytpyridyl~; a prodnrg thereof or a pham~aceuticatly acceptable salt of said compound or said prodcug.
Another preferred t;ompound within Group HE is the compound wherein R° is 3-(5-chloropyridyl), a prodrug thereof or a phamnaceutically acceptable salt of said compound or said~prodrug.
wo oo~s9sio rcrnsooioo2~
Another preferred compound within Group HE is the compound wherein R9 is 3-(6-methylpyridyl), a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Prefer-ed compounds within Group HE are 4-[2-(1R-hydrooy-ethyl)-pyrimidin-
Another preferred t;ompound within Group HE is the compound wherein R° is 3-(5-chloropyridyl), a prodrug thereof or a phamnaceutically acceptable salt of said compound or said~prodrug.
wo oo~s9sio rcrnsooioo2~
Another preferred compound within Group HE is the compound wherein R9 is 3-(6-methylpyridyl), a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Prefer-ed compounds within Group HE are 4-[2-(1R-hydrooy-ethyl)-pyrimidin-
4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid pyridin-3-yl ester, 4-[2-(1R-hydroxy-ethyl~pyrimidin-4-y1j-2R,6S-dimethyl-piperazine-1-carboxylic acid 2-methyl-pyridin-3-yl ester; 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yfJ-2R,6S-dimethyl-piperazine-1-carboxylic acid 5-chloro-pyridin-3-yl ester, and 4-[2-(1 R-hydroxy~thyl~pyrimidin-4-yij-2R,6S~imethyl-piperazine-1-carboxylic aad 6-methyl-pyridin-3-yl ester.
Another preferred group of compounds within Group HB, designated Group HF, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R' is (R)-1-hydroxy-ethyl; and R' is O~\~R°
M N~ vMe N , A preferred compound within the Group HF is the compound wherein R9 is 2-thienyi, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
An espeaally preferred compound within Group HF is (E)-1-{4-[2-(1 R-hydroxy-ethyl)-pyrimidin-4-ylJ-2R,6S-dimethyl-piperazin-1-yl)-3-thiophen-2-yl-propenone.
Another prefer-ed group of compounds within Group HB, designated Group HG, are those compounds, prodnrgs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R' is (R~1-hydroxy-ethyl;
R' is pCTIIB00/00296 Rg .
M N Me and R' is pyrimidyl or triazinyl; said pyrimidyl or triazinyl is optionally substituted with up to two hydroxy, (C,-C,)alkyl, (C3-C,)cycloalkyl, (C,-C,)alkoxy, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkylenyl, phenyl, piperazinyl optionally substituted with (C,-C,)alkyl, or imidazolyl optionally substituted with up to two (C,-C,)alkyf.
A preferred group of compounds within Group HG, designated Group HH, are those compounds, prodrugs thereof and phamiaceutrcally acceptable salts of said compounds or said prodrugs wherein: R' is pyrimid-2-yl optionally ubstituted with up to two (C,-C,)alkyl, hydroxy-(C,-C,)alkyl or (C,-C,)alkoxy-(C,-C,)alkyl.
A preferred compound within the Group HH is the compound wherein R9 is 4,6-dimethytpyrimid-2-yl, a prodrug thereof or a pham~aceutically acceptable soft of said compound or said prodnrg.
Another prefer-ed compound within the Group HH is the compound wherein R° is 4-methoxymethyl-6-methylpyrimid-2-yl, a prodrug thereof or a phanraceutically acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HH is the compound wherein R' is 4-hydroxymethyl-6-methylpyrimid-2-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
A preferred group of compounds within the Group HH are 1 R-(4-[4-(4,6-dimethyl-pyrimidin-2-yl~3R,5S-dimethyl-piperazin-1 ylj-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-methoxymethyl-6-methyl-pyrimidin-2-yI~3R,5S-dimethyl-piperazin-1 y(J-pyrimidin-2-yl}-Ethanol; and 1 R-{4-[4-(4-hydroxyrr~ethyl-6-methyl-pyrimidin-2-yl~
3R.5S-dirc~ethyl-piperazin-1-ylj-pyrimidin-2-yt}-ethanol.
Another preferred group of compounds within the Group HG, designated HI, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein: R° is pyrimid-4-yl optionaNy substfirted with up to two (C,-C,)afkylpiperazin-1-yl or imidazotyl; and said imidazotyl is optionally substituted iNith up to two (C,-C,}alkyl.
-2&
A preferred compound within the Group HI is the compound wherein R9 is 2-{4-methylpiperazin-1-ylrpyrimid-4-yl, a prodrug thereof or a pham~aceuticaliy acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HI is the compound wherein R9 is 2-{4-ethyipiperazin-1-ylr pyrimid~l-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HI is the compound wherein R9 is 2-(4-methy(imidazol-1-yl~ pyrimid-4-yl, a prodnrg thereof or a pharmaceutically acceptable salt of said compound or said prodrug wherein.
Another preferred compound within the Group HI is the compound wherein R9 is 2-(2-methylimidazol-1-y1r pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug wherein.
Another prefer-ed compound within the Group HI is the compound wherein R9 is 2-(2,4-dimethylimidazol-1-yl)- pyrimid-4-yl, a prodrug thereof or a pham~aoeutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group Hl is the compound wherein R' is 2-(4-isopropylpiperazin-1-yl~ pyrimid-4-yl, a prodrug then~f or a pharmaceutically acceptable salt of said compound or said prodrug. ,~
Preferred compounds within Group HI are 1 R-(4-{3R,5S-dimethyf-4-[2-(4-methyl-piperazin-1-yl}-pyrimidin~-yt)-piperazin-1-yl}-pyrimidin-2-yl~ethanol;
1R-(4-{4-[2-(4-ethyl-piperazin-1-yl}-pyrimidin-4-ytj-3R,5S-dimethyl-piperazin-1-y(}-pyrimidin-2-yf~ethanol; 1 R-(4-{3R,5S-dimethyf~-[2-(4-methyl-in~idazol-1-yt)-pyrimidin-4-ylj-piperazin-1-yf}-pyrimidin-2-yl)-ethanol; 1R-(4-{3R,5S-dimethyl~-[2-(2-methyl-imidazof-1-yl~pyrimidin~-ylJ-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1 R-(4-{4-[2-{2,4-dimethyl-imidazol-1-ylrpyrimidin-4-y(j-3R,5S-dimethyl-piperazin-1 yt}-pyrimidin-2-yl~thanol;
and 1 R-(4-{4-[2-(4-isopropyl-piperazin-1-yl~pyrimidin-4-y(j-3R;5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl)-ethanol.
Another preferred group of compounds within Group HG, designated Group HJ, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein: R° is [1,3.5J-triazin-2-yl optionally substituted with up to two hydroxy, (C,-C,~Ikyl, (C3-C,)cydoalkyl, (C,-C,)atkoxy, hydroxy-(G,-C,)atkyl, (C,-C,~Ikylpiperazin-1-yl or phenyl.
pGTJIB00/00296 A preferred compound within the Group HJ is the compound wherein R9 is 4-methyl-6-(4-methylpiperazin-1-ylr[1,3,5)-triazin-2-yl, ,a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodnrg.
Another prefer-ed compound within the Group HJ is the compound wherein R°
is 4-methoxy-6-methyl-[1,3,5J-triazin-2-yl.~ ~ a P~ro9 ~reof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R°
is 4,6-dimethyoxy-[1,3,5]-triazin-2-yl, a prodnrg thereof or a pharmaceutically acceptable salt of said compound or.said prodrug.
p Another prefer-ed compound within the Group HJ is the compound wherein R°
is 4-ethoxy-6-methyl-[1,3,5j-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R°
is 4-isopropoxy-6-methyl-[1.3.5)-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HJ is thewcompound wherein R°
is 4-phenyl-[1,3,5j-triazin-2-yl, a prodnrg thereof or a pharmaceutically acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HJ is the compound wherein R°
is 4-hydroxymethy!-6-methoxy-[1,3.5j-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R°
is 4-isopropoxy-6-methoxy-[1.3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R°
is 4-isopropyl-[1.3,5]-triazin-2-yl, a prodnrg thereof or a phamiaoeutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R°
is 4-ethyl-6-methoxy-[1,3,5j-triazin-2-yl, a prodrug (hereof or a phanraoeutically acceptable salt of said compound or said prodcug.
Another preferred compound within the Group HJ is the compound wherein R°
is 4-cydoprppyl-[1,3.5j-triazin-2-yl, a prodrug thereof or a phamvaoeutically acceptable salt of said compound. or said prodcug:
Another preferred compound within the Group HJ is the compound 'wherein R9 is 4,6-dimethyl-[1,3,5j-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R9 is 4-methyl-6-phenyl-[1,3,5j-triazin-2-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
Preferred compounds within the Group HJ are 1 R-(4-{3R,5S-dimethyl~-(4-methyl-6-{4-methyl-piperazin-1-yIH1,3,5jtriavn-2-yl]-piperazin-1-yl}-Pyrimidin-2-ylr ethanol; 1R-{4-[4-(4-methoxy-6-methyl[1,3,5jtriazin-2-yl~3R,5S-dimethyl-piperazirrl-yQ-pyrimidin-2-yf}-ethanol; 1R-{4-[4-(4,6~imetho~cy-[1,3,5]triazin-2-yl}-3R,5S~imethyl-piperazin-1-yI]-pyrimidin-2-Y(}-ethanol; 1R-{4-[4-(4-ethoxy-6-methyl-[1.3,Sjtriazin-2-y(~
3R,5S-dimethyl-piperazin-1-ylj-pyrimidin-2-yl}~thanol; 1R-{4-[4-(4-isopropoxy-methyl-[1,3,5jtriazin-2-yl)-3R,5S-dimethyl-piperazin-1-y(j-pyrimidin-2-yl}-ethanol; 1R-{4-[3R,5S-dimethyl-4-(4-phenyl-[1,3,5)triazin-2-yl}-piperazin-1-yf J-pyrimidin-2-yl}-ethanol; 1R-{4-[4-{4-hydroxymethyl-G-methoxy-[1,3,5]triazin-2-yl~3R,5S-dimethyl-piperazin-1-ylj-pyrimidin-2-yf}-ethanol; 1 R-{4-[4-(4-isoPropoXy-6=methoxy-[1,3,Sjtriazin-2-yl}-3R,5S-dimethyl-piperazin-1-ylj-pyrimidin-2-yl}~thanol; 1R-{4-[4-(4-isopropyl-[1,3,5jtriazin-2-yl~3R,5S-dimethyl-piperazin-1-y1]-pyrimidin-2-yl}-ethanol;
1 R-{4-[4-(4.6-dimethyl-[1,3,5jtriazin-2-yl}-3R,5S-dimethyl-piperazin-1 y(j-pyrimidin-2-yl}-ethanol; 1 R-{4-[3R,5S~imethyi-4-(4-methyl-fi-phenyl-[1,3,SJtriazin-2-yl}-piperazin-1-y(]pyrimidin-2-y1}-ethanol; 1 R-{4-[4-(4-cydopropyl-[1,3,5jtriazin-2-yl~3R,5S-dimethyl-ptperazin-1-y(j-pyrimidin-2-yI}-ethanol; and 1R-{4-[4-(4-ethyl-6-methoxy-[1.3,5]triazin-2-yl~3R,5S-dimethyl-piperazin-1-Y(j-Pyrimidin-2-YI}-ethanol.
Another group of preferred compounds within the Group HB, designated Group HK, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R' is (R~1-hydroxy-ethyl;
R' is R~
N
Me ~ Me and WO 00!59510 pG"f/IB00/00296 R° is pyrimidyl or triazinyl, said pyrimidyl and triazinyl optionally substituted with up to two hydroxy, (C,-C,)alkyl, (Cs-C,kydoalkyt. (C,-C,)atkoxy, hydroxy-(C,-C,~Ikyl, (C,-C,)atkoxy-(C,-C,)alkyl, triazolyl, acetyl, morpholinyl, (C,-C,)alkylpiperazinyl, phenyl or imidazoiyl optionally substituted with up to two (C~~C,)alkyl.
A preferred group of compounds within the Group HK, designated HL, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein: R9 is pyrimid-2-yl optionally substituted with up to two (C,-C,)alkyl, hydroxy-(C,-C,)alkyl or triazolYl.
A preferred compound within the Group HL is the compound wherein R9 is 4.6-dimethyl-pyrimid-2-yl, a prodrug thereof or a pham~aceuticalfy acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HL is the compound wherein R' is 4-hydroxymethyl-6-methylpyrimid-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said pcodrug.
Another preferred compound within the Group HL is the compound wherein R°
is 4-[1,2,4]-triazol-1-yl-pyrimid-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Preferred compounds within the Group HL are 1 R-{4-[4(4,6-dimethyl-pyrimidin-2-yl}-2R,6S-dimethyl-piperazin-1-yl}- PYrimidin-2-yl}-ethanot;1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-ylj-pyrimidin-2-yl}-ethanol; and 1R-{4-{2R,6S-dimethyl-4-(4-[1,2,4]triazol-1-yl-pyrimidin-2-yl)-piperazin-1-yfj-pyrimidirr2-yl)-ethanol.
Another preferred group of compounds within the Group HK, designated Group HM, are those compounds, prodrugs thereof and phamnaceutically acceptable salts of said compounds or said prodrugs wherein: R9 is pyrimid~-yl optionally substituted with up to two (C,-C,)alkyl, hydroxy-(C,-C,~Ikyl, acetyl, morpholinyt, (C,-C,)alkylpiperazinyl, triazolyl or imidazolyl optionally-substituted with up to two (C,-C,)alkyl.
A preferred compound within the Group HM is the compound wherein R° is 2,6-dimethyl-pyrimid-4-yt, a prodrug thereof or a pham~aceutically axeptable salt of said compound or said prodrug.
WO 00/59510 PC'f/IB00100296 Another preferred compound w'tthin the Group HM is the compound wherein R° is 2-hydroxymethyl-6-methyl-pyrimid-4-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-acetyl-pyrimid~-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-morpholin-4-yl-pyrimid~-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said~prodrug.
0 Another~preferred compound within the Group HM is the compound wherein R9 is 2-(4-methylpiperazin-1-yl~pyrimid~-yl, a prodnrg thereof or a pham~aceuticaliy acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HM is the compound wherein R9 is 2-[1.2,4]-triazol-1-yl-pyrimid-4-yl,a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-(1 S-hydroxyethyl}-pyrimid~-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R' is 2-(1 R-hydroxyethyl)-pyrimid-4 yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-(4-ethyfpiperazin-1-yl}-pyrimid-4-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
Another prefer-ed compound within the Group HM is the compound wherein R° is 2-(4-methylimidazol-1-yl)-Pyrimid-4-yl, a prodnrg thereof or a phamiaceuticaliy acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-(2,4-dimethylimidazol-1-yl~pyrimid~-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodnrg.
Preferred compounds within the HB Group are 1R-{4-[4-(2,6-dimethyl-pyrimidin-4-yl~2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-y1}-ethanol; 1f~-(4-{4-[2-(1R-hydroxy-ethyl~Pyrimidin~-YI]-2R,6S-dimethyl-piperazin-1-YI}-Pyrimidin-2-yl~thanol;
pGTIIB00/00296 1 R-{4-(4-(2-hydroxymethyl-6-methyl-pyrimidin-4-yl~2R,6S-dimethyl-piperazin-1-yfj-pyrimidin-2-yl}-ethanol; 1 R-(4-{4-[2-(7 S-hydroxy-ethyl)-pyrimidin-4-y(]-2R,fiS-dimethyl-piperazin-1-yl}-pyrimidin-2-ylrethanol; (4-{4-[2-(1R-hydroxy-ethyl~pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone; 1R-{4-(2R,6S-dimethyf-4-(2-morpholin-4-yl-pyrimidin-4-yl)-piperazin-1~-ylj-pyrimidin-2-yl}-ethanol; 1 R-(4-{2R,6S-dimethyl~-[2-(4-methyl-piperazin-1-yl}-pyrimidin-4-yQ-piperazin-1-yl}-pyrimidin-2-yl~
ethanol; 1R-{4-[2R,6S-dimethyl-4-(2-[1,2,4]triazol-1-yl-pyrimidin-4-yl~piperazin-1-yl]-pyrimidin-2-yI}-ethanol; 1 R-(4-{4-[2-(1 R-hydroxy-ethyl)-pyrimidin-4-ylj-2R,6R-dimethyl-piperazin-1-yf}-pyrimidin-2-yl~ethanol; ~ 1 R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-~pydmidin-4-ylJ-2R,6S-dirnethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1 R-(4-{2R,6S-dimethyl-4-[2-{4-methyl-imidazol-1-yl)-pyrimidin-4-yfj-piperazin~l-yl}-pyrimidin-2-yl)-ethanol; and 1R-{4-{4-[2-(2,4-dimethyl-imidazol-1-yl~pyrimidin-4-yQ-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl~thanol.
Another prefen-ed compound within the Group HB is the compound wherein R' is (Rr1-hydroxyethyl; R' is R°
N
Me'~~~ N Me and R9 is 2-(1R-hydroxyethyl-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
A preferred group of compounds within the Group HK, designated Group HN, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodnrgs, wherein R9 is (1,3,5]-triazin-2-yl optionally substituted with up to two hydroxy, (C,-C,)alkyl, (C,-C,)cydoalkyl, hydroxy-(C,-C,)alkyl, (C,-C,~Ikoxy-(C,-C,)alkyl, (C,-C,)alkoxy, morpholinyl or phenyl.
A preferred compound within the Group HN is the compound wherein R° is morpholin-4-yl-[1,3,57-triazin-2-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HN is the compound wherein R° is 4-methoxy-6-methyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodnrg.
WO 00159510 PGT/IBOOro0296 _34-Another preferred compound within the Group HN is the,compound wherein R° is 4,6-dimethoxy-[1.3,5]-triazin-2-yl, a prodrug thenaof or a pharmaceutically acceptable salt of said compound or said prodnrg:
Another preferred compound within the Group HN is the compound wherein R9 is 4-phenyl-j1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another prefer-ed compound within the Group HN is the compound wherein R9 is 4-cydopropyl-[7 ,3,5]-triazin-2-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
Another~preferred compound within the Group HN is the compound wherein R9 is 4,6-dimethyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pham~aceuticatly acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HN is the compound wherein R9 is 4-hydroxymethyl-6-phenyl-[1,3,5]-triazin-2-yl, a prodrug then:of or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein R° is 4-methoxy-6-methoxymethyl-[1,3.5]-triazin-2-yl, a prodrug thenof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein R° is 4-methyl-[1,3,5j-triazin-2-yl, a prodrug thereof or a phannaaeutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein R9 is 4-methoxymethyl-6-phenyl-[1,3,5~triazin-2-yl, a prodnrg thereof or a phamiaoeutically acxeptable salt of said compound or said prodrug.
Preferred compounds within the Group HN are 1R-{4-~2R,6S-dimethyl-4-(4-morpholin-4-yl-[1.3,5]triazin-2-yl~Piperazin-1-y(j-Pyrimidin-2-yl}-ethanol;
1R-{4-[4-(.4-methoxy-6-methyl-[1,3,5jtriazin-2-yl}-2R,6S-dimethyl-piperazin-1 y(J-pyrimid'm-2-yl}-ethanol;1 R-{4-[4-(4,6-dimethoxy-[1,3,5]triazin-2-yl~2R,6S-dimethy!-piperazin-1 yIJ-pyrimidin-2-y1}-ethanol; 1R-{4-[4-(4-cydopropy!-[1,3,5)triazin-2-yl]-2R,6S-dimethyl-piperazin-1 yQ-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4,6-dimethyl-[t,3,5jtriazin-2-yl~
2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-hydroxymethyl.~.
phenyl-[1,3,5]triazin-2-yl~2R.6S-dimett~yl-piperazin-1-yl]-pyrimidin-2-yl~ethanot; 1R-{4-[4-(4-methoxy-6-methoxymethyl-[1,3,5]triazin-2-yl}-2R,6S-dimethyl-piperazin-1-y(j-pyrimidin-2-yl}-ethanol; 1 R-(4-[2R,6S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)-piperazin-1-ylj-pyrimidin-2-yl-ethanol; 1R-{4-[4-(4-methoxymethyl-6-phenyl-j1.3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
and 1 R-{4-[2R,6S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl~piperazin-1 ylJ-pyrimidin-2-yl)-ethanol.
Another preferred group of compounds within the Group H8, designated Group HO, are those compounds, prodnrgs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R' is (R)-1-hydroxy-ethyl;
R' is .
R°
N ~.
N
~ ; and R9 is pyrimidyl, quinoxaiyl or oxazoiopyridyl optionally substituted with up to two (C,-C,)alkyl, (C,-C,)alkoxy or hydroxy-(C,-C,)alkyl.
A preferred compound within the Group HO is the compound wherein R°
is 4-hydroxymethyl-6-methyl-pyrimid-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HO is the compound wherein R' is 2-hydroxymethyl-pyrimid-4-yl, a prodrug then~f or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HO is the compound wherein Rg is 2-hydroxymelhyl-6-methyl-pyrimid-4-yI, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HO is the compound wherein Rs is 2-(oxazolo[5,.4-b]pyridyl), a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HO is the compound wherein R9 is 2-(oxazolo[4,5-b]pyridyl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
-pCTIIB00100296 Another preferred compound within the Group HO is the ,compound wherein R9 is 2-quinoxalyl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Preferred compounds within the Group HO are 1 R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl}-35-methyl-piperazin-1-ylJ-pyrimidin-2-yf}-ethanol; 1 R-(4-[4-(2-hydroxymethyl-pyrimidin-4-yl~3S-methyl-piperazin-1-y(j-, pyrimidin-2-yfj~-ethanol; 1 R-[4-[4-(2-hydroxymethyl-6-methyl-pyrtmidin-4-yl~3S-methyl-piperazin-1-yl]-py-rimidin-2-yl}-ethanol; 1 R-[4-(3S-methyl-4-oxazofo[5,4-bjpyridin-2-yl-piperazin-1-yl)~pyrimidin-2-y(j-ethanol; 1R-[4-(3S-methyl-4-oxazolo[4,5-bjpyridin-2-yl-piperazin-1-yl)-pyrimidin-2-y(j-ethanol; and 1 R-[4-(3S-methyl-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-y(J-ethanol.
Another preferred group of compounds within the Group HB, designated Group NP, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R' is (R)-1-hydroxy-ethyl;
R' is R°
N
N Me and R9 is pyrimidyl optionally substituted with up to two (C,-C,)alkyl, (C,-C,)alkoxy, hydroxy-(C,-C,)alkyl:
A preferred compound within the Group HP is the compound wherein R° is 2-(1 R-hydroxyethyl)-pyrimid-4-yl, a prodnrg thereof or a phamaaceutically acceptable salt of said compound or said prodrug.
A preferred compound within the Group HP is 1 R-(4-{4-[2-(1 R-hydroxy-ethylr pyrimidin-4-ylJ-2R-methyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.
Another preferred group of compounds within the Group HB, designated HQ, are those compounds, prodnrgs thereof and pham~aceuticalty acceptable salts of said compounds or said prodrugs wherein:
R' is (R~-1 ~ydroxy-ethyl;
R' is pG"f/IB00/00296 R~ , Me,,, N ~ ' N Me -and R9 is pyrimidyl optionally substituted with up to two (C,-C,)alkyl, (C,-C,)alkoxy, hydroxy-(C,-C,)alkyl.
A preferred compound within the Group HQ is the compound wherein R9 is 2-(1 R-hydroxyethyl)-pyrimid~-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
An especially prefer-ed compound within the Group HQ is (4-(4-~2-(1 R-hydroxy-ethyl}-pyrimidin-4-y~-2R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2~y1}-ethanol.
Another preferred group of compounds within the Group HB, designated Group HR, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R' is (S~1-hydroxy~thyl;
R' is Ro N
Me ~ Me ; and R' is pynmidyl optionally substituted with up to two (C,-C,)alkyl, (C,-C,)alkoxy or hydroxy-(C,-C,)alkyl.
A preferred compound within the Group HR is the compound wherein R9 is 2-(1R-hydroxy~thyl~pyrimid-~-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
An espeaally preferred compound within the Group HR is 1S-(4-{4-(2-(1R-hydroxy-ethyl~pyrimidin-~-yt]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl}-ethanol.
Yet another preferred group of compounds within the Group HB, designated Group HS; are those compounds, prodrugs thereof and pharmaoeuticaAy acceptable salts of said compounds or said prodrugs wherein:
R' is acetyl:
R' is R°
N
Me ~ ~Me and pC'fIB00/00296 R9 is pyrimidyl optionally substituted with up to two (C,-C,~Ikyl, (C,-C,~Ikoxy, acetyl or hydroxy-(C,-C,)alkyl.
A prefer-ed compound within the Group HS is the compound wherein R9 is 2-acetyl-pyrimid~-yl, a prodrug thereof or a phamiaceut~cally acceptable salt of said compound or said prodrug.
A preferred compound within the Group HS is the compound wherein R9 is 2-7 0 (1 R-hydroxyethyl~pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Espeaally preferred compounds within the Group HS are 1-{4r(4-(2-acetyl-pyrimidin-4-ylj-2R'.6S'-dimethyl-piperazin-1-yfJ-pyrimidin-2 yl}-ethanone or 1-j~-{4-j2-('1 R-hydroxy-ethyl)-pyrimidin-4-yQ-2R,6S-dimethyl-piperazin-1-y(}-pyrimidin-2-yl)-ethanone A pharmaceutical composition, designated Composition A, comprising a compound of formula I, a prodrug thereof ar a pharmaceutically acceptable salt of said compound or said prodrug and a pham~aceutically acceptable carrier or diluent.
A method of inhibiting sorbitol dehydrogenase in a mamma! in need of such inhibition comprising administering to said mammal a sorbitol dehydrogenase inhibiting amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodnrg.
A method of treating diabetes in a mammal suffering from diabetes c;ornprising administering to said mammal an effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodnrg.
A method, designated Method A, of treating or preventing diabetic complications in a mammal comprising administering to said mammal an effective pCTIIB00100296 amount of a compound of formula l, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodnrg:
A method of Method A wherein said mammal is suffering from diabetes.
A method of Method A wherein said diabetic complication is diabetic neuropathy.
A method of Method A wherein said diabetic compf~cation is diabetic nephropathy.
A method of Method A wherein said diabetic complication is diabetic retinopathy.
A method of Method A wherein said diabetic complication is foot ~rl~rs.
A method of Method A wherein said diabetic complication is a cardiovascular condition.
A pham~aoeutical composition, designated Composition B, comprising a compound of formula I, a prodrug thereof or a pham~aceutically axeptabfe salt of said ~ 5 compound or said prodrug and an aldose reductase inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said aldose reduetase inhibitor or said prodrug.
A composition of Composition B additionally composing a pham~aceuticatly acceptable carrier or diluent.
A method of treating diabetes in a mammal suffering from diabetes comprising 20 administering to said mammal an effective amount of a compound of fomnula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and an aldose reductase inhibitor, a prodrug of said aldose reductase inhibitor or a pharmaceutically acceptable salt of said aldose reductase inhibitor or said prodrug.
25 "'" A method, designated Method B, of treating or preventing diabetic complications in a mammal comprising administering to said mammal an effective amount of a compound of formula 1, a prodrug thereof or a pham~aoeuticaUy acceptable of said compound or said prodrug and an atdose reductase inhibitor, a prodrug of said aldose reductase inhibitor or a phamvaceuticalfy acceptable salt of 30 said aldose reductase inhibitor or said prodrug thereof.
A method of Method B wherein said mammal is suffering from diabetes.
A method of Method B wherein said diabetic complication is diabetic neuropathy:
-40- , , A method of Method B wherein said diabetic complication is diabetic nephropathy.
A method of Method 8 wherein said. diabetic complication is diabet<c retinopathy.
A method of Method B wherein said diabetic complication is foot~Ulcers.
A method of Method B wherein said diabetic oompf~cation is a cardiovasarlar condition.
A phamiaoeutical composition, designated Composition C, c~rnprising a compound of formula l, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a sodium hydrogen ion exchange (NH~-7 ) inhibitor, a prodrug of said NHE-1 inhibitor or a pham~aceutically acceptable salt of~~aid inhibitor or said prodrug thereof.
A method, designated Method C, of treating ischemia in a mammal suffering from ischemia comprising administering to said mammal an effective amount of a compound of formula I, a prodrug thereof or a pham~aceuticatiy acoeptabfe salt of said compound or said prodrug and a sodium hydrogen ion exchange (NHE-1) inhibitor, a prodrug of said NHE-1 inhibitor or a pham~aceutically acceptable satt of said inhibitor or said prodrug.
A method of Method C wherein said ischemia is perioperatnie myocardial ischemia.
A method of treating or preventing diabetic complications in a mammal, designated Method D, comprising administering to said mammal an effective amount of a compound of fofnwla I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a sodium hydrogen ion exchange (NHE-1 ) inhibitor, a prodrug of said NHE-1 inhibitor or a pham~aceutically acceptable salt of said NHE-l inhibitor or said prodtug.
A method of Method D wherein said mammal is suffering from diabetes.
A method of Method D wherein said diabetic complication is d'~abetic neuropathy.
A method of Method D wherein said diabetic complication is diabetic nephropathy.
A method of Method D wherein said diabetic ~lication is diabetic retinopathy.
~ WO 00/59510 pCT/IB00100296 . -41 _ A method of Method D wherein said diabetic complication is foot ulcers.
A method of Method D wherein said diabetic complication is a cardiovascular condition.
A method of treating diabetes in a mammal suffering from diabetes comprising administering to said mammal an effective aniount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound pr said prodrug, and a sodium hydrogen ion exchange (NHE-1 ) inhibitor, a prodrug of said NHE-1 inhibitor or a pham~aceuticafly acceptable salt of said NHE-1 inhibitor or said prodrug.
A kit comprising:
a. a compound of formula l, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug in a fjrst unit dosage form;
b. an aldose reductase inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said aldose reductase inhibitor in a second unit dosage form; and c. a container.
A kit comprising:
a. a compound of formula 1, a prodrug thereof or a phamfaceuticafly acceptable salt of said compound or said prodrug in a first unit dosage form;
b. a sodium hydrogen ion exchange (NHE-1 ) inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said NHE-1 inhibitor in a second unit dosage form; and c. a container.
A method, designated Method E, of inhibiting sorbitol dehydrogenase in a mammal in need thereof comprising administering to said mammal Composition A.
A method of Method E wherein said ischemia is perioperative myocardial ischemia.
A method of treating ischemia in a mammal suffering from ischemia comprising administering to said mammal Composition C.
A method, designated Method F, of treating or preventing diabetic complications in a mammal comprising administering to said mammal Composition A.
pCTIIB00100296 ~2-A method of Method F wherein said mammal is suffering from diabetes.
A method, designated Method G, of treating or, preventing diabetic complications in a mammal comprising administering to said mammal Composition B.
A method of Method G wherein said mammal is suffering from diabetes.
A method, designated Method H, of treating or preventing diabetic complications in a mammal comprising administering to said mammal Composition C.
A method of Method H wherein said mammal is suffering from diabetes.
A compound of formula I, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodnrg, wherein:
R' is C(OH)R'R~S, where R' and R5 are each independently hydrogen or methyl;
RZ is hydrogen;
R' is X~Ro (CH2)k N
s ( s) ~ G, G or N
wherein said piperazinyl R' is substituted by R6, R' or R°;
G, G' and G2 are taken separately and are each hydrogen and Re is hydrogen or (C,-C,)alkyl; R' and R° are each independently hydrogen or (C,-C,)allcyl; or G and G' are taken together and are (C,-C,jalkylene and R6, R', R° and G2 are hydrogen; or G' and G= are taken together and are (C,-C3~Ikylene and R6, R', R°
and G are hydrogen;
qis0orl;
X is a covalent bond, oxycarbonyl,vinylenylcart~onyl, oxy(C,-C,)alkylenyicarbonyl, thio(C,-C,)alkylenyfcarbonyl or vinylenylsutfonyl; said vinylenylcarbonyl and said vinylenylsulfonyl in the definition of X are optionally substituted on one or iwo vinylenyl carbons with (C,-C,)alkyl, benryl or Ar; said oxy(C,-C,)alkylenytcarbonyl and said pCTIIB00/00296 thio(C,-C,)alkylenylcarbonyl in the definition of X are optionally substituted with up to two (C,-C,)alkyl, benzyl or Ar;
R9 is (C3-C,)cydoalkyl, Ar'-(Co-C,)alkylenyl or (C,-C6)atkyl optionally substituted with up to five fiuoro;
Ar' is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyi, triazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, dnnolinyi, naphthyridinyl;
pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl, pyrimidopyridazinyl, pyrimidopyrimidyl, pyridopyrimidyl; py~dopyrazinyl, pyridopyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyi, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzisoxazoiyl, benzisothiazolyl, pyrrolopyridyl, furopyridyl, thienopyridyi, imidazoiopyridyl, oxazolopyridyl, thiazoiopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazoiopyridyl, pyrrolopyrimidyl, furopyrimidyl, thienopyrimidyl, imidazoiopyrimidyl, oxazolopyrimidyl, thiazolopyrimidyl, pyrazolopyrimidyl, isoxazolopyrimidyl, isothiazolopyrimidyl, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, imidazolopyrazinyl, oxazolopyrazinyl, thiazolopyrazinyl, pyrazolopyrazinyl, isoxazolopyrazinyl, isothiazolopyrazinyl, pyrrolopyridazinyl, furopyridazinyl, thienopyridazinyl, imidazoiopyridazinyl, oxazolopyridazinyl, thiazoiopyridazinyl, pyrazolopyridazinyl, isoxazolopyridazinyl or isothiazolopyridazinyl;
and said Ar' is optionally substituted as set forth above;
k is 0, 1, 2, 3 or 4;
Y' is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R" is (C~-C,)cydoalkyl, Ars-(Co-C,)alkylenyl, NR"R'° or (C,-C6)alkyl optionally substituted with one to five fluoro; provided that when Y' is a covalent bond or oxycarbonyl, then R" is not NR"R'°;
R" and R'° are taken separately and are each independently selected from hydrogen, Ars, (C,-C6)atkyl and Ars-(Ca-C,)alkylenyl; or R" and R'° are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicydo[3.2.2]nonanyl, azabicydo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl, 6,7-dihydro-SH-dibenzojc,ejazepinyl or 5,6,7,&tetrahydropyrido[4,3-djpyrimtdyl;
said azetidinyt in the definition of R" and R'° are optionally substituted with one hydroxy, WO 00/59510 PCTlIB00100Z96 amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy~(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five ftuoro or (C,-C,)alkoxy optionally substituted with up to five ftuoro; said pyrrolidinyi, piperidinyi and azepinyf in the definition of R"
and R'° are optionally substituted with up to two hydroxy, amino, hydroxy-(C;-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyi, (C,-C,)aikyl opfionatlY substituted with up to five fluoro or (C,-C,~ikoxy optionally substituted with up to Eve fiuoro; said morpholinyl in the definition of R" and R'° is optionally substituted with up to two substituents independently selected from hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to ftve fluoro and (C;-C,)alkoxy optionally substituted with up to five ftuoro; said piperazinyl, 9,2,3,4-tetrahydroisoquinolyl and
Another preferred group of compounds within Group HB, designated Group HF, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R' is (R)-1-hydroxy-ethyl; and R' is O~\~R°
M N~ vMe N , A preferred compound within the Group HF is the compound wherein R9 is 2-thienyi, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
An espeaally preferred compound within Group HF is (E)-1-{4-[2-(1 R-hydroxy-ethyl)-pyrimidin-4-ylJ-2R,6S-dimethyl-piperazin-1-yl)-3-thiophen-2-yl-propenone.
Another prefer-ed group of compounds within Group HB, designated Group HG, are those compounds, prodnrgs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R' is (R~1-hydroxy-ethyl;
R' is pCTIIB00/00296 Rg .
M N Me and R' is pyrimidyl or triazinyl; said pyrimidyl or triazinyl is optionally substituted with up to two hydroxy, (C,-C,)alkyl, (C3-C,)cycloalkyl, (C,-C,)alkoxy, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkylenyl, phenyl, piperazinyl optionally substituted with (C,-C,)alkyl, or imidazolyl optionally substituted with up to two (C,-C,)alkyf.
A preferred group of compounds within Group HG, designated Group HH, are those compounds, prodrugs thereof and phamiaceutrcally acceptable salts of said compounds or said prodrugs wherein: R' is pyrimid-2-yl optionally ubstituted with up to two (C,-C,)alkyl, hydroxy-(C,-C,)alkyl or (C,-C,)alkoxy-(C,-C,)alkyl.
A preferred compound within the Group HH is the compound wherein R9 is 4,6-dimethytpyrimid-2-yl, a prodrug thereof or a pham~aceutically acceptable soft of said compound or said prodnrg.
Another prefer-ed compound within the Group HH is the compound wherein R° is 4-methoxymethyl-6-methylpyrimid-2-yl, a prodrug thereof or a phanraceutically acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HH is the compound wherein R' is 4-hydroxymethyl-6-methylpyrimid-2-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
A preferred group of compounds within the Group HH are 1 R-(4-[4-(4,6-dimethyl-pyrimidin-2-yl~3R,5S-dimethyl-piperazin-1 ylj-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-methoxymethyl-6-methyl-pyrimidin-2-yI~3R,5S-dimethyl-piperazin-1 y(J-pyrimidin-2-yl}-Ethanol; and 1 R-{4-[4-(4-hydroxyrr~ethyl-6-methyl-pyrimidin-2-yl~
3R.5S-dirc~ethyl-piperazin-1-ylj-pyrimidin-2-yt}-ethanol.
Another preferred group of compounds within the Group HG, designated HI, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein: R° is pyrimid-4-yl optionaNy substfirted with up to two (C,-C,)afkylpiperazin-1-yl or imidazotyl; and said imidazotyl is optionally substituted iNith up to two (C,-C,}alkyl.
-2&
A preferred compound within the Group HI is the compound wherein R9 is 2-{4-methylpiperazin-1-ylrpyrimid-4-yl, a prodrug thereof or a pham~aceuticaliy acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HI is the compound wherein R9 is 2-{4-ethyipiperazin-1-ylr pyrimid~l-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HI is the compound wherein R9 is 2-(4-methy(imidazol-1-yl~ pyrimid-4-yl, a prodnrg thereof or a pharmaceutically acceptable salt of said compound or said prodrug wherein.
Another preferred compound within the Group HI is the compound wherein R9 is 2-(2-methylimidazol-1-y1r pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug wherein.
Another prefer-ed compound within the Group HI is the compound wherein R9 is 2-(2,4-dimethylimidazol-1-yl)- pyrimid-4-yl, a prodrug thereof or a pham~aoeutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group Hl is the compound wherein R' is 2-(4-isopropylpiperazin-1-yl~ pyrimid-4-yl, a prodrug then~f or a pharmaceutically acceptable salt of said compound or said prodrug. ,~
Preferred compounds within Group HI are 1 R-(4-{3R,5S-dimethyf-4-[2-(4-methyl-piperazin-1-yl}-pyrimidin~-yt)-piperazin-1-yl}-pyrimidin-2-yl~ethanol;
1R-(4-{4-[2-(4-ethyl-piperazin-1-yl}-pyrimidin-4-ytj-3R,5S-dimethyl-piperazin-1-y(}-pyrimidin-2-yf~ethanol; 1 R-(4-{3R,5S-dimethyf~-[2-(4-methyl-in~idazol-1-yt)-pyrimidin-4-ylj-piperazin-1-yf}-pyrimidin-2-yl)-ethanol; 1R-(4-{3R,5S-dimethyl~-[2-(2-methyl-imidazof-1-yl~pyrimidin~-ylJ-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;1 R-(4-{4-[2-{2,4-dimethyl-imidazol-1-ylrpyrimidin-4-y(j-3R,5S-dimethyl-piperazin-1 yt}-pyrimidin-2-yl~thanol;
and 1 R-(4-{4-[2-(4-isopropyl-piperazin-1-yl~pyrimidin-4-y(j-3R;5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl)-ethanol.
Another preferred group of compounds within Group HG, designated Group HJ, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein: R° is [1,3.5J-triazin-2-yl optionally substituted with up to two hydroxy, (C,-C,~Ikyl, (C3-C,)cydoalkyl, (C,-C,)atkoxy, hydroxy-(G,-C,)atkyl, (C,-C,~Ikylpiperazin-1-yl or phenyl.
pGTJIB00/00296 A preferred compound within the Group HJ is the compound wherein R9 is 4-methyl-6-(4-methylpiperazin-1-ylr[1,3,5)-triazin-2-yl, ,a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodnrg.
Another prefer-ed compound within the Group HJ is the compound wherein R°
is 4-methoxy-6-methyl-[1,3,5J-triazin-2-yl.~ ~ a P~ro9 ~reof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R°
is 4,6-dimethyoxy-[1,3,5]-triazin-2-yl, a prodnrg thereof or a pharmaceutically acceptable salt of said compound or.said prodrug.
p Another prefer-ed compound within the Group HJ is the compound wherein R°
is 4-ethoxy-6-methyl-[1,3,5j-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R°
is 4-isopropoxy-6-methyl-[1.3.5)-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HJ is thewcompound wherein R°
is 4-phenyl-[1,3,5j-triazin-2-yl, a prodnrg thereof or a pharmaceutically acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HJ is the compound wherein R°
is 4-hydroxymethy!-6-methoxy-[1,3.5j-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R°
is 4-isopropoxy-6-methoxy-[1.3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R°
is 4-isopropyl-[1.3,5]-triazin-2-yl, a prodnrg thereof or a phamiaoeutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R°
is 4-ethyl-6-methoxy-[1,3,5j-triazin-2-yl, a prodrug (hereof or a phanraoeutically acceptable salt of said compound or said prodcug.
Another preferred compound within the Group HJ is the compound wherein R°
is 4-cydoprppyl-[1,3.5j-triazin-2-yl, a prodrug thereof or a phamvaoeutically acceptable salt of said compound. or said prodcug:
Another preferred compound within the Group HJ is the compound 'wherein R9 is 4,6-dimethyl-[1,3,5j-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HJ is the compound wherein R9 is 4-methyl-6-phenyl-[1,3,5j-triazin-2-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
Preferred compounds within the Group HJ are 1 R-(4-{3R,5S-dimethyl~-(4-methyl-6-{4-methyl-piperazin-1-yIH1,3,5jtriavn-2-yl]-piperazin-1-yl}-Pyrimidin-2-ylr ethanol; 1R-{4-[4-(4-methoxy-6-methyl[1,3,5jtriazin-2-yl~3R,5S-dimethyl-piperazirrl-yQ-pyrimidin-2-yf}-ethanol; 1R-{4-[4-(4,6~imetho~cy-[1,3,5]triazin-2-yl}-3R,5S~imethyl-piperazin-1-yI]-pyrimidin-2-Y(}-ethanol; 1R-{4-[4-(4-ethoxy-6-methyl-[1.3,Sjtriazin-2-y(~
3R,5S-dimethyl-piperazin-1-ylj-pyrimidin-2-yl}~thanol; 1R-{4-[4-(4-isopropoxy-methyl-[1,3,5jtriazin-2-yl)-3R,5S-dimethyl-piperazin-1-y(j-pyrimidin-2-yl}-ethanol; 1R-{4-[3R,5S-dimethyl-4-(4-phenyl-[1,3,5)triazin-2-yl}-piperazin-1-yf J-pyrimidin-2-yl}-ethanol; 1R-{4-[4-{4-hydroxymethyl-G-methoxy-[1,3,5]triazin-2-yl~3R,5S-dimethyl-piperazin-1-ylj-pyrimidin-2-yf}-ethanol; 1 R-{4-[4-(4-isoPropoXy-6=methoxy-[1,3,Sjtriazin-2-yl}-3R,5S-dimethyl-piperazin-1-ylj-pyrimidin-2-yl}~thanol; 1R-{4-[4-(4-isopropyl-[1,3,5jtriazin-2-yl~3R,5S-dimethyl-piperazin-1-y1]-pyrimidin-2-yl}-ethanol;
1 R-{4-[4-(4.6-dimethyl-[1,3,5jtriazin-2-yl}-3R,5S-dimethyl-piperazin-1 y(j-pyrimidin-2-yl}-ethanol; 1 R-{4-[3R,5S~imethyi-4-(4-methyl-fi-phenyl-[1,3,SJtriazin-2-yl}-piperazin-1-y(]pyrimidin-2-y1}-ethanol; 1 R-{4-[4-(4-cydopropyl-[1,3,5jtriazin-2-yl~3R,5S-dimethyl-ptperazin-1-y(j-pyrimidin-2-yI}-ethanol; and 1R-{4-[4-(4-ethyl-6-methoxy-[1.3,5]triazin-2-yl~3R,5S-dimethyl-piperazin-1-Y(j-Pyrimidin-2-YI}-ethanol.
Another group of preferred compounds within the Group HB, designated Group HK, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R' is (R~1-hydroxy-ethyl;
R' is R~
N
Me ~ Me and WO 00!59510 pG"f/IB00/00296 R° is pyrimidyl or triazinyl, said pyrimidyl and triazinyl optionally substituted with up to two hydroxy, (C,-C,)alkyl, (Cs-C,kydoalkyt. (C,-C,)atkoxy, hydroxy-(C,-C,~Ikyl, (C,-C,)atkoxy-(C,-C,)alkyl, triazolyl, acetyl, morpholinyl, (C,-C,)alkylpiperazinyl, phenyl or imidazoiyl optionally substituted with up to two (C~~C,)alkyl.
A preferred group of compounds within the Group HK, designated HL, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein: R9 is pyrimid-2-yl optionally substituted with up to two (C,-C,)alkyl, hydroxy-(C,-C,)alkyl or triazolYl.
A preferred compound within the Group HL is the compound wherein R9 is 4.6-dimethyl-pyrimid-2-yl, a prodrug thereof or a pham~aceuticalfy acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HL is the compound wherein R' is 4-hydroxymethyl-6-methylpyrimid-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said pcodrug.
Another preferred compound within the Group HL is the compound wherein R°
is 4-[1,2,4]-triazol-1-yl-pyrimid-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Preferred compounds within the Group HL are 1 R-{4-[4(4,6-dimethyl-pyrimidin-2-yl}-2R,6S-dimethyl-piperazin-1-yl}- PYrimidin-2-yl}-ethanot;1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-ylj-pyrimidin-2-yl}-ethanol; and 1R-{4-{2R,6S-dimethyl-4-(4-[1,2,4]triazol-1-yl-pyrimidin-2-yl)-piperazin-1-yfj-pyrimidirr2-yl)-ethanol.
Another preferred group of compounds within the Group HK, designated Group HM, are those compounds, prodrugs thereof and phamnaceutically acceptable salts of said compounds or said prodrugs wherein: R9 is pyrimid~-yl optionally substituted with up to two (C,-C,)alkyl, hydroxy-(C,-C,~Ikyl, acetyl, morpholinyt, (C,-C,)alkylpiperazinyl, triazolyl or imidazolyl optionally-substituted with up to two (C,-C,)alkyl.
A preferred compound within the Group HM is the compound wherein R° is 2,6-dimethyl-pyrimid-4-yt, a prodrug thereof or a pham~aceutically axeptable salt of said compound or said prodrug.
WO 00/59510 PC'f/IB00100296 Another preferred compound w'tthin the Group HM is the compound wherein R° is 2-hydroxymethyl-6-methyl-pyrimid-4-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-acetyl-pyrimid~-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-morpholin-4-yl-pyrimid~-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said~prodrug.
0 Another~preferred compound within the Group HM is the compound wherein R9 is 2-(4-methylpiperazin-1-yl~pyrimid~-yl, a prodnrg thereof or a pham~aceuticaliy acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HM is the compound wherein R9 is 2-[1.2,4]-triazol-1-yl-pyrimid-4-yl,a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-(1 S-hydroxyethyl}-pyrimid~-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R' is 2-(1 R-hydroxyethyl)-pyrimid-4 yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-(4-ethyfpiperazin-1-yl}-pyrimid-4-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
Another prefer-ed compound within the Group HM is the compound wherein R° is 2-(4-methylimidazol-1-yl)-Pyrimid-4-yl, a prodnrg thereof or a phamiaceuticaliy acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HM is the compound wherein R9 is 2-(2,4-dimethylimidazol-1-yl~pyrimid~-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodnrg.
Preferred compounds within the HB Group are 1R-{4-[4-(2,6-dimethyl-pyrimidin-4-yl~2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-y1}-ethanol; 1f~-(4-{4-[2-(1R-hydroxy-ethyl~Pyrimidin~-YI]-2R,6S-dimethyl-piperazin-1-YI}-Pyrimidin-2-yl~thanol;
pGTIIB00/00296 1 R-{4-(4-(2-hydroxymethyl-6-methyl-pyrimidin-4-yl~2R,6S-dimethyl-piperazin-1-yfj-pyrimidin-2-yl}-ethanol; 1 R-(4-{4-[2-(7 S-hydroxy-ethyl)-pyrimidin-4-y(]-2R,fiS-dimethyl-piperazin-1-yl}-pyrimidin-2-ylrethanol; (4-{4-[2-(1R-hydroxy-ethyl~pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone; 1R-{4-(2R,6S-dimethyf-4-(2-morpholin-4-yl-pyrimidin-4-yl)-piperazin-1~-ylj-pyrimidin-2-yl}-ethanol; 1 R-(4-{2R,6S-dimethyl~-[2-(4-methyl-piperazin-1-yl}-pyrimidin-4-yQ-piperazin-1-yl}-pyrimidin-2-yl~
ethanol; 1R-{4-[2R,6S-dimethyl-4-(2-[1,2,4]triazol-1-yl-pyrimidin-4-yl~piperazin-1-yl]-pyrimidin-2-yI}-ethanol; 1 R-(4-{4-[2-(1 R-hydroxy-ethyl)-pyrimidin-4-ylj-2R,6R-dimethyl-piperazin-1-yf}-pyrimidin-2-yl~ethanol; ~ 1 R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-~pydmidin-4-ylJ-2R,6S-dirnethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1 R-(4-{2R,6S-dimethyl-4-[2-{4-methyl-imidazol-1-yl)-pyrimidin-4-yfj-piperazin~l-yl}-pyrimidin-2-yl)-ethanol; and 1R-{4-{4-[2-(2,4-dimethyl-imidazol-1-yl~pyrimidin-4-yQ-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl~thanol.
Another prefen-ed compound within the Group HB is the compound wherein R' is (Rr1-hydroxyethyl; R' is R°
N
Me'~~~ N Me and R9 is 2-(1R-hydroxyethyl-pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
A preferred group of compounds within the Group HK, designated Group HN, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodnrgs, wherein R9 is (1,3,5]-triazin-2-yl optionally substituted with up to two hydroxy, (C,-C,)alkyl, (C,-C,)cydoalkyl, hydroxy-(C,-C,)alkyl, (C,-C,~Ikoxy-(C,-C,)alkyl, (C,-C,)alkoxy, morpholinyl or phenyl.
A preferred compound within the Group HN is the compound wherein R° is morpholin-4-yl-[1,3,57-triazin-2-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HN is the compound wherein R° is 4-methoxy-6-methyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodnrg.
WO 00159510 PGT/IBOOro0296 _34-Another preferred compound within the Group HN is the,compound wherein R° is 4,6-dimethoxy-[1.3,5]-triazin-2-yl, a prodrug thenaof or a pharmaceutically acceptable salt of said compound or said prodnrg:
Another preferred compound within the Group HN is the compound wherein R9 is 4-phenyl-j1,3,5]-triazin-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another prefer-ed compound within the Group HN is the compound wherein R9 is 4-cydopropyl-[7 ,3,5]-triazin-2-yl, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
Another~preferred compound within the Group HN is the compound wherein R9 is 4,6-dimethyl-[1,3,5]-triazin-2-yl, a prodrug thereof or a pham~aceuticatly acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HN is the compound wherein R9 is 4-hydroxymethyl-6-phenyl-[1,3,5]-triazin-2-yl, a prodrug then:of or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein R° is 4-methoxy-6-methoxymethyl-[1,3.5]-triazin-2-yl, a prodrug thenof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein R° is 4-methyl-[1,3,5j-triazin-2-yl, a prodrug thereof or a phannaaeutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HN is the compound wherein R9 is 4-methoxymethyl-6-phenyl-[1,3,5~triazin-2-yl, a prodnrg thereof or a phamiaoeutically acxeptable salt of said compound or said prodrug.
Preferred compounds within the Group HN are 1R-{4-~2R,6S-dimethyl-4-(4-morpholin-4-yl-[1.3,5]triazin-2-yl~Piperazin-1-y(j-Pyrimidin-2-yl}-ethanol;
1R-{4-[4-(.4-methoxy-6-methyl-[1,3,5jtriazin-2-yl}-2R,6S-dimethyl-piperazin-1 y(J-pyrimid'm-2-yl}-ethanol;1 R-{4-[4-(4,6-dimethoxy-[1,3,5]triazin-2-yl~2R,6S-dimethy!-piperazin-1 yIJ-pyrimidin-2-y1}-ethanol; 1R-{4-[4-(4-cydopropy!-[1,3,5)triazin-2-yl]-2R,6S-dimethyl-piperazin-1 yQ-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4,6-dimethyl-[t,3,5jtriazin-2-yl~
2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;1R-{4-[4-(4-hydroxymethyl.~.
phenyl-[1,3,5]triazin-2-yl~2R.6S-dimett~yl-piperazin-1-yl]-pyrimidin-2-yl~ethanot; 1R-{4-[4-(4-methoxy-6-methoxymethyl-[1,3,5]triazin-2-yl}-2R,6S-dimethyl-piperazin-1-y(j-pyrimidin-2-yl}-ethanol; 1 R-(4-[2R,6S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)-piperazin-1-ylj-pyrimidin-2-yl-ethanol; 1R-{4-[4-(4-methoxymethyl-6-phenyl-j1.3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
and 1 R-{4-[2R,6S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl~piperazin-1 ylJ-pyrimidin-2-yl)-ethanol.
Another preferred group of compounds within the Group H8, designated Group HO, are those compounds, prodnrgs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R' is (R)-1-hydroxy-ethyl;
R' is .
R°
N ~.
N
~ ; and R9 is pyrimidyl, quinoxaiyl or oxazoiopyridyl optionally substituted with up to two (C,-C,)alkyl, (C,-C,)alkoxy or hydroxy-(C,-C,)alkyl.
A preferred compound within the Group HO is the compound wherein R°
is 4-hydroxymethyl-6-methyl-pyrimid-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HO is the compound wherein R' is 2-hydroxymethyl-pyrimid-4-yl, a prodrug then~f or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HO is the compound wherein Rg is 2-hydroxymelhyl-6-methyl-pyrimid-4-yI, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug.
Another preferred compound within the Group HO is the compound wherein Rs is 2-(oxazolo[5,.4-b]pyridyl), a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodnrg.
Another preferred compound within the Group HO is the compound wherein R9 is 2-(oxazolo[4,5-b]pyridyl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
-pCTIIB00100296 Another preferred compound within the Group HO is the ,compound wherein R9 is 2-quinoxalyl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Preferred compounds within the Group HO are 1 R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl}-35-methyl-piperazin-1-ylJ-pyrimidin-2-yf}-ethanol; 1 R-(4-[4-(2-hydroxymethyl-pyrimidin-4-yl~3S-methyl-piperazin-1-y(j-, pyrimidin-2-yfj~-ethanol; 1 R-[4-[4-(2-hydroxymethyl-6-methyl-pyrtmidin-4-yl~3S-methyl-piperazin-1-yl]-py-rimidin-2-yl}-ethanol; 1 R-[4-(3S-methyl-4-oxazofo[5,4-bjpyridin-2-yl-piperazin-1-yl)~pyrimidin-2-y(j-ethanol; 1R-[4-(3S-methyl-4-oxazolo[4,5-bjpyridin-2-yl-piperazin-1-yl)-pyrimidin-2-y(j-ethanol; and 1 R-[4-(3S-methyl-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-y(J-ethanol.
Another preferred group of compounds within the Group HB, designated Group NP, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R' is (R)-1-hydroxy-ethyl;
R' is R°
N
N Me and R9 is pyrimidyl optionally substituted with up to two (C,-C,)alkyl, (C,-C,)alkoxy, hydroxy-(C,-C,)alkyl:
A preferred compound within the Group HP is the compound wherein R° is 2-(1 R-hydroxyethyl)-pyrimid-4-yl, a prodnrg thereof or a phamaaceutically acceptable salt of said compound or said prodrug.
A preferred compound within the Group HP is 1 R-(4-{4-[2-(1 R-hydroxy-ethylr pyrimidin-4-ylJ-2R-methyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.
Another preferred group of compounds within the Group HB, designated HQ, are those compounds, prodnrgs thereof and pham~aceuticalty acceptable salts of said compounds or said prodrugs wherein:
R' is (R~-1 ~ydroxy-ethyl;
R' is pG"f/IB00/00296 R~ , Me,,, N ~ ' N Me -and R9 is pyrimidyl optionally substituted with up to two (C,-C,)alkyl, (C,-C,)alkoxy, hydroxy-(C,-C,)alkyl.
A preferred compound within the Group HQ is the compound wherein R9 is 2-(1 R-hydroxyethyl)-pyrimid~-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
An especially prefer-ed compound within the Group HQ is (4-(4-~2-(1 R-hydroxy-ethyl}-pyrimidin-4-y~-2R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2~y1}-ethanol.
Another preferred group of compounds within the Group HB, designated Group HR, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds or said prodrugs wherein:
R' is (S~1-hydroxy~thyl;
R' is Ro N
Me ~ Me ; and R' is pynmidyl optionally substituted with up to two (C,-C,)alkyl, (C,-C,)alkoxy or hydroxy-(C,-C,)alkyl.
A preferred compound within the Group HR is the compound wherein R9 is 2-(1R-hydroxy~thyl~pyrimid-~-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
An espeaally preferred compound within the Group HR is 1S-(4-{4-(2-(1R-hydroxy-ethyl~pyrimidin-~-yt]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl}-ethanol.
Yet another preferred group of compounds within the Group HB, designated Group HS; are those compounds, prodrugs thereof and pharmaoeuticaAy acceptable salts of said compounds or said prodrugs wherein:
R' is acetyl:
R' is R°
N
Me ~ ~Me and pC'fIB00/00296 R9 is pyrimidyl optionally substituted with up to two (C,-C,~Ikyl, (C,-C,~Ikoxy, acetyl or hydroxy-(C,-C,)alkyl.
A prefer-ed compound within the Group HS is the compound wherein R9 is 2-acetyl-pyrimid~-yl, a prodrug thereof or a phamiaceut~cally acceptable salt of said compound or said prodrug.
A preferred compound within the Group HS is the compound wherein R9 is 2-7 0 (1 R-hydroxyethyl~pyrimid-4-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Espeaally preferred compounds within the Group HS are 1-{4r(4-(2-acetyl-pyrimidin-4-ylj-2R'.6S'-dimethyl-piperazin-1-yfJ-pyrimidin-2 yl}-ethanone or 1-j~-{4-j2-('1 R-hydroxy-ethyl)-pyrimidin-4-yQ-2R,6S-dimethyl-piperazin-1-y(}-pyrimidin-2-yl)-ethanone A pharmaceutical composition, designated Composition A, comprising a compound of formula I, a prodrug thereof ar a pharmaceutically acceptable salt of said compound or said prodrug and a pham~aceutically acceptable carrier or diluent.
A method of inhibiting sorbitol dehydrogenase in a mamma! in need of such inhibition comprising administering to said mammal a sorbitol dehydrogenase inhibiting amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodnrg.
A method of treating diabetes in a mammal suffering from diabetes c;ornprising administering to said mammal an effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodnrg.
A method, designated Method A, of treating or preventing diabetic complications in a mammal comprising administering to said mammal an effective pCTIIB00100296 amount of a compound of formula l, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodnrg:
A method of Method A wherein said mammal is suffering from diabetes.
A method of Method A wherein said diabetic complication is diabetic neuropathy.
A method of Method A wherein said diabetic compf~cation is diabetic nephropathy.
A method of Method A wherein said diabetic complication is diabetic retinopathy.
A method of Method A wherein said diabetic complication is foot ~rl~rs.
A method of Method A wherein said diabetic complication is a cardiovascular condition.
A pham~aoeutical composition, designated Composition B, comprising a compound of formula I, a prodrug thereof or a pham~aceutically axeptabfe salt of said ~ 5 compound or said prodrug and an aldose reductase inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said aldose reduetase inhibitor or said prodrug.
A composition of Composition B additionally composing a pham~aceuticatly acceptable carrier or diluent.
A method of treating diabetes in a mammal suffering from diabetes comprising 20 administering to said mammal an effective amount of a compound of fomnula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and an aldose reductase inhibitor, a prodrug of said aldose reductase inhibitor or a pharmaceutically acceptable salt of said aldose reductase inhibitor or said prodrug.
25 "'" A method, designated Method B, of treating or preventing diabetic complications in a mammal comprising administering to said mammal an effective amount of a compound of formula 1, a prodrug thereof or a pham~aoeuticaUy acceptable of said compound or said prodrug and an atdose reductase inhibitor, a prodrug of said aldose reductase inhibitor or a phamvaceuticalfy acceptable salt of 30 said aldose reductase inhibitor or said prodrug thereof.
A method of Method B wherein said mammal is suffering from diabetes.
A method of Method B wherein said diabetic complication is diabetic neuropathy:
-40- , , A method of Method B wherein said diabetic complication is diabetic nephropathy.
A method of Method 8 wherein said. diabetic complication is diabet<c retinopathy.
A method of Method B wherein said diabetic complication is foot~Ulcers.
A method of Method B wherein said diabetic oompf~cation is a cardiovasarlar condition.
A phamiaoeutical composition, designated Composition C, c~rnprising a compound of formula l, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a sodium hydrogen ion exchange (NH~-7 ) inhibitor, a prodrug of said NHE-1 inhibitor or a pham~aceutically acceptable salt of~~aid inhibitor or said prodrug thereof.
A method, designated Method C, of treating ischemia in a mammal suffering from ischemia comprising administering to said mammal an effective amount of a compound of formula I, a prodrug thereof or a pham~aceuticatiy acoeptabfe salt of said compound or said prodrug and a sodium hydrogen ion exchange (NHE-1) inhibitor, a prodrug of said NHE-1 inhibitor or a pham~aceutically acceptable satt of said inhibitor or said prodrug.
A method of Method C wherein said ischemia is perioperatnie myocardial ischemia.
A method of treating or preventing diabetic complications in a mammal, designated Method D, comprising administering to said mammal an effective amount of a compound of fofnwla I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a sodium hydrogen ion exchange (NHE-1 ) inhibitor, a prodrug of said NHE-1 inhibitor or a pham~aceutically acceptable salt of said NHE-l inhibitor or said prodtug.
A method of Method D wherein said mammal is suffering from diabetes.
A method of Method D wherein said diabetic complication is d'~abetic neuropathy.
A method of Method D wherein said diabetic complication is diabetic nephropathy.
A method of Method D wherein said diabetic ~lication is diabetic retinopathy.
~ WO 00/59510 pCT/IB00100296 . -41 _ A method of Method D wherein said diabetic complication is foot ulcers.
A method of Method D wherein said diabetic complication is a cardiovascular condition.
A method of treating diabetes in a mammal suffering from diabetes comprising administering to said mammal an effective aniount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound pr said prodrug, and a sodium hydrogen ion exchange (NHE-1 ) inhibitor, a prodrug of said NHE-1 inhibitor or a pham~aceuticafly acceptable salt of said NHE-1 inhibitor or said prodrug.
A kit comprising:
a. a compound of formula l, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug in a fjrst unit dosage form;
b. an aldose reductase inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said aldose reductase inhibitor in a second unit dosage form; and c. a container.
A kit comprising:
a. a compound of formula 1, a prodrug thereof or a phamfaceuticafly acceptable salt of said compound or said prodrug in a first unit dosage form;
b. a sodium hydrogen ion exchange (NHE-1 ) inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said NHE-1 inhibitor in a second unit dosage form; and c. a container.
A method, designated Method E, of inhibiting sorbitol dehydrogenase in a mammal in need thereof comprising administering to said mammal Composition A.
A method of Method E wherein said ischemia is perioperative myocardial ischemia.
A method of treating ischemia in a mammal suffering from ischemia comprising administering to said mammal Composition C.
A method, designated Method F, of treating or preventing diabetic complications in a mammal comprising administering to said mammal Composition A.
pCTIIB00100296 ~2-A method of Method F wherein said mammal is suffering from diabetes.
A method, designated Method G, of treating or, preventing diabetic complications in a mammal comprising administering to said mammal Composition B.
A method of Method G wherein said mammal is suffering from diabetes.
A method, designated Method H, of treating or preventing diabetic complications in a mammal comprising administering to said mammal Composition C.
A method of Method H wherein said mammal is suffering from diabetes.
A compound of formula I, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodnrg, wherein:
R' is C(OH)R'R~S, where R' and R5 are each independently hydrogen or methyl;
RZ is hydrogen;
R' is X~Ro (CH2)k N
s ( s) ~ G, G or N
wherein said piperazinyl R' is substituted by R6, R' or R°;
G, G' and G2 are taken separately and are each hydrogen and Re is hydrogen or (C,-C,)alkyl; R' and R° are each independently hydrogen or (C,-C,)allcyl; or G and G' are taken together and are (C,-C,jalkylene and R6, R', R° and G2 are hydrogen; or G' and G= are taken together and are (C,-C3~Ikylene and R6, R', R°
and G are hydrogen;
qis0orl;
X is a covalent bond, oxycarbonyl,vinylenylcart~onyl, oxy(C,-C,)alkylenyicarbonyl, thio(C,-C,)alkylenyfcarbonyl or vinylenylsutfonyl; said vinylenylcarbonyl and said vinylenylsulfonyl in the definition of X are optionally substituted on one or iwo vinylenyl carbons with (C,-C,)alkyl, benryl or Ar; said oxy(C,-C,)alkylenytcarbonyl and said pCTIIB00/00296 thio(C,-C,)alkylenylcarbonyl in the definition of X are optionally substituted with up to two (C,-C,)alkyl, benzyl or Ar;
R9 is (C3-C,)cydoalkyl, Ar'-(Co-C,)alkylenyl or (C,-C6)atkyl optionally substituted with up to five fiuoro;
Ar' is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyi, triazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, dnnolinyi, naphthyridinyl;
pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl, pyrimidopyridazinyl, pyrimidopyrimidyl, pyridopyrimidyl; py~dopyrazinyl, pyridopyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyi, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzisoxazoiyl, benzisothiazolyl, pyrrolopyridyl, furopyridyl, thienopyridyi, imidazoiopyridyl, oxazolopyridyl, thiazoiopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazoiopyridyl, pyrrolopyrimidyl, furopyrimidyl, thienopyrimidyl, imidazoiopyrimidyl, oxazolopyrimidyl, thiazolopyrimidyl, pyrazolopyrimidyl, isoxazolopyrimidyl, isothiazolopyrimidyl, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, imidazolopyrazinyl, oxazolopyrazinyl, thiazolopyrazinyl, pyrazolopyrazinyl, isoxazolopyrazinyl, isothiazolopyrazinyl, pyrrolopyridazinyl, furopyridazinyl, thienopyridazinyl, imidazoiopyridazinyl, oxazolopyridazinyl, thiazoiopyridazinyl, pyrazolopyridazinyl, isoxazolopyridazinyl or isothiazolopyridazinyl;
and said Ar' is optionally substituted as set forth above;
k is 0, 1, 2, 3 or 4;
Y' is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R" is (C~-C,)cydoalkyl, Ars-(Co-C,)alkylenyl, NR"R'° or (C,-C6)alkyl optionally substituted with one to five fluoro; provided that when Y' is a covalent bond or oxycarbonyl, then R" is not NR"R'°;
R" and R'° are taken separately and are each independently selected from hydrogen, Ars, (C,-C6)atkyl and Ars-(Ca-C,)alkylenyl; or R" and R'° are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicydo[3.2.2]nonanyl, azabicydo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl, 6,7-dihydro-SH-dibenzojc,ejazepinyl or 5,6,7,&tetrahydropyrido[4,3-djpyrimtdyl;
said azetidinyt in the definition of R" and R'° are optionally substituted with one hydroxy, WO 00/59510 PCTlIB00100Z96 amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy~(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five ftuoro or (C,-C,)alkoxy optionally substituted with up to five ftuoro; said pyrrolidinyi, piperidinyi and azepinyf in the definition of R"
and R'° are optionally substituted with up to two hydroxy, amino, hydroxy-(C;-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyi, (C,-C,)aikyl opfionatlY substituted with up to five fluoro or (C,-C,~ikoxy optionally substituted with up to Eve fiuoro; said morpholinyl in the definition of R" and R'° is optionally substituted with up to two substituents independently selected from hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to ftve fluoro and (C;-C,)alkoxy optionally substituted with up to five ftuoro; said piperazinyl, 9,2,3,4-tetrahydroisoquinolyl and
5,fi,7,&tetrahydro[4,3-d]pyrimidyl in the definition of R" and R'° are optionally substituted with up to three hydroxy, amino, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)altcyt, (C;-C,)alkyl optionally substituted with up to five ftuoro or (C; C,)alkoxy optionally substituted with up to five ftuoro; and said fi,7-dihydro-SH-~iibenzo[c,e]azepinyl in the definition of R"
and R'° are optionally substituted with up to four hydroxy, amino, halo, hydroxy-(C,-C,)atkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C;)alkyl optionally substituted with up to fare ftuoro or (C,-C,~Ikoxy optionally substituted with up to five ftuoro;
Ars is independently defined as set forth for Ar and Ar' above;
Ars is optionally independently substituted as set forth for Ar and Ar' above.
A compound selected from 1 R-(4-(1'-[2-(1 R-hydroxy-ethyl)-pyrimidin-4 y(j-[4,4~bipiperidinyl-1-yl}-pysimidin-2-yt)-ethanol; faro[3,2-c]pyridin-2-yl-(4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-ylj-3R,5S-dimethyl-piperazin-i-yl}-methanone; (4-chloro-furo[3,2-c]pyridin-2-yl)-{4-[2-(1 R-hydroxy-ethyl)-pyrimidin~-y~-3R,5S-dimethyl-piperazin-1-yl}-methanone; (4-[2-(1R-hydroxy~thyt)-Pyrimidin-4-yi]-3R,5S-dimethyl-piperazin-1 yt}-(4-pyrrotidin-1-y!-furo[3,2-c]Pyridin 2 yl)-methar~one; ~4-[2-(1R-hydroxy_ ethyl)-pytimidin-4-yt)-3R,5S-dimethyl-piperazin-1-yI}-(4-morpholin~-yl-furo(3,2-cjpyridin-2-yl)-methanone; (4-i2-(1R-hydroxy~thyl)-pyrimidin-4-yt]-3R,SS-dimethy!-piperazin-1-yl}-imidazo[1,2-a]pyridin-2-yI-methanone; furo[3,2-cjpyridin-2-y1~4-[2-(1R-hydroxy-ethyl}-pyrimidin-4-ytJ-2R,6S-dimethyl-piperazin-i-yl}-methanone; 4-[2-(1R
hydroxy-ethyl)-Pyrimidin~-ylj-2R,6S-dimethyt-piperazine-1-carboxylic acid pyridin-3-yl ester; 4-[2-(1R-hydroxy-ethylJ-pyrimidin-4-y!]-2R,6S~imethyl-piperaZine-1-carboxylic aad 2-methyl-pyridin-3-yl ester 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-y(J-2R,6S-dimethyl-piperazine-1- carboxylic aad 5-chtoro-pyridin-3-yl ester, 4-[2-(1R-hydroxy-pC'I'/IB00~0296 ethyl)-pyrimidin-4-yt]-2R.6S-dimethyl-piperazine-1-carboxylic acid 6-methyl-pyridin-3-yl ester;.(Ej-1-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-y(}-2R,6S-dimethyl-piperazin-1-y1}-3-thiophen-2-yl-propenone; 1 R-{4-(4-(4,6-dimethyl-pyrtmidin-2-yl)-3R,5S-dimethyl-piperazin-1-yt]-pyrimidin-2-yi}-ethanot;1 R-{4-[4-(4-methoxymethyl~-methyl-Pyrimidin-2-yl~3R,5S-dimethyl-piperazin-1-ylJ-pyrimidin-2-yl}-ethanol;1 R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl~3R,5S-dimethyl-piperazin-1-yl]-pycrimidin-2-y1}-ethanol; 1 R-(4-{3R,5S-dimethyt-4-[2-(4-methyl-piper-azin-1-yl~pyrimidin-4-yl]-piperazin-1-yl}-pYrimidin-2-yl)-ethanol;1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-Pyrirtiidin-4-yl]-3R.5S-dimethyl-piperazin-1-yl}-pyrimidin-2-ylrethanol;1 R-(4-{3R,5S~imethyl-4-(2-(4-methyl-imidazol-1-ylj-pyrimidin-4-ytj-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{3R,5S-dimethyl-4-[2-(2-methyl-imidazol-1-yl)-pyrimidin-4-ylj-piperazin-1-y(}-pyrimidin-2-yl~ethanol; 1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl~pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{4-[2-(4-isopropyl-Plperazin-1-yl)-pyrimidin~-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl~ethanol; 1R-(4-{3R,5S-dimethyl-4-[4-methyl-6-(4-methyl-piperazin-1-yIH1,3,5]triazin-2-Yl)-Piperazin-1-YI}-pyrimidin-2-yl~thanot;1R-{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2 yl~-3R,5S-dimethyl-piperazin-7-y~-pyrimidin-2-y1}-ethanol;1R-(4-[4-(4,6-dimethoxy-[1,3.5]triazin-2-yl~3R.5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yt}-ethanol;1R-{4-[4-(4-ethoxy-
and R'° are optionally substituted with up to four hydroxy, amino, halo, hydroxy-(C,-C,)atkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C;)alkyl optionally substituted with up to fare ftuoro or (C,-C,~Ikoxy optionally substituted with up to five ftuoro;
Ars is independently defined as set forth for Ar and Ar' above;
Ars is optionally independently substituted as set forth for Ar and Ar' above.
A compound selected from 1 R-(4-(1'-[2-(1 R-hydroxy-ethyl)-pyrimidin-4 y(j-[4,4~bipiperidinyl-1-yl}-pysimidin-2-yt)-ethanol; faro[3,2-c]pyridin-2-yl-(4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-ylj-3R,5S-dimethyl-piperazin-i-yl}-methanone; (4-chloro-furo[3,2-c]pyridin-2-yl)-{4-[2-(1 R-hydroxy-ethyl)-pyrimidin~-y~-3R,5S-dimethyl-piperazin-1-yl}-methanone; (4-[2-(1R-hydroxy~thyt)-Pyrimidin-4-yi]-3R,5S-dimethyl-piperazin-1 yt}-(4-pyrrotidin-1-y!-furo[3,2-c]Pyridin 2 yl)-methar~one; ~4-[2-(1R-hydroxy_ ethyl)-pytimidin-4-yt)-3R,5S-dimethyl-piperazin-1-yI}-(4-morpholin~-yl-furo(3,2-cjpyridin-2-yl)-methanone; (4-i2-(1R-hydroxy~thyl)-pyrimidin-4-yt]-3R,SS-dimethy!-piperazin-1-yl}-imidazo[1,2-a]pyridin-2-yI-methanone; furo[3,2-cjpyridin-2-y1~4-[2-(1R-hydroxy-ethyl}-pyrimidin-4-ytJ-2R,6S-dimethyl-piperazin-i-yl}-methanone; 4-[2-(1R
hydroxy-ethyl)-Pyrimidin~-ylj-2R,6S-dimethyt-piperazine-1-carboxylic acid pyridin-3-yl ester; 4-[2-(1R-hydroxy-ethylJ-pyrimidin-4-y!]-2R,6S~imethyl-piperaZine-1-carboxylic aad 2-methyl-pyridin-3-yl ester 4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-y(J-2R,6S-dimethyl-piperazine-1- carboxylic aad 5-chtoro-pyridin-3-yl ester, 4-[2-(1R-hydroxy-pC'I'/IB00~0296 ethyl)-pyrimidin-4-yt]-2R.6S-dimethyl-piperazine-1-carboxylic acid 6-methyl-pyridin-3-yl ester;.(Ej-1-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-y(}-2R,6S-dimethyl-piperazin-1-y1}-3-thiophen-2-yl-propenone; 1 R-{4-(4-(4,6-dimethyl-pyrtmidin-2-yl)-3R,5S-dimethyl-piperazin-1-yt]-pyrimidin-2-yi}-ethanot;1 R-{4-[4-(4-methoxymethyl~-methyl-Pyrimidin-2-yl~3R,5S-dimethyl-piperazin-1-ylJ-pyrimidin-2-yl}-ethanol;1 R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl~3R,5S-dimethyl-piperazin-1-yl]-pycrimidin-2-y1}-ethanol; 1 R-(4-{3R,5S-dimethyt-4-[2-(4-methyl-piper-azin-1-yl~pyrimidin-4-yl]-piperazin-1-yl}-pYrimidin-2-yl)-ethanol;1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-Pyrirtiidin-4-yl]-3R.5S-dimethyl-piperazin-1-yl}-pyrimidin-2-ylrethanol;1 R-(4-{3R,5S~imethyl-4-(2-(4-methyl-imidazol-1-ylj-pyrimidin-4-ytj-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{3R,5S-dimethyl-4-[2-(2-methyl-imidazol-1-yl)-pyrimidin-4-ylj-piperazin-1-y(}-pyrimidin-2-yl~ethanol; 1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl~pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol; 1R-(4-{4-[2-(4-isopropyl-Plperazin-1-yl)-pyrimidin~-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl~ethanol; 1R-(4-{3R,5S-dimethyl-4-[4-methyl-6-(4-methyl-piperazin-1-yIH1,3,5]triazin-2-Yl)-Piperazin-1-YI}-pyrimidin-2-yl~thanot;1R-{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2 yl~-3R,5S-dimethyl-piperazin-7-y~-pyrimidin-2-y1}-ethanol;1R-(4-[4-(4,6-dimethoxy-[1,3.5]triazin-2-yl~3R.5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yt}-ethanol;1R-{4-[4-(4-ethoxy-
6-methyl-[1,3,5]triazin-2-yl~3R,5S-dimethyi-piperazin-1-yt)-pyrimidin-2-yl}-ethanol; 1R_ .
{4-[4-(4-isopropoxy-8-methyl-[7,3,5]triazin-2-yl)-3R,5S-dimethyf-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[3R,5S-dimethyl-4-(4-phenyl-[1,3,S~ria~zin-2-yl}-piperazin-1-y(]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-hydroxymethy!-6-n~ethoxy-j1,3.5]triazin-2-ylr3R.5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-{4-(4-isopropoxy-6-methoxy-[1,3,5]triazin-2-yIr3R.5S~imethyl-piperazin-1-yIj-pYrirrlidin-2-yl}-ethanol; 1R-{4-[4-(4-isopropyl-[1,3,5]triazin-2-yl)-3R,5S~iimethyl-piperazin-1-yt]-pyrimidin-2-yl}-ethanol; 1R~4-[4-(4-ethyl-methoxy-[1,3.5)biazin-2 ylj-3R,5S-dimethyl-piperazin-1-ylj-pyrimidin-2-y(}-ethanol; 1R-{4-[4-(4,6-dimethyl-pyrimidin-2-yl}-2R.6S-dimethyl-piperazin-1 ylj- pyrimidin-2-YI)-ethanol;1R-(4-~4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-ylj.pyrimidin-2-yl}-ethanol;
1R-{4-[2R,6S-dimethyl-4~-(4-[1,2,4]triazo!-1-yf-pyrimidin-2-yl~piperazin-1 y(j-pyrimidin-2-ylr ethanol;1 R-(4-[4-(2.6-dimethyl-pyrimidin-4-yly-2R,6S-dimethyl-piperazin-1 y~-pyrimidin-2-yt}-ethanol; 1 R-(4-{4-[2-(1 R-hydroxy~thyl~Pyrimidin-4-yl]-2R.fiS-dimethyl-piperazin-1-Y(}-pYrimidin-2-yl~ethanol;1R-{4-[4-(2-hydroxymethyl-6-methyl-pyrimidin-pC'flIB00100296 WO 00!59510 4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-y1}-ethanol; 1 R-(4-{4-(2-(1 S=hydroxy-ethyI~PYnmidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-PYrimidin-2=yf~ethanot: 1 S-(4-{4-[2-(1 R-hydroxy-ethyl~Pyrimidin-4-YI)-2R,6S-dimethyl-piperazin-1-yl}-Pyrimidin-2-yl~
ethanol; 1-{4-[4-(2-acetyl-pyrimidin~-yl)-2R,6S-dimethyl-piperazin-1-YI]-pyrimidin-2-yl}-ethanone; 1 RS-(4-{4-[2-(1 RS-hydroxy-ethyl)-pyrimidin-4-ylj-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl~-ethanol; (4-(4-(2-(1R-hydroxy-ethyl)-pyrimidin-4-y1]-3R,5S-dimethyf-piperazin-1-yl)-pyrimidin-2-yl~-ethanone; 1R-{4-[2R,6S-dimethyl-4-(2-morpholin-4-yl-pyrimidin-4-yl)-piperazin-1-yQ-pyrimidin-2-yl)-ethanol; 1 R-(4-{2R,6S-dimethyl-4-(2-{4-methyl-piperazin-1 yl}=pyrimidin-4-yl]-piperazin-1-yl}-pyimidin-2-yl~
ethanol; 1 R~4-[2R,6S-dimethy!-4-(2-[1,2,4]triazol-1-yl-pyrimidin-4-yl)-Piperazirrl-yl]-pyrimidin-2-yi)ethanol;1R-(4-{4-(2-(1R-hydroxy-ethyl)-pyrimidin-4-ylj-2R,fiR-dimethyl-piperazin-1-yl}-pyrimidin-2-yl~ethanol;1 R-(4-{4-[2-(4-ethyl-piperazin-1 yl~pyrimidin-4-yQ-2R.6S~imethyl-piperazin-1-yl}-pyrimidin-2 yl~ethanol; 1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-imidazol-1-ylrpyrimidin-4-ytj-piperazin-1 yl}-pyrimidin-2-yl}-ethanol; 18-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl~Pyrimidin-4-yt]-2R.6S-dimethyl-piperazin-1-yl}-pyrimidin-2-y1)-ethanol; 1R-{4-[2R,6S-dimethyl-4-(4-morpholin-4-yl-(1,3,5]triazin-2-yl~
piperazin-1-y~-pyrimidin-2-Y1}-ethanol; 1R-(4-(4-(4-rr~thoxy-6-methyl-[1.3,5]triazin-2-yl)-2R,6S-dimethy(-piperazin-1-yfj-Pyrimidin-2-YI}-ethanol; 1 R-[4-(4-(4.6-dimethoxy_ [1.3.51thazin-2-yl~2R,6S~imethy>-piperazin-1-ylj-pyrimidin-2-yl}-ethanol;1 8-{4-[2R,6S-dimethyl-4-(4-phenyl-(1,3,5]triazin-2-yl)-piperazin-1'-ylj-pyrimidin-2-yl}-ethanol;
1 R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yIr3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(2-hydroxymethyl-pyrimidin-4-yl~3S-methyl-PiPe~n-1-Y9-PYnmidin-2-yl}-ethanol; 1R-{4-[4-(2-hydroxymethyl-6-methyl-PYrimidin-4-yl~3S-methyl-piperazin-1-yI]-py-rimidin-2-yl}~thanol;1 R-[4-(3S-methyl-4-oxazolo[5,4-b]pyridin-2-Yl-PiPerazin-1-YIrPYrimidin-2-y(j-ethanol;1R-(4-(3S-methyl-4-oxazolo[4,5-b]pyridin-2-yl-piperazin-1-yl~pyrimidin-2-ylJ-ethanol;1R-j4-(3S-methyl-4-quinoxalin-2-yt-piperazin-1 yl}.pyrimidin-2-yl]~thanot; (4-{4-[2-(1R-hydroxy-ethyl pyimidin-4-yt]-2R,5S-dimethyi-piperazin-1-yl}-pyrimidin-2-y1)-ethanol; 1 R-{4-(4-(4,6-dimethyl-(1.3.5]triazin-2-yly-3R.5S-dimethyl-piperazin-1 yl]-pyrimidin-2-y1}-ethanol:1 R-{4-[3R,5S-~imethyl-4-(4-methyl-phenyl-[1,3,5]triazin-2 yi)-piper3zin-1 yfjpyrimidin-2-yI}-ethanol; 1R-{4-[4-(4-cydcpropyl-[1,3,5]triazin-2-yl~3R,5S-dimethyl-piperazin-1-ylJ-pyrimidin-2-yI}-ethanol;1 R-{4-[4-(4-cydopropyl-[1.3,5jtriaan-2-yl~2R,6S~dimefhyf-piperazin-1-y(]-pyrimidin-2-y(}-ethanol; 1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-~2 yl~
-4?-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yt}-ethanol; 1R-{4-[4-(4-hydroxymethyl-6-phenyl-[1,3.5]triazin-2 ylr2R,6S-dimethyl-piperazin-1-ylj-Pyrimidiri-2-yi}-ethanol; 1 R-{4-[4-(4-methoxy-6-methoxymethyi-[1,3,5]triazin-2 yl~2R,8S-dimethyl-piperazin-1-yl]-pyrimidin-2-yt]-ethanol; 1R-(4-[2R,fiS-dimethyl-4-(4-methyl-[1,3,5jttiazin-2-yt)-piperazin-1-yl]-pyrimidin-2-yl-ethanol;1-{4-[4-(2-acetyl-pyrimidin-4-yl~2R=,6S'-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanone; 1-(-4-{4-[2-(1R-hydroxy.-ethyp pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl)~thanone; 1 R-{4-j4-(4-methoxymethyt-6-phenyl-[1,3,Sj-triazin-2-yl)-2R,6 S-dimethyi-piperazin-1-yl]-pyrimidin-2-yi}-ethanol; and 1 S-(4-{4-[2-(1 R-hydroxy-ethyl)-pyrimidin-4 ylj-2R,6S-dim~thyl-piperazin-1-yf}-pyrimidin-2-yl)~thanol.
A compound of the formula I"
R' ~N
N R' IA
wherein:
R' is C-(OR°°)R'R5, where R°° is independently (C,-C,)alkyl, ber~zyl, (C,-C6)alkylcarbonyl or phenyicarbonyl, where said benzyi and said phenyl are optionally substituted with up to three (C,-C,)alkyl, (C,-C,)alkoxy, halo or vitro;
R' and RS are each independently hydrogen, methyl, ethyl or hydroxy-(C,-C,~Ikyl;
RZ is hydrogen, (C,-C,)alkyl or (C,-C,)alkoxy;
R' is a radical of the fom~ula ~ _R' ~ . : Rm ~ , TN N I RZs I
z)aG G, ( z)r 3G~ N
3a N ; N .
R
' R~ ~ , R3~ N , R29 N se ~R
~~'~~'N
Rn R~ _ I
pCTIIB00/00296 R3s R33 33 ~ ~ R37 R \
A_N ~N 0 \ B N /N O
R~ ~ R~
R3s R3s R3a I . Rsn I , R3.
R3s R3' R4Z' Rsz HO R~z' N~R~u R4, R~u R4, R"a E
N N
R3e R3s R~ I R~ ( ' ~sa ' R~~ Y~
a. , Y
R \NiYwRa3 Ras ~ s~ N
~N~R
~s R \ ~Y (CHz)m (CHI)n N
R3m I ' R3n ~ .
R,s/N\ R~
Y' N i \ R43 Ru\N~Y WRaa (CHz)k or N
Rap I N
R3a I _ wherein said radical of formula R'' is substituted by R6,~ R' and R°;
said radical of formula R'° is substituted by R'°, R'9 and R~°;
G, G' and GZ are taken separately and are each hydrogen and R° is hydrogen; (C,-C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,~Ikyl, hydroxy-(C,-C,)alkyl or phenyl optionally independently substituted with up to three hydroxy, hafq, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl or (C,-C,)alkoxy, wherein said (C,-C,)alkyl in the definition of R° and said (C,-C,)alkoxy in the definition of R°are optiona0y and independently substituted with up to five fluoro; R' and R° are each independently hydrogen or (C,-C,)alkyl; or G and G' are taken together and are (C,-C,)alkylene and R6, R', R° and G~ are hydrogen; or G' and Gz are taken together and are (C,-C,)alkylene and R°, R', R° and G are hydrogen;
qis0orl;
X is a covalent bond, -(C=NR'°~, oxycarbonyl, vinylenylcarbonyl, oxy(C,-C,)alkylenylcarbonyl, (C,-C,)alkylenylcarbonyi, (C,-C,)alkenylcarbonyl, thio(C,-C,)alkylenylcarbonyl, vinylenylsulfonyl, sulfinyl-(C,-C,)alkylenylcarbonyl, sulfonyl-(C,-C,)alkylenylcarbonyl or carbonyl(C°-C,)alkylenylcarbonyl; wherein said oxy(C,-C,)alkylenyfcarbonyl, (C,-C,)alkylenylcarbonyl, (C,-C,)alkenylcarbonyf and thio(C,-C,)alkyfenylcarbonyl in the definition of X are each optionally and independently substituted with up to two (C,-C,)alkyl, benzyl or Ar; said vinylenylsulfonyi and said vinyienyicacbonyl in the definition of X are optionally substituted independently on one or two vinylenyi carbons with (C,-C,)alkyl, benzyl or Ar; and said carbonyl(C°-C,)alkylenylcarbonyi in the definition of X is optionally substituted indepedently with up to three (C,-C,)alkyl, benzyl or Ar;
R'° is hydn~gen or (C,-C,)alkyl;
R° is (C.°-C,)cydoalkyl, Ar'-(C°-C,)alkylenyl or (C,-C°)alkyl optionally substituted with up to five fiuoro; provided that when q = 0 and X is a covalent bond, oxycarbonyl or (C,-C,)alkylenylcarbonyl, then R° is not (C,-C°)alkyl;
Ar and Ar' are independently a fully saturated, partially saturated or fully unsaturated five- to eight-membered ring optiona8y having up to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicydic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated 'five- to seven-membered rings, taken independently, optionally, having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricydic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five to seven membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially saturated, fully saturated ring or fully unsaturated monocydic ring, bicydic ring or tricydic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur, Ar and Ar' are optionally independently substituted on carbon or nitrogen, on one ring if the moiety is monocydic, on one or both rings if the moiety is bicydic, or on one, two or three rings if the moiety is tricydic, with up to a total of four substituents independently selected from R", R'~, R'3 and R"; wherein R", R'z, R'3 and R"
are each taken separately and are each independently halo, formyt, (C,-C6)alkoxycarbonyl, (C,-Cs)alkylenyloxycarbonyl, (C,-C,)alkoxy-(C,-C,)alkyt, C(OH)R'5R'6, naphthyl, phenyl, imidazolyl. PY~YI, t~yl, morpholinyi, (Ca-C,)alkylsulfamoyl, N-(Co-C,)alkytcarbarr~yl, N,N-di-(C,-C,~Ikylcarbamoyl, N-phenylcarbamoyl, N-(C,-C,~Ikyl-N-phenylcarbamoyt, N,N-diphenyi carbamoyl, (C,-C,~Ikylcarbonyiamido, (C9-C,)cydoalkytcarbonylamido, phenylcarbonytamido, piperidinyl, pyrrolidinyl, piperazinyl, cyano, benzimidazolyl, amino, anilino, pyrimidyl, oxazolyl, isoxazolyl, tetrazolyl, thienyl, thiazolyt, benzothiazolyl, pyrroty(, pyrazolyt, tetrahydroquinoiyl, tetrahydroisoquinoiyl, benzoxa~oiyl, pyridazinyl, pyridyloxy, pyridylsutfanyl, furanyl, t3-(C,-C,)alkyl-3,t3-diaza{3.2.1)bicydooctyl, 3,5~lioxo-1,2,4-triazinyl, phenoxy, thiophenoxy, (C,-C,)atkylsulfanyl, (C,-C,)alkylsutfonyt, (C~-C,)cydoalkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,~tkoxy optionally substituted with up to five fluoro; said naphthyl, phenyl, pyridyl, piperidinyl, benzimidazolyl; pyrimidyl, thienyt, benzothia~olyl. PY~Iy<.
tetrahydroquinolyl, tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfanyl, furanyl, thiophenoxy, anilino and phenoxy in the definifion of R", R'Z, R" and R" are optionally substituted with up to three substituents independently selected from hydroxy, halo, hydroxy-(C,-C,~lkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,~,~Ikyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the defiri~tion of wo oas9sio rcr~aooioo2~
R". R'~, R" and R" are optionally substituted with up to two subsfttuents independently selected from hydroxy, halo, hydroxy-(C,-C,)atkyl, (C,-C,)atkoxy-(C,-C,)alkyi, (C,-C,)aikyl optionally substituted with up to fnre fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R", S R'2, R" and R" is optionally substituted with up to two substi~ents independently selected from (C,-C,)alkyi; said pyrrolidinyl in the definition of R", Ru, R','~and'R" is optionalty substituted with up to two substituents independently selected from hydroxy, hydroxy-(C,-C,)alkyl, (C,-C,)aikoxy-(C,-C,)alkyi, (C,-C,)alkyi optionally substituted with up to five fluoro and (C,-C,)aikoxy optionally substituted with up to five fluoro; said piperazinyi in the definition of R", R'=, R" and R" is optionally substituted with up to three substituents independently selected from (C,-C,~Ikoxy-(C,-C,~Ikyl;
hydroxy-(C,-C,)alkyl, phenyl, pyridyt, (Co-C,~lkylsulfamoyt, (C,-C,~ikyl optionaliy~
substituted with up to fwe fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro: said triazolyt in the def nition of R", R", R" and R" is optionally substituted with hydroxy, halo, hydroxy-(C,-C')atkyt, (C,-C,~Ikoxy-(C,-C,)alkyi, (C,-C,)aiky! optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said tetrazotyl in the definition of R", R'z, R" and R" is optiona!!y substituted with hydroxy-(C2-C3~iky1 or (C,-C,)aHcyl optionally substituted with up to five fluoro;
and said phenyl and pyridyl which are optionally substituted on piperazine in the definition of R", R'~, R" and R" are optionally substituted with up to three hydroxy, halo, hydroxy-(C,~C,)a)kyl. (C,-C')alkoxy-(C,-C,)alkyl. (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy op6onaliy substituted with up to five fluoro; or R" and R's are taken together on adjacent carbon atoms and are 2S -CH=OC(CHs)ZOCHZ- or -0-(CH~p-O-, and R" and R" are taken separately and are each independently hydrogen or (C,-C'~Ikyt;
pisl,2ot3;
R's and R'6 are taken separately and are each independently hydrogen, (C,-C,~Ikyl optionally substituted with up to five fluoro; or R's and R'6 are taken separately and R'°
is hydrogen arid R'6 is (C,-Cs)cycloalkyl, hydroxy-(C,-C,)alkyi, phenyl, pyridyi, pyrimidyl. thienyt, furanyt, thiazolyl, oxazolyl, imidazolyl, benzothiazolyl or benzoxazolyl; or R's and R'6 are taken together and are (C,-Cs~lkylene;
G', G' and G5 are taken separately and are each hydrogen; r is v0: R'°
is hydrogen, (C,-C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,=C,~Ikyl, hydroxy-(C,-C,~lkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,)atkyl, (C,-C,)alkoxy-(C,-C,)aikyl, (C,-.C,)alkyl or (C,-C,)alkoxy, wherein said (C,-C,)alkyl in the definition of R6 and said (C,-C,)alkoxy in the definition of RB are optionally and independently substituted .with up to five fluoro; and R'° and R~° are each independently (C,-C,)altcyt; or G', G' and G5 are taken separately and are each hydrogen; r is 1; R'°
is hydrogen, (C,-C,)atkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,)alkyl, hydroxy-(C,-C,)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyt. (C,-C,~Ikyl or (C,-C,)alkoxy, wherein said (C,-C,)aikyl in'the definition of R6 and said (C,-C,)alkoxy in the definition of Rbare optionally and independenfly substituted with up to five_fiuoro; and R" and R~° are each independently hydrogen or (C,-C,)a(kyl; or G' and G' are taken together and are (C,-C,)alkylene; r is 0 or 1; arui R'°, R", R~° and GS are hydrogen; or G' and G5 are taken together and are (C,-C,)alkylene; r is 0 or 1; and R'°, R'°, Rm and G' are hydrogen;
R" is SOxNR~'R~, CONRZ'R~, (C,-C6)alkoxycarbonyl,. (C,-C6)atkylcarbonyl, Arz-carbonyl, (C;-C6)atkylsulfonyl, (C,-C6)a!lcylsulfinyl, Arz-sulfonyl, Ars-sufinyl and (C,-C6)alkyl:
R2' and R~ are taken separately and are each independently selected from hydrogen, (C,-C°)alkyl, (C3-C,)cydoalkyt and Arz-(Co-C,)alkylenyl; or R~' and R~ are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyt, piperazinyl, morphoUnyl, azepinyl, azabicyGo[3.2.2jnonanyl, azabicydo[2.2.1 jheptyl, fi,7-dihydro-SH-dibenzo[c,ejazepinyl,1,2,3,4-tetrahydro-isoquinolyt or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of RZ' and R~ is optionally substduted independently with one substituent selected from hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)aikoxy-(C,-C,~Ikyl, (C,-G,)atkyl optionally substituted with up to free fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl,~azepinyl in the definition of R=' and R~ are optionalhr substituted independently with up to two substituents independently selected 'from hydroxy, WO 00/59510 PC'f/IB00/00296 amino, hydroxy-(C,-C,)aikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~ikyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of Rz' and R~ is optionally substituted with up to two substituents independently selected from fiydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-6 (C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definition of,R~' and R~ is optionally substituted independently with up to three substituents independently selected from phenyl, pyridyl, pyrimidyl, (C,-C,)alkoxyca~bonyf and (C,-C,)alkyl optionally substituted with up to five fluoro; said 7,2,3,4-tetrahydro-isoquinolyl and said 5,6,7,8-tetrahydropyrido[4,3-dJpyrtmidy! in the definition of R2' and R~ are optionally substituted independently with up to three substituents independently selected from hydroxy, amino, halo, hydroxy-(C,-C,~lkyt, .(C,-C,~tkoxy-(C,-C,)alkyt, (C,-C,~Ikyl optionally substituted with up to flue fluoro and (C,-C,~lkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-SH-dibenzo[c,e)azepinyl in the definition of Rz' and R~ is optionally substituted with up to four substituents independently selected from hydroxy, amino, halo, hydroxy-(C,-C,~ltcyt, (C,-C;)afkoxy~C,=C,)atiryl, (C,-C,)alkyl optionally substituted with up to fnre fluoro and (C,-C,~Ikoxy optionally substituted with up to fnre fluoro; said pyrimidyl; pyridyl and phenyl which are optionally substituted on said piperazine in the definition of R2' and R~ is optionally substituted: with up to three substituents selected from hydroxy, amino, hydroxy-(C,-C,)atkyt, (C,-C,)alkoxy-~C,-C,~Ikyt, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to flue fluoro;
Ar2 is independently defined as set forth for Ar and Ar' above;
said Are is optionally independently substituted as set forth for Ar and Ar' above;
R~ is CONR~'R~ or S02R~'R~, wherein R~ is hydrogen (C,-C,~tkyt or Ar'-(C,p-C,~Ikyienyi and R~ is Ar'-(Co-C,)atkylenyl; provided that when Ar' is phenyl, naphthyl or biphenyl, then R~' cannot be CONR~R~ where R~ is hydrogen or Ar' and R~° is R~' is hydrogen, (C,-C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,~IkYI;
hydroxy-(C,-C,)alkyl or phenyl optionally independenby substituted with up to three hydroxy, halo, hydroxy-(C,-C,~alkyl, (C,-C,)alkoxy-(C,-C,)alkyi. (C,"C,~Ikyl or (C,-C,~Ikoxy, wherein said (C,-C,)alkyl in the defenition of R° and said (C,-C,)alkoxy in the definition of R° are optionally and independently substituted with up to flue fluoro;
WO 00/59510 pCTIIB00100296 -5b-Ar' is independently defined as set forth for Ar and Ar' above; ' said Ar' is optionally independently substituted as set forth for Ar and Ar' above;
RZ' is hydrogen or (C,-C,)alkyl;
R~° and R~ are each independently hydrogen,, hydroxy,, halo, hydroxy-(C,-C,~Ikyl, (C,-C,}alkoxy-(C,-C,)alkyl, (C,-C,~Iky! optionally substituted with up to five fluoro, (C,-C,~lkoxy optionally substituted with up to five fluoro, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S02NR'°R", CONR'°R" or NR'°R";
said thienyl, pyrimidyt, furanyl, thiazolyi and oxazolyl in the definition of R~° and R~ are op~ona8y substituted by up to two hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-i 0 (C,-C,)alkyl, (C,~C,)alkyl optionally substituted with up to five fluoro or (C,-C,~lkoxy optionally substituted with up to five fluoro; said phenyl, pyridyl, phenoxy and thiophenoxy in the definition of R" and R~ are optionally substituted by up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,~lkoxy (C,-C,)alkyt, (C,-C,~Ikyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
R'° and R" are each independently hydrogen, (C,-C,)alkyl, (C,-C,)cydoalky! or phenyl, said phenyl is optionally substituted with up to three hydroxy, halo, hydroxy-(C,-C,}alkyl, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,~Ikyl opfronally substituted with up to five fluoro or (C,-C,~lkoxy optionally substituted with up to five fluoco; or R'° and R" are taken together with the nitrogen to which they are attached to form indolinyt, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; said pyrrolidinyl and piperidinyt in the definition of R'° and R" are optionally substituted with up to two hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-{C,-C,)alkyl, {C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,}alkoxy optionally substituted with up to five fluoro; said indotinyl and piperazinyl in the definition of R'° and R" are optionally substituted with up to three hydroxy, amino, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,~alkyl, (C,-C,}atkoxycarbonyl, (C,-C,jalkyl optionally subst~rted with up to five fluoro of (C,-C,)alkoxy optionally substituted with up to five fluoro; said morphotinyl in the deftnition of R'° and R" is optionally substituted with up to two substituents independently selected from hydroxy-(C,-C,)alkyl, {C,-C,~lkoxy-{C,-C,~ikyl. (C,-C,~Ikyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro;
A is N optionally substituted with hydrogen or (C,-C,~Ikyl and B is carbonyl;
or WO 00/59510 pCT/IB00/00296 -5ti-A is carbonyl and 8 is N optionally substituted with hydrogen or,(C,-C,)alkyl;
R'~ is hydrogen or (C,-C,)alkyk R" is phenyl, PYddYI. pYri~dYl, thiazolyl, oxazofyl. benzyi, quinoiyl, isoquinoiyl, phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyi or benzothienyl;
said phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl, phthatizinyi, quinoxanlyl, benzothiazoyl, berizoxazolyl, benzofuranyi and 4enzothienyl in the definition of R" are optionally substituted with up to three phenyl, phenoxy, NR~'R'~, halo; hydroxy, hydroxy-(C,-C.)alkyl, (C,-C.)alkoxy-(C,-C.~Ikyl, (C,-C.~Ikyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to fnre fluoro;
R~' and R'~ are each independently hydrogen, (C,-C, alkyl), phenyl or phenylsutfonyt;
said phenyl and phenylsulfonyl in the definition of R" and R'~ are optionally substituted with up to three halo, hydroxy, (C,-C,~Ikyl optionally substituted with up to five fluoro or (C,-C,)aikoxy optionally substituted with up to five fluoro;
D is CO, CHOH or CHI;
E is O, NH or S;
R'~ and R" are taken separately and are each independently hydrogen, halo, cyano, hydroxy, amino. (C,-C6)alkylamino, di-(C,-Cs~lkylamino, pyrrolidino, pipeddino, morpholino, (C,-C,~tkoxy-(C,-C,)atkyl, hYdroxY-(C,-C.~lkyl, Ar''. (C,-C.)alkyl optionally substituted with up to five fluoro or (C,-C,~Ikoxy optionally substituted with up to five fluoro;
R'°, R'~ and R'° are each independently hydrogen or (C,-C,}-alley!;
Ar is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl;
said Ar~ being optionally substituted with up to three hydroxy, (C,-C,~Ikoxy-(C,-C,~Ikyle halo, hydroxy-(C,-C,~lkyl, (C,-C,~Ikyl optionally substituted with up to 5ve fluoro or (C,-C,~Ikoxy optionally substituted with up to five fluoro; or R'~ and R" are taken together on adjacent carbon atoms and are -O-(CHI,-O-;
tisl,2or3;
Y is (CZ-Cs~lkylene:
R", R'S and R'° are each independently hydrogen or (C,-C,)alkyl;
m and n are each independently 1, 2 or 3, provided that the sum of m and n is 2, 3 or 4;
k is 0,' 1, 2, 3 or 4;
Y' is a covalent bond, carbonyl, suffonyl or oxycarbonyt;
R" is (C,-C,)cydoatkyi, Ar5-(Co-C,jalkylenyt, NR"R'° or (C,-C6)alkyl optionally ' ' substituted with one to five fluoro; provided that when Y' is a covalent bond or oxycarbonyl, then R" is not NR"R'°;
R" and R'° are taken separately and are each independently selected from hydrogen, Ars, (C,-Ce)alkyl and Ars (C4-C,)alkylenyt; or R" and R'° are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrroiidinyl, pipecidinyl, .piperazinyl, mo~holinyl, azepinyl, azabicyclo[3.2.2]nonanyl, azabicydo[2.2.t]heptyl,1,2.3,4-tetrahydroisoquinoiyt, 6,7-111 dihydro-5H-dibenzo[c,e]azepinyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyi;said azetidinyt in the deftnition of R" and R'° are optionally substituted with one hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)aikoxy-(C,-C,)alkyl, (C,-C,)alkyl optio~aliy substituted with up to five fluoro or (C,-C,)aikoxjr optionally substituted with up to five fluoro; said pyrroiidinyl, piperidiny! and azeptnyl in the definition of R"
and R'° are optionally substituted with up to two hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)aikyl, (C,-C,)alkyl optionally substituted with up to fire fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyt in the definition of R" and R'° is optionally substituted with up to two substituents independently selected from hydroxy-(C,-C,)alkyl, (C,-C,)atkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,~alkoxy optionally substituted with up to five fluoro; said piperazinyl, 1,2,3,4-tetrdhydroisoquinoiyl artd 5,8,7,8-tetrahydro[4,3-d]pyrimidyl in the definition of R" and R'° are optionally substituted with up to three hydroxy, amino, Nato, hydroxy-(C,-C,)atkyl, (C,-C4)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)atkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c:e]azepinyl in the definition of R"
and R'° are optionally substituted with up to four hydroxy, amino, halo, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,)aikyt. (C,-C,)alkyi optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
Ar5 is independently defined as set forth for Ar and Ar' above;
3t? Ar5 is optionally independently substituted as set forth for Ar and Ar' above;
R'~ and R'~ are independently hydrogen, (C,-C,jcydoaikyl, Ars-(Co-C3~ikyleny, Ata-(C=-C,~Ikenyl, Arb-carbonyl or (C,-C~alkyf optionally substituted with up to five fluoro;
Ar6 is independently de5ned as set forth for Ar and Ar' above;
WO 00/59510 pCT/IB0010029b Ar° is optionally independently substituted as set forth for Ar and Ar' above; and R" and R"' are each independently hydrogen or (C,=tr,~lkyl.
A compound of formula 1" selected from 1 R-(4-{4-[2-(1 R-butyryloxy-ethyl}-pyrimidin-4-yt]-2R,6S-dimethyl-piperazinyl-yl}-pyrimidin-2-yl)-ethyl butyrate;
{4-[4-(4-isopropoxy-8-methyl-[7,3,5]triazin-2-yl)-3R,5S-dimethyf-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[3R,5S-dimethyl-4-(4-phenyl-[1,3,S~ria~zin-2-yl}-piperazin-1-y(]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(4-hydroxymethy!-6-n~ethoxy-j1,3.5]triazin-2-ylr3R.5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-{4-(4-isopropoxy-6-methoxy-[1,3,5]triazin-2-yIr3R.5S~imethyl-piperazin-1-yIj-pYrirrlidin-2-yl}-ethanol; 1R-{4-[4-(4-isopropyl-[1,3,5]triazin-2-yl)-3R,5S~iimethyl-piperazin-1-yt]-pyrimidin-2-yl}-ethanol; 1R~4-[4-(4-ethyl-methoxy-[1,3.5)biazin-2 ylj-3R,5S-dimethyl-piperazin-1-ylj-pyrimidin-2-y(}-ethanol; 1R-{4-[4-(4,6-dimethyl-pyrimidin-2-yl}-2R.6S-dimethyl-piperazin-1 ylj- pyrimidin-2-YI)-ethanol;1R-(4-~4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperazin-1-ylj.pyrimidin-2-yl}-ethanol;
1R-{4-[2R,6S-dimethyl-4~-(4-[1,2,4]triazo!-1-yf-pyrimidin-2-yl~piperazin-1 y(j-pyrimidin-2-ylr ethanol;1 R-(4-[4-(2.6-dimethyl-pyrimidin-4-yly-2R,6S-dimethyl-piperazin-1 y~-pyrimidin-2-yt}-ethanol; 1 R-(4-{4-[2-(1 R-hydroxy~thyl~Pyrimidin-4-yl]-2R.fiS-dimethyl-piperazin-1-Y(}-pYrimidin-2-yl~ethanol;1R-{4-[4-(2-hydroxymethyl-6-methyl-pyrimidin-pC'flIB00100296 WO 00!59510 4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-y1}-ethanol; 1 R-(4-{4-(2-(1 S=hydroxy-ethyI~PYnmidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-PYrimidin-2=yf~ethanot: 1 S-(4-{4-[2-(1 R-hydroxy-ethyl~Pyrimidin-4-YI)-2R,6S-dimethyl-piperazin-1-yl}-Pyrimidin-2-yl~
ethanol; 1-{4-[4-(2-acetyl-pyrimidin~-yl)-2R,6S-dimethyl-piperazin-1-YI]-pyrimidin-2-yl}-ethanone; 1 RS-(4-{4-[2-(1 RS-hydroxy-ethyl)-pyrimidin-4-ylj-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl~-ethanol; (4-(4-(2-(1R-hydroxy-ethyl)-pyrimidin-4-y1]-3R,5S-dimethyf-piperazin-1-yl)-pyrimidin-2-yl~-ethanone; 1R-{4-[2R,6S-dimethyl-4-(2-morpholin-4-yl-pyrimidin-4-yl)-piperazin-1-yQ-pyrimidin-2-yl)-ethanol; 1 R-(4-{2R,6S-dimethyl-4-(2-{4-methyl-piperazin-1 yl}=pyrimidin-4-yl]-piperazin-1-yl}-pyimidin-2-yl~
ethanol; 1 R~4-[2R,6S-dimethy!-4-(2-[1,2,4]triazol-1-yl-pyrimidin-4-yl)-Piperazirrl-yl]-pyrimidin-2-yi)ethanol;1R-(4-{4-(2-(1R-hydroxy-ethyl)-pyrimidin-4-ylj-2R,fiR-dimethyl-piperazin-1-yl}-pyrimidin-2-yl~ethanol;1 R-(4-{4-[2-(4-ethyl-piperazin-1 yl~pyrimidin-4-yQ-2R.6S~imethyl-piperazin-1-yl}-pyrimidin-2 yl~ethanol; 1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-imidazol-1-ylrpyrimidin-4-ytj-piperazin-1 yl}-pyrimidin-2-yl}-ethanol; 18-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl~Pyrimidin-4-yt]-2R.6S-dimethyl-piperazin-1-yl}-pyrimidin-2-y1)-ethanol; 1R-{4-[2R,6S-dimethyl-4-(4-morpholin-4-yl-(1,3,5]triazin-2-yl~
piperazin-1-y~-pyrimidin-2-Y1}-ethanol; 1R-(4-(4-(4-rr~thoxy-6-methyl-[1.3,5]triazin-2-yl)-2R,6S-dimethy(-piperazin-1-yfj-Pyrimidin-2-YI}-ethanol; 1 R-[4-(4-(4.6-dimethoxy_ [1.3.51thazin-2-yl~2R,6S~imethy>-piperazin-1-ylj-pyrimidin-2-yl}-ethanol;1 8-{4-[2R,6S-dimethyl-4-(4-phenyl-(1,3,5]triazin-2-yl)-piperazin-1'-ylj-pyrimidin-2-yl}-ethanol;
1 R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yIr3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol; 1R-{4-[4-(2-hydroxymethyl-pyrimidin-4-yl~3S-methyl-PiPe~n-1-Y9-PYnmidin-2-yl}-ethanol; 1R-{4-[4-(2-hydroxymethyl-6-methyl-PYrimidin-4-yl~3S-methyl-piperazin-1-yI]-py-rimidin-2-yl}~thanol;1 R-[4-(3S-methyl-4-oxazolo[5,4-b]pyridin-2-Yl-PiPerazin-1-YIrPYrimidin-2-y(j-ethanol;1R-(4-(3S-methyl-4-oxazolo[4,5-b]pyridin-2-yl-piperazin-1-yl~pyrimidin-2-ylJ-ethanol;1R-j4-(3S-methyl-4-quinoxalin-2-yt-piperazin-1 yl}.pyrimidin-2-yl]~thanot; (4-{4-[2-(1R-hydroxy-ethyl pyimidin-4-yt]-2R,5S-dimethyi-piperazin-1-yl}-pyrimidin-2-y1)-ethanol; 1 R-{4-(4-(4,6-dimethyl-(1.3.5]triazin-2-yly-3R.5S-dimethyl-piperazin-1 yl]-pyrimidin-2-y1}-ethanol:1 R-{4-[3R,5S-~imethyl-4-(4-methyl-phenyl-[1,3,5]triazin-2 yi)-piper3zin-1 yfjpyrimidin-2-yI}-ethanol; 1R-{4-[4-(4-cydcpropyl-[1,3,5]triazin-2-yl~3R,5S-dimethyl-piperazin-1-ylJ-pyrimidin-2-yI}-ethanol;1 R-{4-[4-(4-cydopropyl-[1.3,5jtriaan-2-yl~2R,6S~dimefhyf-piperazin-1-y(]-pyrimidin-2-y(}-ethanol; 1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-~2 yl~
-4?-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yt}-ethanol; 1R-{4-[4-(4-hydroxymethyl-6-phenyl-[1,3.5]triazin-2 ylr2R,6S-dimethyl-piperazin-1-ylj-Pyrimidiri-2-yi}-ethanol; 1 R-{4-[4-(4-methoxy-6-methoxymethyi-[1,3,5]triazin-2 yl~2R,8S-dimethyl-piperazin-1-yl]-pyrimidin-2-yt]-ethanol; 1R-(4-[2R,fiS-dimethyl-4-(4-methyl-[1,3,5jttiazin-2-yt)-piperazin-1-yl]-pyrimidin-2-yl-ethanol;1-{4-[4-(2-acetyl-pyrimidin-4-yl~2R=,6S'-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanone; 1-(-4-{4-[2-(1R-hydroxy.-ethyp pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl)~thanone; 1 R-{4-j4-(4-methoxymethyt-6-phenyl-[1,3,Sj-triazin-2-yl)-2R,6 S-dimethyi-piperazin-1-yl]-pyrimidin-2-yi}-ethanol; and 1 S-(4-{4-[2-(1 R-hydroxy-ethyl)-pyrimidin-4 ylj-2R,6S-dim~thyl-piperazin-1-yf}-pyrimidin-2-yl)~thanol.
A compound of the formula I"
R' ~N
N R' IA
wherein:
R' is C-(OR°°)R'R5, where R°° is independently (C,-C,)alkyl, ber~zyl, (C,-C6)alkylcarbonyl or phenyicarbonyl, where said benzyi and said phenyl are optionally substituted with up to three (C,-C,)alkyl, (C,-C,)alkoxy, halo or vitro;
R' and RS are each independently hydrogen, methyl, ethyl or hydroxy-(C,-C,~Ikyl;
RZ is hydrogen, (C,-C,)alkyl or (C,-C,)alkoxy;
R' is a radical of the fom~ula ~ _R' ~ . : Rm ~ , TN N I RZs I
z)aG G, ( z)r 3G~ N
3a N ; N .
R
' R~ ~ , R3~ N , R29 N se ~R
~~'~~'N
Rn R~ _ I
pCTIIB00/00296 R3s R33 33 ~ ~ R37 R \
A_N ~N 0 \ B N /N O
R~ ~ R~
R3s R3s R3a I . Rsn I , R3.
R3s R3' R4Z' Rsz HO R~z' N~R~u R4, R~u R4, R"a E
N N
R3e R3s R~ I R~ ( ' ~sa ' R~~ Y~
a. , Y
R \NiYwRa3 Ras ~ s~ N
~N~R
~s R \ ~Y (CHz)m (CHI)n N
R3m I ' R3n ~ .
R,s/N\ R~
Y' N i \ R43 Ru\N~Y WRaa (CHz)k or N
Rap I N
R3a I _ wherein said radical of formula R'' is substituted by R6,~ R' and R°;
said radical of formula R'° is substituted by R'°, R'9 and R~°;
G, G' and GZ are taken separately and are each hydrogen and R° is hydrogen; (C,-C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,~Ikyl, hydroxy-(C,-C,)alkyl or phenyl optionally independently substituted with up to three hydroxy, hafq, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl or (C,-C,)alkoxy, wherein said (C,-C,)alkyl in the definition of R° and said (C,-C,)alkoxy in the definition of R°are optiona0y and independently substituted with up to five fluoro; R' and R° are each independently hydrogen or (C,-C,)alkyl; or G and G' are taken together and are (C,-C,)alkylene and R6, R', R° and G~ are hydrogen; or G' and Gz are taken together and are (C,-C,)alkylene and R°, R', R° and G are hydrogen;
qis0orl;
X is a covalent bond, -(C=NR'°~, oxycarbonyl, vinylenylcarbonyl, oxy(C,-C,)alkylenylcarbonyl, (C,-C,)alkylenylcarbonyi, (C,-C,)alkenylcarbonyl, thio(C,-C,)alkylenylcarbonyl, vinylenylsulfonyl, sulfinyl-(C,-C,)alkylenylcarbonyl, sulfonyl-(C,-C,)alkylenylcarbonyl or carbonyl(C°-C,)alkylenylcarbonyl; wherein said oxy(C,-C,)alkylenyfcarbonyl, (C,-C,)alkylenylcarbonyl, (C,-C,)alkenylcarbonyf and thio(C,-C,)alkyfenylcarbonyl in the definition of X are each optionally and independently substituted with up to two (C,-C,)alkyl, benzyl or Ar; said vinylenylsulfonyi and said vinyienyicacbonyl in the definition of X are optionally substituted independently on one or two vinylenyi carbons with (C,-C,)alkyl, benzyl or Ar; and said carbonyl(C°-C,)alkylenylcarbonyi in the definition of X is optionally substituted indepedently with up to three (C,-C,)alkyl, benzyl or Ar;
R'° is hydn~gen or (C,-C,)alkyl;
R° is (C.°-C,)cydoalkyl, Ar'-(C°-C,)alkylenyl or (C,-C°)alkyl optionally substituted with up to five fiuoro; provided that when q = 0 and X is a covalent bond, oxycarbonyl or (C,-C,)alkylenylcarbonyl, then R° is not (C,-C°)alkyl;
Ar and Ar' are independently a fully saturated, partially saturated or fully unsaturated five- to eight-membered ring optiona8y having up to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicydic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated 'five- to seven-membered rings, taken independently, optionally, having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricydic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five to seven membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially saturated, fully saturated ring or fully unsaturated monocydic ring, bicydic ring or tricydic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur, Ar and Ar' are optionally independently substituted on carbon or nitrogen, on one ring if the moiety is monocydic, on one or both rings if the moiety is bicydic, or on one, two or three rings if the moiety is tricydic, with up to a total of four substituents independently selected from R", R'~, R'3 and R"; wherein R", R'z, R'3 and R"
are each taken separately and are each independently halo, formyt, (C,-C6)alkoxycarbonyl, (C,-Cs)alkylenyloxycarbonyl, (C,-C,)alkoxy-(C,-C,)alkyt, C(OH)R'5R'6, naphthyl, phenyl, imidazolyl. PY~YI, t~yl, morpholinyi, (Ca-C,)alkylsulfamoyl, N-(Co-C,)alkytcarbarr~yl, N,N-di-(C,-C,~Ikylcarbamoyl, N-phenylcarbamoyl, N-(C,-C,~Ikyl-N-phenylcarbamoyt, N,N-diphenyi carbamoyl, (C,-C,~Ikylcarbonyiamido, (C9-C,)cydoalkytcarbonylamido, phenylcarbonytamido, piperidinyl, pyrrolidinyl, piperazinyl, cyano, benzimidazolyl, amino, anilino, pyrimidyl, oxazolyl, isoxazolyl, tetrazolyl, thienyl, thiazolyt, benzothiazolyl, pyrroty(, pyrazolyt, tetrahydroquinoiyl, tetrahydroisoquinoiyl, benzoxa~oiyl, pyridazinyl, pyridyloxy, pyridylsutfanyl, furanyl, t3-(C,-C,)alkyl-3,t3-diaza{3.2.1)bicydooctyl, 3,5~lioxo-1,2,4-triazinyl, phenoxy, thiophenoxy, (C,-C,)atkylsulfanyl, (C,-C,)alkylsutfonyt, (C~-C,)cydoalkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,~tkoxy optionally substituted with up to five fluoro; said naphthyl, phenyl, pyridyl, piperidinyl, benzimidazolyl; pyrimidyl, thienyt, benzothia~olyl. PY~Iy<.
tetrahydroquinolyl, tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfanyl, furanyl, thiophenoxy, anilino and phenoxy in the definifion of R", R'Z, R" and R" are optionally substituted with up to three substituents independently selected from hydroxy, halo, hydroxy-(C,-C,~lkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,~,~Ikyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the defiri~tion of wo oas9sio rcr~aooioo2~
R". R'~, R" and R" are optionally substituted with up to two subsfttuents independently selected from hydroxy, halo, hydroxy-(C,-C,)atkyl, (C,-C,)atkoxy-(C,-C,)alkyi, (C,-C,)aikyl optionally substituted with up to fnre fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R", S R'2, R" and R" is optionally substituted with up to two substi~ents independently selected from (C,-C,)alkyi; said pyrrolidinyl in the definition of R", Ru, R','~and'R" is optionalty substituted with up to two substituents independently selected from hydroxy, hydroxy-(C,-C,)alkyl, (C,-C,)aikoxy-(C,-C,)alkyi, (C,-C,)alkyi optionally substituted with up to five fluoro and (C,-C,)aikoxy optionally substituted with up to five fluoro; said piperazinyi in the definition of R", R'=, R" and R" is optionally substituted with up to three substituents independently selected from (C,-C,~Ikoxy-(C,-C,~Ikyl;
hydroxy-(C,-C,)alkyl, phenyl, pyridyt, (Co-C,~lkylsulfamoyt, (C,-C,~ikyl optionaliy~
substituted with up to fwe fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro: said triazolyt in the def nition of R", R", R" and R" is optionally substituted with hydroxy, halo, hydroxy-(C,-C')atkyt, (C,-C,~Ikoxy-(C,-C,)alkyi, (C,-C,)aiky! optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said tetrazotyl in the definition of R", R'z, R" and R" is optiona!!y substituted with hydroxy-(C2-C3~iky1 or (C,-C,)aHcyl optionally substituted with up to five fluoro;
and said phenyl and pyridyl which are optionally substituted on piperazine in the definition of R", R'~, R" and R" are optionally substituted with up to three hydroxy, halo, hydroxy-(C,~C,)a)kyl. (C,-C')alkoxy-(C,-C,)alkyl. (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy op6onaliy substituted with up to five fluoro; or R" and R's are taken together on adjacent carbon atoms and are 2S -CH=OC(CHs)ZOCHZ- or -0-(CH~p-O-, and R" and R" are taken separately and are each independently hydrogen or (C,-C'~Ikyt;
pisl,2ot3;
R's and R'6 are taken separately and are each independently hydrogen, (C,-C,~Ikyl optionally substituted with up to five fluoro; or R's and R'6 are taken separately and R'°
is hydrogen arid R'6 is (C,-Cs)cycloalkyl, hydroxy-(C,-C,)alkyi, phenyl, pyridyi, pyrimidyl. thienyt, furanyt, thiazolyl, oxazolyl, imidazolyl, benzothiazolyl or benzoxazolyl; or R's and R'6 are taken together and are (C,-Cs~lkylene;
G', G' and G5 are taken separately and are each hydrogen; r is v0: R'°
is hydrogen, (C,-C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,=C,~Ikyl, hydroxy-(C,-C,~lkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,)atkyl, (C,-C,)alkoxy-(C,-C,)aikyl, (C,-.C,)alkyl or (C,-C,)alkoxy, wherein said (C,-C,)alkyl in the definition of R6 and said (C,-C,)alkoxy in the definition of RB are optionally and independently substituted .with up to five fluoro; and R'° and R~° are each independently (C,-C,)altcyt; or G', G' and G5 are taken separately and are each hydrogen; r is 1; R'°
is hydrogen, (C,-C,)atkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,)alkyl, hydroxy-(C,-C,)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyt. (C,-C,~Ikyl or (C,-C,)alkoxy, wherein said (C,-C,)aikyl in'the definition of R6 and said (C,-C,)alkoxy in the definition of Rbare optionally and independenfly substituted with up to five_fiuoro; and R" and R~° are each independently hydrogen or (C,-C,)a(kyl; or G' and G' are taken together and are (C,-C,)alkylene; r is 0 or 1; arui R'°, R", R~° and GS are hydrogen; or G' and G5 are taken together and are (C,-C,)alkylene; r is 0 or 1; and R'°, R'°, Rm and G' are hydrogen;
R" is SOxNR~'R~, CONRZ'R~, (C,-C6)alkoxycarbonyl,. (C,-C6)atkylcarbonyl, Arz-carbonyl, (C;-C6)atkylsulfonyl, (C,-C6)a!lcylsulfinyl, Arz-sulfonyl, Ars-sufinyl and (C,-C6)alkyl:
R2' and R~ are taken separately and are each independently selected from hydrogen, (C,-C°)alkyl, (C3-C,)cydoalkyt and Arz-(Co-C,)alkylenyl; or R~' and R~ are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyt, piperazinyl, morphoUnyl, azepinyl, azabicyGo[3.2.2jnonanyl, azabicydo[2.2.1 jheptyl, fi,7-dihydro-SH-dibenzo[c,ejazepinyl,1,2,3,4-tetrahydro-isoquinolyt or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of RZ' and R~ is optionally substduted independently with one substituent selected from hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)aikoxy-(C,-C,~Ikyl, (C,-G,)atkyl optionally substituted with up to free fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyl,~azepinyl in the definition of R=' and R~ are optionalhr substituted independently with up to two substituents independently selected 'from hydroxy, WO 00/59510 PC'f/IB00/00296 amino, hydroxy-(C,-C,)aikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~ikyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of Rz' and R~ is optionally substituted with up to two substituents independently selected from fiydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-6 (C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definition of,R~' and R~ is optionally substituted independently with up to three substituents independently selected from phenyl, pyridyl, pyrimidyl, (C,-C,)alkoxyca~bonyf and (C,-C,)alkyl optionally substituted with up to five fluoro; said 7,2,3,4-tetrahydro-isoquinolyl and said 5,6,7,8-tetrahydropyrido[4,3-dJpyrtmidy! in the definition of R2' and R~ are optionally substituted independently with up to three substituents independently selected from hydroxy, amino, halo, hydroxy-(C,-C,~lkyt, .(C,-C,~tkoxy-(C,-C,)alkyt, (C,-C,~Ikyl optionally substituted with up to flue fluoro and (C,-C,~lkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-SH-dibenzo[c,e)azepinyl in the definition of Rz' and R~ is optionally substituted with up to four substituents independently selected from hydroxy, amino, halo, hydroxy-(C,-C,~ltcyt, (C,-C;)afkoxy~C,=C,)atiryl, (C,-C,)alkyl optionally substituted with up to fnre fluoro and (C,-C,~Ikoxy optionally substituted with up to fnre fluoro; said pyrimidyl; pyridyl and phenyl which are optionally substituted on said piperazine in the definition of R2' and R~ is optionally substituted: with up to three substituents selected from hydroxy, amino, hydroxy-(C,-C,)atkyt, (C,-C,)alkoxy-~C,-C,~Ikyt, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to flue fluoro;
Ar2 is independently defined as set forth for Ar and Ar' above;
said Are is optionally independently substituted as set forth for Ar and Ar' above;
R~ is CONR~'R~ or S02R~'R~, wherein R~ is hydrogen (C,-C,~tkyt or Ar'-(C,p-C,~Ikyienyi and R~ is Ar'-(Co-C,)atkylenyl; provided that when Ar' is phenyl, naphthyl or biphenyl, then R~' cannot be CONR~R~ where R~ is hydrogen or Ar' and R~° is R~' is hydrogen, (C,-C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,~IkYI;
hydroxy-(C,-C,)alkyl or phenyl optionally independenby substituted with up to three hydroxy, halo, hydroxy-(C,-C,~alkyl, (C,-C,)alkoxy-(C,-C,)alkyi. (C,"C,~Ikyl or (C,-C,~Ikoxy, wherein said (C,-C,)alkyl in the defenition of R° and said (C,-C,)alkoxy in the definition of R° are optionally and independently substituted with up to flue fluoro;
WO 00/59510 pCTIIB00100296 -5b-Ar' is independently defined as set forth for Ar and Ar' above; ' said Ar' is optionally independently substituted as set forth for Ar and Ar' above;
RZ' is hydrogen or (C,-C,)alkyl;
R~° and R~ are each independently hydrogen,, hydroxy,, halo, hydroxy-(C,-C,~Ikyl, (C,-C,}alkoxy-(C,-C,)alkyl, (C,-C,~Iky! optionally substituted with up to five fluoro, (C,-C,~lkoxy optionally substituted with up to five fluoro, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S02NR'°R", CONR'°R" or NR'°R";
said thienyl, pyrimidyt, furanyl, thiazolyi and oxazolyl in the definition of R~° and R~ are op~ona8y substituted by up to two hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-i 0 (C,-C,)alkyl, (C,~C,)alkyl optionally substituted with up to five fluoro or (C,-C,~lkoxy optionally substituted with up to five fluoro; said phenyl, pyridyl, phenoxy and thiophenoxy in the definition of R" and R~ are optionally substituted by up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,~lkoxy (C,-C,)alkyt, (C,-C,~Ikyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
R'° and R" are each independently hydrogen, (C,-C,)alkyl, (C,-C,)cydoalky! or phenyl, said phenyl is optionally substituted with up to three hydroxy, halo, hydroxy-(C,-C,}alkyl, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,~Ikyl opfronally substituted with up to five fluoro or (C,-C,~lkoxy optionally substituted with up to five fluoco; or R'° and R" are taken together with the nitrogen to which they are attached to form indolinyt, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; said pyrrolidinyl and piperidinyt in the definition of R'° and R" are optionally substituted with up to two hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-{C,-C,)alkyl, {C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,}alkoxy optionally substituted with up to five fluoro; said indotinyl and piperazinyl in the definition of R'° and R" are optionally substituted with up to three hydroxy, amino, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,~alkyl, (C,-C,}atkoxycarbonyl, (C,-C,jalkyl optionally subst~rted with up to five fluoro of (C,-C,)alkoxy optionally substituted with up to five fluoro; said morphotinyl in the deftnition of R'° and R" is optionally substituted with up to two substituents independently selected from hydroxy-(C,-C,)alkyl, {C,-C,~lkoxy-{C,-C,~ikyl. (C,-C,~Ikyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro;
A is N optionally substituted with hydrogen or (C,-C,~Ikyl and B is carbonyl;
or WO 00/59510 pCT/IB00/00296 -5ti-A is carbonyl and 8 is N optionally substituted with hydrogen or,(C,-C,)alkyl;
R'~ is hydrogen or (C,-C,)alkyk R" is phenyl, PYddYI. pYri~dYl, thiazolyl, oxazofyl. benzyi, quinoiyl, isoquinoiyl, phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyi or benzothienyl;
said phenyl, pyridyl, pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl, phthatizinyi, quinoxanlyl, benzothiazoyl, berizoxazolyl, benzofuranyi and 4enzothienyl in the definition of R" are optionally substituted with up to three phenyl, phenoxy, NR~'R'~, halo; hydroxy, hydroxy-(C,-C.)alkyl, (C,-C.)alkoxy-(C,-C.~Ikyl, (C,-C.~Ikyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to fnre fluoro;
R~' and R'~ are each independently hydrogen, (C,-C, alkyl), phenyl or phenylsutfonyt;
said phenyl and phenylsulfonyl in the definition of R" and R'~ are optionally substituted with up to three halo, hydroxy, (C,-C,~Ikyl optionally substituted with up to five fluoro or (C,-C,)aikoxy optionally substituted with up to five fluoro;
D is CO, CHOH or CHI;
E is O, NH or S;
R'~ and R" are taken separately and are each independently hydrogen, halo, cyano, hydroxy, amino. (C,-C6)alkylamino, di-(C,-Cs~lkylamino, pyrrolidino, pipeddino, morpholino, (C,-C,~tkoxy-(C,-C,)atkyl, hYdroxY-(C,-C.~lkyl, Ar''. (C,-C.)alkyl optionally substituted with up to five fluoro or (C,-C,~Ikoxy optionally substituted with up to five fluoro;
R'°, R'~ and R'° are each independently hydrogen or (C,-C,}-alley!;
Ar is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl;
said Ar~ being optionally substituted with up to three hydroxy, (C,-C,~Ikoxy-(C,-C,~Ikyle halo, hydroxy-(C,-C,~lkyl, (C,-C,~Ikyl optionally substituted with up to 5ve fluoro or (C,-C,~Ikoxy optionally substituted with up to five fluoro; or R'~ and R" are taken together on adjacent carbon atoms and are -O-(CHI,-O-;
tisl,2or3;
Y is (CZ-Cs~lkylene:
R", R'S and R'° are each independently hydrogen or (C,-C,)alkyl;
m and n are each independently 1, 2 or 3, provided that the sum of m and n is 2, 3 or 4;
k is 0,' 1, 2, 3 or 4;
Y' is a covalent bond, carbonyl, suffonyl or oxycarbonyt;
R" is (C,-C,)cydoatkyi, Ar5-(Co-C,jalkylenyt, NR"R'° or (C,-C6)alkyl optionally ' ' substituted with one to five fluoro; provided that when Y' is a covalent bond or oxycarbonyl, then R" is not NR"R'°;
R" and R'° are taken separately and are each independently selected from hydrogen, Ars, (C,-Ce)alkyl and Ars (C4-C,)alkylenyt; or R" and R'° are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrroiidinyl, pipecidinyl, .piperazinyl, mo~holinyl, azepinyl, azabicyclo[3.2.2]nonanyl, azabicydo[2.2.t]heptyl,1,2.3,4-tetrahydroisoquinoiyt, 6,7-111 dihydro-5H-dibenzo[c,e]azepinyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyi;said azetidinyt in the deftnition of R" and R'° are optionally substituted with one hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)aikoxy-(C,-C,)alkyl, (C,-C,)alkyl optio~aliy substituted with up to five fluoro or (C,-C,)aikoxjr optionally substituted with up to five fluoro; said pyrroiidinyl, piperidiny! and azeptnyl in the definition of R"
and R'° are optionally substituted with up to two hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)aikyl, (C,-C,)alkyl optionally substituted with up to fire fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyt in the definition of R" and R'° is optionally substituted with up to two substituents independently selected from hydroxy-(C,-C,)alkyl, (C,-C,)atkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,~alkoxy optionally substituted with up to five fluoro; said piperazinyl, 1,2,3,4-tetrdhydroisoquinoiyl artd 5,8,7,8-tetrahydro[4,3-d]pyrimidyl in the definition of R" and R'° are optionally substituted with up to three hydroxy, amino, Nato, hydroxy-(C,-C,)atkyl, (C,-C4)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)atkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c:e]azepinyl in the definition of R"
and R'° are optionally substituted with up to four hydroxy, amino, halo, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,)aikyt. (C,-C,)alkyi optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
Ar5 is independently defined as set forth for Ar and Ar' above;
3t? Ar5 is optionally independently substituted as set forth for Ar and Ar' above;
R'~ and R'~ are independently hydrogen, (C,-C,jcydoaikyl, Ars-(Co-C3~ikyleny, Ata-(C=-C,~Ikenyl, Arb-carbonyl or (C,-C~alkyf optionally substituted with up to five fluoro;
Ar6 is independently de5ned as set forth for Ar and Ar' above;
WO 00/59510 pCT/IB0010029b Ar° is optionally independently substituted as set forth for Ar and Ar' above; and R" and R"' are each independently hydrogen or (C,=tr,~lkyl.
A compound of formula 1" selected from 1 R-(4-{4-[2-(1 R-butyryloxy-ethyl}-pyrimidin-4-yt]-2R,6S-dimethyl-piperazinyl-yl}-pyrimidin-2-yl)-ethyl butyrate;
7 R-(4-{4-[2-(1 S-butyryloxy-ethyl~Pyrimidin-4-yt}-2R.6S-dimethyt-piperazin-1-YI}-Pyrimidin-2-yi)-ethyl butyrate:1 S-(4-{4-[2-(1 R-butyiyloxy-ethyl)-pyrimidin-~4-ytj-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethyl butyrate; (E)-1 R-{4-[4-(2-methyl-32-phenyl-aayloyl~piperazin-1-YIJ-Pyrimidin-2-yl}-ethyl acetate; (R~1-[4-(4-quinoxafin-2-yi-piperazin-1-ylrpyrimidin-2-yl]-ethyl acetate;1 R-(4-{4-j2-(1RS-hydroxy-ethyt~
pydmidin-~4-y(]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethyl butyrate;1 RS-(4-{4-[2-(1 R-hydroxy-ethyl)-Pyrimidin-.4-yl)-3R,5S=dimethyl-piperazin-1-YI)-pyrimidin-2-ylj-ethyl butyrate; iR-[4-(3S-methyl-4-oxazolo[5,4-b)pyridin-2-yl-piperdzin-i-yl~pyrimidin-2-yQ-ethyl butyrate; 1R-{4-[3R,5S-dimethyi-4-(4-methyl-6-phenyl-[1,3,5)tria~n-2 yi)-piperazin-1-Yil-PY~midin-2-Yl}-ethyl butyrate: 1R-(4-[4-(4-cYdoProPYi-[~.3,5)hiazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate; 1R-{4..[4.(4-cydopropyf-[1,3,5jtriazin-2-yl)-2R.6S-dimethyt-piperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate; iR-{4-[4-(4,6-ciimethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yt)-PYhmidin-2-YI}-ethyl butyrate;1R-{4-[4-(4-hydroxymethyl-6-phenyl-[1,3,5)triazin-2-yl~
2R.6S-dimethyt-piperazin-1-yi]-pYrimidin-2-y!}-ethyl butyrate: 1R-(4-[4-(4-methoxy-6-methoxymethyl-[1,3,5)triazin-2-yl~-R,6S-dimethyt-piperazin-1 yiJ-pyrimidin-2-yl}-ethyl butyrate; and 1R-{4-[2R,6S-dimethyl~-(4-methyl-[1,3,5)triazin-2-yl~-piperazin-1-ylJ-PY~midin-2-yi)-ethyl butyrate.
This invention is atso directed to a mutual prodnrg of the fomwta te, R' R~
~N
N R' IB
wherein:
R' is C-(OR°')R'R5, wherre R°' is independently an acy! radical of a cartioxyiic add aldose reductase inhibitor, R' and R5 are each independently hydrogen, methyl, ethyl or hydroxy-(C,-C,)alkyl;
RZ is hydrogen, (C,-C,~Ikyl or.(C,~,)alkoxy;
pCT/IB00/00296 radical of the formula R fs a , , , X,~R9 , , , , Rt7 R23 I
~N , ' ) G3N 4 a N
G C Z ~ GAG R2 ~G N N , R~ ~ R3b l ~ R~ I
..
. . R2B v Rzs N Rae / N RZS
R2~ ~ R
R~ N ~ ~ R3f ~ , Rae , , Rs~
R33 R33 y / ~N D
A~N ~ \
B , N /N O
Rs2 ~ , Rs~ . R3a ~Rss . , Rs9 N R3" ' R3' N
R4za R42 R"
R36 HO R4z , R4ta R4t R4ts N 1 R4o R4' E , , R3i N
R3s R3k R
N
R3i ,..,43 R4~ Y1 Y, ~/tt L
N
R ~N,Y~R43 R~~N~Ra4 ,s , ~Ct"~~yCm ~CH~~"
R ~NiY .
3m ~ R3n R R4a /N \ R~
N~Yt~ Ra3 R'4\N~YwRa3 ~C~~k Of R3v ~ Rye wherein said radical of formula R" is substituted by f~,1Z' and R°;
said radical of formula R'° is substituted by R'°, R'9 and R~°;
G, G' and G2 are taken separately and are each hydrogen and R6 is hydrogen, (C,-C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,)alkyi, hydroxy-(C,-C,)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C;)alkoxy-(C,-C,)alkyl, (C,-C,~Ikyl or (C,-C,~tkoxy, wherein said (C,-C,)alkyl in the definition of R6 and~said (C,-C,)alkoxy in the definition of R6 are optionally and.independentfy substituted with up to five fluoro; R' and R° are each t 0 independently hydrogen or (C,-C,~Ikyl; or G and G' are taken together and are (C,-C,)alkytene and R6, R', R° and GZ are hydrogen; or G' and Gz are taken together and are (C,-C3)alkylene and R6, R', R' and G are hydrogen;
1~ qis0orl;
X is a covalent bond, -(C=NR'°)-, oxycarbonyl, vinylenylcarbonyl, oxy(C,-C,)alkylenylcarbonyl, (C,-C,)alkylenyicarbonyl, (C,-C,~Ikenylcart~onyl, thio(C,-C,)aikylenytcarbonyl, vinylenytsulfonyl, sulfinyl-(G,-C,~lkylenylcarbonyl, sulfonyf-(C,-C,)alkylenylcarbonyl or carbonyl(C°-C,)alkylenylcarbonyl; wherein said oxy(C,-20 C,)alkylenylcarbonyl, (C,-C,)alkyfenyicarbonyl, (C,-C,)atkenylcart~onyl and thio(C,-C,)aikyienyicarbonyl in the definition of X are each optionally and independently substituted with up to two (C,-C,)alkyl, benzyl or Ar said vinytenylsulfonyl and said vinylenylcarbonyl in the definition of X are optionally substituted independently on one or two vinyienyl carbons with (C,-C,)alkyl, benzyf or Ar; and said carbonyl(C°-25 C,)alkytenylcarbonyl in the deflri~tion of X is optionally substituted indepedently with up to three (C,-C,)alkyl, benzyl or Ar, R'° is hydrogen or (C,-C,~tkyl;
R' is (C,-C,)cydoalkyl, Ar'-(C°-C~)alkylenyl or (C,-C6~Ikyl optionally substituted with up to five fluoro; provided that when q = 0 and X is a covalent bond, oxycarbonyl or 30 (C,-C,~Ikylenylcarbonyl, then R' is not (C,-Ca~lkyl;
Ar and Ar' are independently a fully saturated, partially saturated or fully unsaturated five- to eight-membered ring optionally having up to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicydic ring consisting of two WO 00159510 PCT/IB00/00~96 fused independently partially saturated, fully saturated or fully unsaturated t'ave- to , seven-membered rings, taken independently, opttonalty having up to four heteroatoms 1 selected independently from riatrogen, sulfur and oxygen, or a tricydic ring consisting of three fused independently partially saturated, ftally saturated or fully unsaturated fare to seven membered rings, taken independently, optionally having up to tour heteroatoms selected independently, from nitrogen, sulfur and oxygen, said partially saturated, fully saturated ring or fully unsaturated monocydic ring, bicydic ring or tricydic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur .
Ar and Ar' are optionally independently substituted on carbon or nitrogen,1on one ring if the moiety is monocydic, on one or both rings if the moiety is bicydic, or on one, two or three rings if the moiety is tricydic, with up to a total of four substituents independently selected from R", R'2, R" and R"; wherein R", R'Z, R" and R" are each taken separately and are each independently halo, formyl, (C,-C6~Ikoxycarbonyl, (C,-C6)alkylenyloxycarbonyl, (C,-C')alkoxy-(C,-C,)alkyl, C(OH)R'SR'6, naphthyl, phenyl, tmidazolyl, pycidyl, triazolyl, morpholinyl, (Co-C')alkylsulfamoyl, N-(Co-C,)alkylcarbamoyl, N,N-di-(C,-C,)alkylcarbamoyl, N-phenytcarbamoyl, N-(C,-C,)alkyl-N-phenylcarbamoyl, N,N-Biphenyl cari~amoyl, (G,-C')alkylcarbonylamido, (C,-C,,)cydoatkylcarbonylamido, phenylcarbonylamido, piperidinyl, pyrrolidinyl, piperazinyl, cyano, benzimidazolyf, amino, anitino, pyrimidyl, oxazolyl, isoxazolyt, tetrazolyl, thienyl, thiazolyl, berazothiazolyl, pyrrolyl, pyrazolyl, tetrahydroquinolyl, tetrahydroisoquinolyf, benzoxazolyl, pyridazinyl, pyridytoxy, pyridylsutfanyl, furanyl, 8-(C,-C')atky(-3,8-diaza[3.2.1)bicydooctyl, 3,S~iioxo-1,2,4-triazinyl, phenoxy, thiophenoxy, (C,-C,)alkylsulfanyl, (C,-C,)altrylsulfonyl, (Cs-C,)cydoalkyl, (C,-C,~Ikyl optionally substituted with up to flue fluoro or (C,-C'~Ikoxy optionally substituted with up to five fluoro; said naphthyl, phenyl, pyaidyl, piperidinyl, benzimidazolYl, pyrimidyl, thienyl, benzothiazolyl. PY~IYI.
tetrahydroquinotyl, tetrahydroisoquinolyl, benzoxazoiyl, pyridazinyl, pyridyloxy, pyridylsutfanyf, furanyl, thiophenoxy, anilino and phenoxy in the definition of R", R'2, R" and R" are optionally substituted with up to three substituents independently selected fiom hydroxy, halo, hydroxy-(C,-C')atkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C4)alkyl optionally substituted with up to fare fluoro and (C,-C')alkoxy optionally substituted with up to five fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazoiyi and pyrazolyl in .the definition of WO 00/59510 PfrTIIB00/00296 R", R'=, R" and R" are optionally substituted with up to two substituents independently selected from hydroxy, halo, hydroxy-(C,fC,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to flue fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R", R'z, R" and R" is optionally substituted with up to two substituents independently selected from (C,-C,)alkyl; said pyrrolidinyl in the definition of R", R'2, R'a and R" is optionally substituted with up to two substituents independently selected from hydroxy, hydroxy-(C,-C3)alkyl, (C,-C,)alkoxy-(C,-C,)afkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five filuoro; said piperazinyl in the definition of R", R'2, R" and R" is optionally substituted with up to three substituents independently selected from (C,-C,~lkoxy-(C,-C,~lkyf;
hydroxy-(C,-C3)alkyl, phenyl, pyridyl, (Co-C,~Ikylsuffamoyl, (C,-C,)alkyl optionally~substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to ftve ftuoro: said triazolyl in the deftnition of R", R'Z, R" and R" is optionally substituted with hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,~Ikyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said tetrazofyl in the definition of R", R'2, R" and R" is optionally substituted with hydroxy-(C2-C3~Ikyi or (C,-C,~Ikyl optionally substituted with up to five fluoro;
and said phenyl and pyridyl which are optionally substituted on piperazine in the definition of R", R'2, R" and R" are optionally substituted with up to three hydroxy, halo, hydroxy-(C,-C,)atkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)atkyl optionally substituted with up to fwe fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; or R" and R'~ are taken together on adjacent carbon atoms and are -CH~OC(CH,)20CH~- or -O-(CHZ)p-O-, and R" and R" are taken separately and are each independently hydrogen or (C,-C,)alkyl;
pisl,2or3;
R'S and R'6 are taken separately and are each independently hydrogen, (C,-C,~Ikyl optionally substituted with up to five fluoro; or R's and R'a are taken separately and R's is hydrogen and R'° is (C,-C6)cycloalkyl, hydroxy-(C,-C~)alkyl, phenyl, pyridyl, PYn~dY<. thienyl, furanyl. thiazolyl, oxazolyl, imidazolyl, benzothiazolyl or benzoxazolyl; or R's and R'6 are taken together and are (C~-C6~lkylene;
wo oois9sio pc~r~sooroo2~
G', G, and GS are taken separately and are each hydrogen; r is 0: R'°
is hydrogen, (C,-C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C4~lkoxy-(C,-C4~Ikyl, hydroxy-(C,-C,)alky! or phenyl optionally independently substituted with up tv three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~Ikyl or (C,-C,~tkoxy, wherein said (C,-C,~tky! in the definition of R6 and said (C,-C,)atkoxy in the definition of R°are optionally and independently substituted with up to five ttuoro; and R'° and, R~° are each independently (C,-C,)alkyl; or G', G' and Gs are taken separately and are each hydrogen; r is 1; R'°
is hydrogen, (C,-C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,)alkyl, hydroxy-(C,-C,)atkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-G,)alkoxy-(C,-C,)alkyi, (C,-C,)alkyl or (C,-C,)atkoxy, wherein said (C,-C,)alkyl in the definition of R° and said (C,-C,)alkoxy in the definition Qf R° are optionally and independently substituted with up to five fluoro; and R'° and R'° are each independently hydrogen or (C,-C,)alkyl; or G' and G' are taken together and are (C,-C,)alkylene; r is 0 or 1; and R'°, R", R~° and G5 are hydrogen; or G' and G5 are taken together and are (C,-C3)alkylene; r is 0 or 1; and R'°, R'°, R~° and G' are hydrogen; , R" is S02NRZ'R~, CONR2'R~, (C,-CB)atkoxycartionyl, (C,-C6)alkyicarbonyl, At=-carbonyl, (C,-C°)alkylsulfonyl, (C,-C°~Ikylsul~nyl, ArZ-sulfonyl, Are-sufinyl and (C,-C°)atkyl, R2' and R~ are taken separately and are each independently selected from hydrogen, (C,-Cs)alkyl, (C,-G,k,Ydoalkyl and Arz-(Co-C,~Ikylenyl: or RZ' and R~ are taken together with the nitrogen atom to which they are attached to form aze6dinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicycto[322]nonanyl, azabicydoj22.1]hepiyl, 6,7-dihydro-SH-dibenzojc,e]azepinyl,1,2,3,4-tetrahydro-isoquinolyl or 5.6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of RZ' and R~ is optionally substituted independently with one substituent selected from hydroxy, amino, hydroxy-(C,-C,)afkyl, (C,-C,)atkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyf, azepinyl in the definition of R~' and R'~ are optionally subst~rted independently with up to two substituents independently selected from trydroxy, pCTIIB00100296 WO 00!59510 amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl. (C,-C,~aikyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of RZ' and R~ is optionally substituted with up to two substituents independent#y selected from hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definition of.R=' and R~ is optionally.substituted independently with up to three substituents independently selected from phenyl, pyridyl, pyrimidyl, (C,-C,)alkoxycarbonyl and (C,-C,~Ikyl optionally substituted with up to five fluoro; said 1,2.3.4-tetrahydro-isoquinolyl and said 5,6,7,8-tetrahydropyrido[4,3-djpyrfmidyl in the definition of R~' and R~ are optionally substituted independently with up to three substituents independently selected from hydroxy, amino, halo; hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and ~(C,-C,)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-SH~ibenzo(c,eJazepinyl in the defnition of RZ' and R~ is optionally substituted with up to four substituents independently selected from hydroxy, amino, halo, hydroxy-(C,-C,)alkyt, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said pyrimidyl, pytidyl and phenyl which are optionally substituted on said piperazine in the definition of R~' and R~ is optionally substituted with up to three substituents selected from hydroxy, amino, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to flue fluoro;
Ar2 is independently defined as set forth for Ar and Ar' above;
said Are is optionally independently substituted as set forth for Ar and Ar' above;
R~' is CONR'~R~ or SO=R~R~, wherein R~ is hydrogen (C,-C,)alkyl or Ar'-(Co-C,)alkylenyt and R~° is Ar'-(C°-C,)alkylenyl; provided that when Ar-' is phenyl, naphthyl or biphenyl, then Ra cannot be CONR~R~ where Rte' is hydrogen or Ar' and R~° is Ar';
R~' is hydrogen, (C,-C,)alkyl, (C,-C,)alkoxycarbonyl. (C,rC,)alkoxy-(C,-C,)alkyl, hydroxy-(C,-C,)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C.)alkyl or (C,-C.)alkoxy. wherein said (C,-C,)alkyl in the definition of R° and said (C,-C,~Ikoxy in the definition of R6 are optionally and independently substituted with up to five fluoro;
WO 00!59510 -fi6-Ar' is independently defined as set forth for Ar and Ar' above;
said A~ is optionally independently substituted as set forth for Ar and Ar' above;
R~' is hydrogen or (C,-C,)alkyl;
R~° and R~ are each independently hydrogen, hydroxy, halo, hydroxy-(C,-C,)alkyl, .
(C,-C,)alkoxy-{C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro, (C,-C,)alkoxy optionally substituted with up to five fluoro, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazofyl, oxazolyl, phenoxy, thiophenoxy, SOzNR'°R", CONR'°R" or NR'°R";
said thienyl, pyrimidyl, furanyl, thiazolyl and oxazofyl in the definition of R~° and R~ are optionally substituted by up to two hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C;-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said.phenyl, pyridyl, phenoxy and thiophenoxy in the definition of R~° and R~ are optionally substituted by up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)a~koxy-(C,-C,)alkyf, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
R'° and R" are each independently hydrogen, (C,-C,)alkyl, (C'-C,kydoalkyl or phenyl, said phenyl is optionally substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,~Ikoxy optionally substituted with up to flue fluoro; or R'° and R" are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; said pyrrolidinyl and piperidinyl in the definition of R'° and R" are optionally substituted with up to two hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)allcyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said indolinyl and piperazinyl in the definition of R'° and R" are optionally substituted with up to three hydroxy, amino, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkyl optionally substituted with up to flue fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R'° and R" is optionally substituted with up to two substituents independently selected from hydroxy-(C,-C,)alkyl, (C,-C,~Ikoxy-{C,-C,)alkyl, (C,-C,~lkyl optionally substituted with up to five fluoro and tC,-C,)alkoxy optionally substituted with up to five fluoro;
A is N optionally substituted with hydrogen or (C,-C,)alkyl and B is carbonyl;
or WO 00!59510 pCTIIB00100296 A is carbonyl and B is N optionally substituted with hydrogen or (C,-C,)alkyl;
R'~ is hydrogen or (C,-C,)alkyl;
R" is phenyl. PY~dYI. PY~midyl, thiazolyl. oxazolyl, benzyl, quinolyl.
isoquinolyl, phthaiizinyl, quinoxanlyl, benzothiazoyl, benzoxazoiyi, benzofuranyl or benzothienyl;
said phenyl, pyridyl, pyrimidyl, thiazoiyl, oxazolyl, benzyl; quinolyl.
isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl and benzothienyl in the definition of R" are optionally substituted with up to three phenyl, ptienoxy, NR"R", halo, hydroxy, hydroxy-~C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to 5ve fluoro;
R" and R's are each~independently hydrogen, (G,-C, alkyl), phenyl or phenyfsulfonyl;
said phenyl and phenytsulfonyl in the definition of R" and R's are optionally substituted with up to three halo, hydroxy, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to flue fluoro;
D is CO, CHOH or CH2;
EisO,NHorS;
R'~ and R" are taken separately and are each independently hydrogen, halo, cyano, hydroxy, amino, (C,-C6)alkylamino, di-(C,-Cs)alkylamino, pyn'olidino, piperidino, morphoiino, (C,-C,~Ikoxy-(C; C,)alkyl, hydroxy-(C,-C,)alkyl, A~', (C,-C,~Ikyl optionally substituted with up to five tluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
R'°, R~ and R'° are each independently hydrogen or (C,-C,~alkyl;
Ar is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl;
said Ar" being optionally substituted with up to three hydroxy, (C,-C,)alkoxy-(C,-C,)alkyl, halo, hydroxy-(C,-C,)alkyi, 7(C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,~Ikoxy optionally substituted with up to five fluoro; or R'~ and R" are taken together on adjacent carbon atoms and are -O-(CH~~-O-;
tisl,2or3;
Y is (Cz-Cs~lkylene;
R", R's and R's are each independently hydrogen or (C,-C,~Ikyl;
m and n are each independently i, 2 or 3, provided that the sum of m and n is 2, 3 or kis0,1,2,3or4;
Y' is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R" is (C3-C,)cydoalkyl, Ars-(Co-C,)alkylenyl, NR"R'° or (C,-C6)alkyl optionally substituted with one to five fluoro; provided that when Y' is a covalent bond or oxycarbonyi, then R" is not NR"R'°; , ~ , R" and R'° are taken separately and are each independently selected from hydrogen, Ars, (C,-C6)alkyl and Ars-(Co-C,)alkylenyl; or , R" and R'° are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicydo[3.2.2]nonanyl, azabicydo[2.2.1)heptyl, 1,2.3,4-tetrahydroisoquinolyl, 6,7-dihydro-5H-dibenzo[c.e]azepinyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidy(;
said azetidinyl in the definition of R" and R'° are optionally substituted with one hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl.optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said pyrroiidinyl, piperidinyl and azepinyl in the definition of R"
and R'° are optionally substituted with up to two h~roxy, amino, hydroxy-(C, C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R" and R'° is optionally substituted with up to tWo substituents independently selected from hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C; C,)alkoxy optionally substituted with up to five fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and 5,6,7;8-tetrahydro[4,3-djpyrimidyl in the definition of R" and R'° are op6onalty substituted with up to three hydroxy, amino, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy~(C,-C,)alkyl, (C,-C,)atkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the defiti~ti~ of R"
and R'° are optionally substituted with up to four hydroxy, amino, halo, hydroxy-(C,-C.~I~. (C,-C.~Ikoxy-(C,-C.)alkyl. (C,-C:~Ikyl optionally substituted with up to fnre fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
Are is independently defined as set forth for Ar and Ar' above;
Ars is optionally independently substituted as set forth for Ar and Ar' above;
R'Z and R'~ are independently hydrogen, (C,-C,kydoalkyl; Are-(Co-C3)alkylenyl, A~°
(Cz-C,)alkenyl, A~-carbonyl or (C,-Cs)alkyl optionally substituted with up to five fiuoro;
Ar° is independently defined as set forth for Ar and Ar' above;
. ' WO 00/59510 PCT/IB00/00296 Ars is optionally indepenc)ently substituted as set forth for Ar and Ar' above; and R" and ~R"' are each independently hydrogen or (C,-C;~alkyl. ' A preferred group of compounds within the compound of formula 1° are those compounds wherein R°' is the acyl radical of ponaUesiat, tolrestai, zenarastat, zopolrestat, epalrestat, ZD5522 or sorbinil.
Espeaally preferred mutual ~prodrvgs of this invention are selected from (Er [4-oxo-3-(5-triouoromethyl-benzothiazol-2-ylmethyl~-3,4-dihydro-phthafazin-1-yl]-acetic acid 1 R-[4-(4-quinoxalin-2-yl-piperazin-1-yl}-pyrimidin-2-yl]-ethyl ester and (E~-[4-Oxo-3-(5-trifluoromethyl-benzothiazol-2-ylmethyl}-3,4-dihydro-phthalatin-'I-yl]-acetic aad 1 R-{4-[4-(3-thiophen-2-yl-acryloylrpiperazin-1-yl]-pyrimidin-2-yl}-ethyl ester.
This invention is also directed to intem~ediate compounds of the fotmula Z
Me Z
This invention is still further directed to intermediate compounds, designated Group AA, of the formula T1, ,oo Me ZZ
wherein R'°° is (C,-Ca~lkyl, benzyl or phenyl wherein said benzyl and phettyt are optionally substituted with up to three halo or (C,-C,~Ikyl.
A preferred group of compounds within Group AA, designated Group AB, are those compounds wherein R'°° is (C,-C,~Ikyl.
More preferred compounds within the Group AB are those cod wherein R'°° is n-butyl or ethyl.
This invention is still further directed to a compound of the formula Z~1, Rio, , , , N
Me N Me ~OCOR'°°
~- YYN
Me Zu wherein:
R'°° is (C,-Ca)alkyl, benzyl or phenyl wherein said benzyl and phenyl are optionally substituted with up to three halo or (C,-C,~tkyl: and R'°' is hydrogen or a suitable amine protecting group.
A preferred group of compounds of formula ZZZ, designated Group AC, are those compounds wherein R'°° is (C,-C,)alkyl and R'°' is benzyl or tert-butyloxycarbonyi. ' A preferred group of compounds within the Group AC are those compounds wherein R'°° is n-butyl or ethyl and R'°' is benzyl.
Another preferred group of compounds within the Group AC are those compuunds wherein R'°° is n-butyl or ethyl and R'°' is tert-butyloxycarbonyl.
This invention is also directed to a process for preparing a compound of the formula Z, OH
~N
~OH
~' YYN
Me Z
comprising:
_71_ a) reacting R-(+~-2-hycfroxy-propionamide with trieth~rioxonium ' tetrafluoroborate in a reaction inert solvent for 10 minutes; to 24 hours at 0 °C to ambient temperature to form the corresponding imidate;
b) reacting said corresponding imidate with anhydrous anunonia in a reaction inert solvent for 2 hours to 24 hours at 0 °C to ambient temperature to form R-(+~2-hydroxy-propionamidine hydrochloride; and c) reacting said R-(+)-2-hydroxy-propionanridine hydrochloride with ethyl 3-hydroxy-acrylate sodium salt and a suitable base in a n:action inert solvent to form said compound of formula Z .
This invention is also directed to a pham~aceutical composifwn, designated Composition AA, comprising a compound of fomwla !, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said c~mmpourd, and~a glycogen phosphorylase inhibitor (GPI), a prodrug of said GPI or a pharmaceutically acceptable salt of said GPI or said prodrug.
This invention is also directed to a Itit cx?r~tising:
a. a -compound of formula !, a prodnrg thereof or a pham~aceutically acceptable salt of said prodrug or said compound in a first unit dosage forth;
b. a glycogen phosphorylase inhibitor. (GPI), a prodrug thereof or a phamiaceuticaAy acceptable salt of said prodrug or said GPI in a second unit dosage form; and c. a container.
This invention is also directed to a method of treating or preventing diabetic complications in a mammal comprising administering to said mammal a pham~aoeutical composition of Composition AA.
This invention is also directed to a method of treating hyperglycemia in a mammal oorraprising administering to said mammal a phamvaoeuticat composition of Composition AA.
This invention is also directed to a method of treating ischemia in a mammal suffering from ischemia comprising administering to said mammal a pham~aceutical position of Composition AA.
This invention is also directed to a method of treating diabetes in a mammal ,, comprising adminstering to said mammal a phamiaoeutical composition of Composition AA.
This invention is also directed to a method of treating diabetic complications in a mammal comprising adminstering to said mammal a compound of formula i, a prodrug thereof or a pham~aceutically axeptable salt of said compound or said prodrug and a glycogen phosphorylase inhibitor (GPI), a prodnrg of said GPI or a pharmaceutically acceptable salt of said GPI or said prodnrg.
This invention is also directed to a method of treating hyperglycemia in a mammal comprising administering to said mammal a compound of fomurla I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a glycogen phosphorytase inhibitor (GP!), a prodnrg of said GPI or a pharmaceutically acceptable salt of said GPI or said prodcug.
This invention is also directed to a method of treating ischemia in a mammal comprising administering to said mammal a compound of formula 1, a prodrug f or a pharmaceutically acceptable salt of said compound or sad prodrug and a glycogen phosphorylase inhibitor (GPI), a prodrug of said GPI or a pharrnaoeuti~lyr acceptable salt of said GPI or said prodrug.
This invention is also directed to a method of treating diabetes ut a rtramrnal comprising administering to said mammal a compound of fom~ula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a glycogen phosphorylase inhibitor (GPI), a prodrug of said GP1 or a pham~aceutically acceptable salt of said GPI or said prodrug.
The subject invention also inGudes isotopically-labeled compounds, which are identical to those rented in Formula I, but for the fad that one or more at~ns are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention indude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as =fi,'H, "C, "C,'SN,'°C. ,W,'~P,'~P~'~S,'°I= and'~CI, respectively.
Compounds of the present invention, prodrugs thereof, and phamiaoeutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes andlor other isotopes of other atoms are within the scope of this invention. Certain pCTIIB00/00296 isotopicalfy-labeted compounds of the present invention; for example those into which radoactive isotopes such as'H and "C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e.,'H, and carbon-14, i.e., "C, isotopes are particularly preferred for their ease of preparation and detectability.
Further, substitution w'tth heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages re$ulting from greater metabolic stabifity~, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some arcumstances. Isotopically labeled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out.the procedures disclosed in the Schemes and lot: in the Examples and Preparations below, by substituting a readily available isotopicalfy labeled reagent for a non-isotopically labeled reagent.
The term "reduction" is intended to include partial prevention or prevention which, although greater than that which would result from taking no compound or from taking a placebo, is less than 100% in addition to substantially total prevention.
The term "damage resulting from ischemia" as employed herein refers to conditions directly associated with reduced blood flow to tissue, for example due to a dot or obstruction of blood vessels which supply blood to the subject tissue and which result, inter alia, in lowered oxygen transport to such tissue, impaired tissue perfom~ance, tissue dysfunction andlor necrosis. Alternatively, where blood flow or organ perfusion may be quantitatively adequate, the oxygen cartying capaaty of the blood or organ perfusion medium may be reduced, e.g., in hypoxic environment, such that oxygen supply to the tissue is knnrenrd, and impaired tissue perfom~ance, tissue dysfunction, and/or tissue necrosis ensues.
The term "treating", "treat" or "treatment" as used herein includes preventafrve (e.g., prophylactic) and palliative treatment.
By "pharmaceutically acceptable" it is meant the carrier, diluent, exapients, andlor salt must be compatible with the other ingredients of the formulation, and not deleterious to the reapient thereof.
The expression "prodnrg" refers to compounds that are drug precursors which foIIoHring administration, release the drug in vivo via some chemical or physiological process (e:g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form).
This invention is further directed to compounds.which are mutual proiirugs of , aldose reductase inhibitors and sorbitol dehydrogenase inhibitors. By mutual prodnrg is meant a compound which contains two active components, in this case, an aldose reductase inhibitor and a sorbitol dehydrogenase, inhibitor, which, following administration, is deaved, releasing each individual active component. Such mutual prodrugs of an aldose reductase inhibitor and a sorbitol dehydrogenase inhibitor are formed under standard esterification conditions weft known to those skilled in the art.
By alkyiene is meant saturated hydrocarbon (straight drain or branched) wherein a hydrogen atom is removed from each of the temunal carbons. Exemplary of such groups (as'suming the designated length encompasses the particular example) are methytene, ethylene, propylene, butylene, pentylene, hexylene, hepiylene.
By halo is meant diloro, bromo, iodo, or fiuoro.
By alkyl is meant straight chain saturated hydrocarbon or branched saturated hydrocarbon. Exemplary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, seo butyl, tertiary butyl, pentyl, isopentyl, neopenlyl, tertiary pentys, 1-methylbutyl, 2 methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
By alkoxy is meant straight chain saturated alkyl or branched saturated alkyl bonded through an oxygen. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy .
It is to be understood that if a carbocydic or heterocydic moiety may be bonded or otherwise attached to a designated substrate through differing ring atoms without denoting a spedfic point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivatent nitrogen atom. For example, the term "pyridyl" means 2-, 3-, or 4-pyridyl. the term 'thienyl"
means 2-, or 3-thienyl, and so forth.
The expression °pharmaoeutically-acceptable salt" refers to nontoxic anionic salts containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, dtrate, gluconate: methanesutfonate and 4-toluene-sulfonate. Where rt~ore than one basic moiety exists the expression indudes multiple salts (e.g., di-salt). The expnsssion also refers to nontoxic cationic salts such as (but not limited to) sodium, potassium.
calcium, magnesium, ammonium or protonated benzathine (N,N'-dibenzylethyfenediamine), choiine, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methyl-glucamine), benethamine (N,-benzylphenethyiamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).
As used herein, the expressions "reaction inert solvent" and "inert solvent"
refers to a solvent or mixture of solvents which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
The chemist of ordinary skill will recognize that certain compounds of formula I
of this invention wilt contain one or more atoms which may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All such isomers and mixtures thereof are included in this invention. Compounds of formula t may be chiral. In such cases, the isomer wherein R' has the R configuration is preferred. Hydrates of the compounds of formula I of this invention are also included.
The chemist of ordinary skill in the art will also recognize that certain compounds of formula 1 of this invention can exist in tautomeric form, i.e., that an equilibrium exists between two isomers which are in rapid equilibrium with each other.
A common example of tautomerism is keto-snot tautomerism, i.e., H
O O
N~
F~camples of compounds which can exist as tautomers include hydroxypyridines, hydroxypym~idines and hydroxyquinolines. Other examples will be recognized by those skilled in the art. Ali such tautomers and mixtures thereof are included in this invention.
DMF means N,N-dimethylfom~amide. DMSO means dimethyl sulfoxide. THE
means tetrahydrofuran.
Whenever the structure of a cyclic radical is shown with a bond drawn from outside the ring to inside the ring, it will be understood by those of ordinary skill in the art to mean that the bond may be attached to any atom on the sing with an available site for bonding. If the cyclic radical is a bicydic or tricydic radical, then the bond may be attached to any atom on any of the rings with an available site for bonding. For example, , ~N ' represents any or all of the following radicals:
\ v \ W \ W
I
~N . I ~N / / N
N N ~ N
I\ ~ w N~N and I / / N
N
Other features and advantages will be apparent from the spedfication and claims which describe the invention.
In general the compounds of formula I of this invention can be made by processes which include processes known in the chemical arts, partiartarly in light of the description contained herein. Certain processes for the manufacture of the compounds of formula t of this invention are provided as further features of the invention and are illustrated by the following reaction schemes. Other processes are described in the experimental section.
Scheme 1 Lv R' R2 Rx ( ~N, ~- R'-H I ~N
~R~
1-y N R
WO OOI59510 pCT/IB00/00296 -n-Compounds of formula 1-3 (i.e., formula I) are prepared as set forth in Scheme 1, particularly as described below.
Compounds of formula 1-3 are prepared by the displacement reaction of a pyrimidine of the formula 1-1 where R' and R2 are defined herein. Lv is a leaving group preferably selected from fluoro, chloro, bromo, iodo, thiomethyf, methylsulfone.
or OSOz,J wherein J is (C,-C6}-lower alkyl, trifluoromethyl, pentafluoroethyl, phenyl optionally substituted with up to three (C,-C,)alkyl, vitro or halo. The leaving group Lv is displaced by~an amine of the formula 1-2 where R' is defined above. The reaction is conducted in the presence of a non,aqueous base, preferably an organic amine or an inorganic base. ?refer-ed organic amines include triethylamine, pyridine, dimethylaminopyridine and N,N'-diisopropylethylamine (Hunig's base). Preferred inorganic bases include alkaline metal carbonates and bicarbonates such as sodium or potassium carbonate and sodium or potassium bicarbonate. An espeaally preferred inorganic base is potassium carbonate. An espeaally preferred organic amine is triethylamine. Alternatively, an excess of the reacting amine 1-2 can be used as the base for this reaction. The reaction can be conducted in the absence of solvent or in a reaction inert solvent. Where used herein, "reaction inert solvent" refers to a solvent which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product Preferred reaction inert solvents include aqueous media, pyridine, (C,-C,~ioohol, (C~-CB)glycol, halocarbon, aliphatirJaromatic hydrocarbon, ethereal solvent, polar aprotic solvent, ketonic solvent, or combinations thereof. The reaction time ranges from 15 minutes to 3 days arid the reaction temperature ranges from 0 °C to 180 °C.
Conveniently, the reaction may be conducted at the retlux temperature of the solvent being used. The reaction is preferably conducted at ambient pressure. The term ambient pressure, where used herein, refers to the pressure of the room in which the reaction is being conducted. The term ambient temperature, where used herein, refers to the temperature of the room in which the reaction is being oonduded.
When R' .contains a hydroxy group, the hydroxyl group may or may not be protected. When the hydroxyl group is protected, the protecting group may be any suitable h~idroxyl protecting group. The conditions used to remove such optional hydroxyl protecting groups contained in R' in compounds of formula 1-3 are as follows. When the protecting group is an ester, removal of such ester protecting groups is conducted under basic conditions using inorganic hydroxides or carbonates, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide or potassium carbonate. The reaction is carried out in.a reactibn inert solvent, preferably an alcoholic solvent. Especially preferred is methanol or methanol in combination with co-solvents such as water, tetrahydrofuran, or dioxane. The reaction time ranges from minutes to 24 hours and the reaction temperature ranges from 0 °C to 100 °C or to the reflux temperature of the solvents) of use. Alternatively, ester cleavage may be accomplished under acidic conditions. It is preferred to utilize aqueous hydrochloric 10 acid, genefally 2 N to concentrated, with or without a co-solvent. When a co-solvent is used, dioxane or methanol are preferred. The reaction time ranges from 4 hours to 3 days and the reaction temperature ranges from 0 °C to 60 °C.
When the protecting group is an alkyl ether, removal of such alkyl ether protecting groups is conducted using well known dealkylative conditions. For 15 example, the alkyl ether may be cleaved by reaction with boron tribromide or diethylboron bromide in a reaction inert solvent, preferably a halocarbon solvent. It will be recognized by those skilled in the art that a buffer such as triethyiamine may faalitate the reaction. The reaction times range from 15 minutes to 24 hours and the reaction temperature ranges from 0 °C to 60 °C. tn addition, a benzyl ether protecting group can be removed via standard or transfer hydrogenolysis using a palladium catalyst such as palladium on carbon. The hydrogenolysis reaction is conducted under a hydrogen atmosphere at ambient pressure to 50 psi in a reaction inert solvent, preferably methanol. The hydrogen source may be hydrogen gas, ammonium formate or trialkylammonium fortnate or cydohexene. The reaction temperature ranges from room temperature to the reflux temperature of the solvent employed. The reaction time ranges from 15 minutes to 24 hours.
When a silyl ether protecting group is employed, removal of such silyl ether protecting groups is conducted under addic conditions, preferably with aqueous hydrochloric aad such as 1 N to 6 N hydrochloric acid. The de-protection may be carried out in the presence of a co-solvent such as methanol or tetrahydrofuran. The reaction time ranges from 2 hours to 48 hours and the reaction temperature ranges from 0 °C'to 100 °C. Alternatively, the silyl ether protecting group maybe removed via fluoride-mediated deprotection. fn this case, deprotection is conducted using tetrabutylammonium fluoride or one of a variety of hydrofluoric acid sources in a , reaction inert solvent. It is preferred to use ethereal sohrents such as diethyl ether, .
dioxane or tetrahydrofuran, with tetrahydrofuran being especially preferred.
The reaction time ranges from 2 hours to 48 hours and~the reaction temperatures range from 0°C to the reflux temperature of the solvent being used. Other methods for removal of the aforementioned protecting groups are well known to those skilled in the art or can be found in Greene, T. W.; Wuts, P. G. M., Protective Groups in Organic Synthesis, 2"° ed.; John Wiley and Sons Inc.: New York, 1991. Other suitable hydroxyl protecting groups and methods for their removal may be found also be found therein.
The method of ~ Scheme I is preferred when RS is R"'~ ~'~'~ °~ °
"'° °. Thus, compounds of formula 1-2 are reacted with compounds of formula 1-1. Compounds of fortnuia 1-where R' is R3'' ~'"'~ 0. ° °' ° are commercially available or can be prepared, by methods well known to those skilled in the art.
~ WO OOI59510 PCT/IB00100296 Scheme 2 O N R~°
R
~ac~d \
Rz; ~- , r R NHz "w"~ ~R -.
N
2-2 , , r.
Lv R
__ Rzs ~ Rx N
~Rz' N
H
2~T
Compounds of formula 2-7 are prepared as set forth in Scheme 2, particularly as descxibed below.
WO 00/59510 PCT/iB00/00296 Where R~' is H, ethyl i-benzyf-3-oxo-4-piperidine-carboxytate hydrochloride, the compound of formula 2-1, which is available from Aldrich, is condensed with compounds of formula 2-2 to give compounds of formula 2-3. The compounds of formula 2-1 where R~' is not H can be prepared according to methods well known to those skilled in the art The reaction is conducted in the presence of excess base including non-aqueous bases, organic amines and inorganic bases. Preferred organic amines include triethyiamine and pyridine. Preferred non-aqueous bases include alkaline metal (C,-C,)alkoxides. Preferred inorganic bases include potassium carbonate. The reaction is conducted in a reaction inert solvent. Preferred such solvents include (C,-G,)alcohols, aromatic or aliphatic hydrocarbons, polar aprotic solvents, halocarbons, and ethereal solvents. (C,-C,)Atcohots are espeaally preferred. The reaction time ranges from 2 hours to 3 days. The reaction temperature ranges from ambient temperature to the reflex temperature of the solvent being .
employed. The reaction is preferably run at ambient pressure but may be conducted at pressures up to 250 psi.
Compounds of formula 2-4 are prepared from compounds of formula 2-3 by converting a compound of formula 2-3 into an activated compound of formula 2-4 where Lv' is selected from fluoro, chtoro, bromo, iodo, trifluvromethanesulfonate, (C,-CB)alkylsulfonate, or phenylsutfonate, wherein said phenyl is optionally substituted with up to three (C,-C,)allcyl, halo or vitro. This reaction is accomplished by reading compounds of formula 2-3 with a chlorinating agent such as phosphorus oxychloride andlor phosphonrs pentachloride to provide compounds of formula 2-4 where Lv' is chtoro. This reaction is conducted at ambient pressure in the absence of solvent or in a reaction inert solvent, preferably a hatocarbon solvent at. temperatures ranging from ambient temperature to 180 °C. Treatment of the chforo compound thus fom~ed with the requisite mineral add provides a compound of formula 2~t where Lv' is bromo or iodo. A sutfonate of formula 2-4 is prepared by reaction of a compound of fomwla 2-3 with a sulfonic add chloride or anhydride in the presence of an organic amine base, preferably triethyiamine or pyridine. in certain cases recognized by those skilled in the art, it may be necessary to add a catalyst to the reaction, fn those cases, a preferted catatyst is 4-dimethyiaminopyridine. This reaction is conducted at ambient pressure in a reaction inert solvent, preferably pyridine, a halocarbon such as chloroform, dichloromethane or carbon tetrachloride, an aromatic or aliphatic hydrocarbon, an pC't'IIB00/00296 ethereal solvent, or combinations thereof. The reaction temperature ranges from -20°
C to 100 °C and the reaction time ranges from 15 minutes to 1 day.
Compounds of formula 2-5 wherein R~ is defined above are prepared from compounds of formula 2-4 by a reduction reaction or by displacement of Lv' with a nudeophile. The reduction is conducted with a reduang agent, preferably ammonium formate or hydrogen gas, in a reaction inert solvent. The reduction is conducted in the presence of a palladium catalyst at ambient pressure or under a hydrogen pressure of up to 50 psi. Preferred solvents include. (C,-C,}alcohols such as methanol and ethanol, and ether solvents such as diethyl ether, dioxane and tetrahydrofuran. The nucleophilic displacement reaction may be conducted by adding the nudeophile directly or by pre-forming the nudeophile separately or in situ from a nudeophile precursor. Preferred nucleophiies include organoaluminum, organoboron, organocopper, organotin, organozinc or Grignard reagent; R~-H; or, where R~' contains a hydroxyl or thiol group, the anion of Rte. The term "organo" in the terms organoaluminum, organoboron, organocopper, organotin and organozinc refers to an organic radical selected from Rte. It will be recognized by those s>u'lled in the art that transition-metal catalysts may be required to effect reaction in certain displacement reactions. When required, such transition metal catalysts may include palladium(0), palladium(//), nickel(0), and nidcel(II) complexes. Palladium(//) bis(diphenylphosphinobutane) dichloride is a preferred such catalyst.
Additionally, an aqueous or non-aqueous base may be required in the displacement reaction.
Preferred such bases include sodium carbonate, sodium hydride, triethyiamine and sodium tert-butoxide. The reaction is conducted at ambient pressure in a reaction inert solvent such as -a halocarbon, an aromatic or aliphatic hydrocarbon, an ether or a polar aprotic solvent or a combination thereof. In certain cases, a (C,-C,)alcohol is used as a solvent or co-solvent. The reaction temperature ranges from 20 °C to the reflux temperature of the solvent employed. The reaction time ranges from 1 hour to 3 days.
Compounds of formula 2-6 are prepared by removal of the benzyl protecting group from compounds of formuta 2-3 or 2-5. This transformation is accomplished using the freebase, or preferably the pre-formed hydrochloride or similar salt, under standard ortransfer hydrogenolysis conditions. The catalysts which may be used in the hydrogenofysis reaction include, but are not limited to, palladium on carbon, palladium hydroxide on carbon and platinum(IV) oxide.. The reaction is conducted in a reaction inert solvent, preferably methanol or ethanol and the reaction temperature ranges from room temperature to the reflux temperature of the solvent being employed. The hydrogen source is hydrogen gas, ammonium fom~ate, trialkyiammonium fomiate, or cyGohexene. The reaction time ranges from 15 minutes to 3 days. Generally the reaction i~ conducted at ambient pressure but pressures of up to 50 psi of hydrogen may be employed. Altemativeiy, if appropriate, the benzyl protecting group is removed in two steps via chloroformate-induced acylative dealkylation. This involves reaction with a chtorofom~ate derivative to form a carbamate followed by Geavage of the carbamate. While this reaction is preferably conducted with 1-chloroethyl chloroformate and sodium iodide catalysis, it will be recognized by those skilled in the art that catalysis may not be required 9n certain cases. The reaction is conducted at ambient~temperature in a reat~tion inert solvent such as a halocarbon, an aromatic or aliphatic hydrocarbon, a ketone, an ether or a potar aprotic solvent. The reaction temperature ranges from -78 °C to the reflux temperature of the solvent being employed and the reaction time ranges from 15 minutes to 1 day. Cleavage of the carbamate formed by reaction with 1-chloroethyl chloroformate is accomplished upon exposure to methanol or ethanol at ambient pressure to give compounds of formula 2-6 as a hydrochloride salt. The reaction proceeds at temperatures from room temperature to the ~reflux temperaturE of the solvent being employed and the reaction time ranges from 15 minutes to 1 day.
Deprotection conditions for other carbamates can be found in Greene, T. W.;
Wuts, P.
G. M. Protective Groups in Organic Synthesis, 2"° ed.; John Wiley and Sons Inc.: New York, 1991, pp 315-348.
Compounds of formula 2-7 are prepared from the displacement reaction of amine 2-G as described in Scheme 1, where the amine 2-6 is equivalent to R'-NH.
Alternatively, compounds of fomwia 2 7 where R~ is as defined above are prepared from compounds of formula 2-3 wherein R~° is OH according to the sequence outlined in Scheme 2a below, wherein the conditions are as set forth as described for Scheme 2.
pCTIIB00/00296 Scheme 2a O N R~°
NH
llacid ~ N
~~ Rze~NH2 ~, ~ R~ ~
N~
2-2 , z-i. 2-3 /
--.~ .
2a-1 Rze Rie R' 2a~ 2-7 Compounds of formula 2-2 which are used in Schemes 2 and 2a above are commeraally available or ace prepared according to methods well known to those skilled in the art, such as those described in March, J. Advanced Organic Chemistry, 3'° ed.; John wley and Sons.: New York,1985, p 359, 374.
2a 2 ' PCT/IBOOI00296
pydmidin-~4-y(]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethyl butyrate;1 RS-(4-{4-[2-(1 R-hydroxy-ethyl)-Pyrimidin-.4-yl)-3R,5S=dimethyl-piperazin-1-YI)-pyrimidin-2-ylj-ethyl butyrate; iR-[4-(3S-methyl-4-oxazolo[5,4-b)pyridin-2-yl-piperdzin-i-yl~pyrimidin-2-yQ-ethyl butyrate; 1R-{4-[3R,5S-dimethyi-4-(4-methyl-6-phenyl-[1,3,5)tria~n-2 yi)-piperazin-1-Yil-PY~midin-2-Yl}-ethyl butyrate: 1R-(4-[4-(4-cYdoProPYi-[~.3,5)hiazin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate; 1R-{4..[4.(4-cydopropyf-[1,3,5jtriazin-2-yl)-2R.6S-dimethyt-piperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate; iR-{4-[4-(4,6-ciimethyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yt)-PYhmidin-2-YI}-ethyl butyrate;1R-{4-[4-(4-hydroxymethyl-6-phenyl-[1,3,5)triazin-2-yl~
2R.6S-dimethyt-piperazin-1-yi]-pYrimidin-2-y!}-ethyl butyrate: 1R-(4-[4-(4-methoxy-6-methoxymethyl-[1,3,5)triazin-2-yl~-R,6S-dimethyt-piperazin-1 yiJ-pyrimidin-2-yl}-ethyl butyrate; and 1R-{4-[2R,6S-dimethyl~-(4-methyl-[1,3,5)triazin-2-yl~-piperazin-1-ylJ-PY~midin-2-yi)-ethyl butyrate.
This invention is atso directed to a mutual prodnrg of the fomwta te, R' R~
~N
N R' IB
wherein:
R' is C-(OR°')R'R5, wherre R°' is independently an acy! radical of a cartioxyiic add aldose reductase inhibitor, R' and R5 are each independently hydrogen, methyl, ethyl or hydroxy-(C,-C,)alkyl;
RZ is hydrogen, (C,-C,~Ikyl or.(C,~,)alkoxy;
pCT/IB00/00296 radical of the formula R fs a , , , X,~R9 , , , , Rt7 R23 I
~N , ' ) G3N 4 a N
G C Z ~ GAG R2 ~G N N , R~ ~ R3b l ~ R~ I
..
. . R2B v Rzs N Rae / N RZS
R2~ ~ R
R~ N ~ ~ R3f ~ , Rae , , Rs~
R33 R33 y / ~N D
A~N ~ \
B , N /N O
Rs2 ~ , Rs~ . R3a ~Rss . , Rs9 N R3" ' R3' N
R4za R42 R"
R36 HO R4z , R4ta R4t R4ts N 1 R4o R4' E , , R3i N
R3s R3k R
N
R3i ,..,43 R4~ Y1 Y, ~/tt L
N
R ~N,Y~R43 R~~N~Ra4 ,s , ~Ct"~~yCm ~CH~~"
R ~NiY .
3m ~ R3n R R4a /N \ R~
N~Yt~ Ra3 R'4\N~YwRa3 ~C~~k Of R3v ~ Rye wherein said radical of formula R" is substituted by f~,1Z' and R°;
said radical of formula R'° is substituted by R'°, R'9 and R~°;
G, G' and G2 are taken separately and are each hydrogen and R6 is hydrogen, (C,-C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,)alkyi, hydroxy-(C,-C,)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C;)alkoxy-(C,-C,)alkyl, (C,-C,~Ikyl or (C,-C,~tkoxy, wherein said (C,-C,)alkyl in the definition of R6 and~said (C,-C,)alkoxy in the definition of R6 are optionally and.independentfy substituted with up to five fluoro; R' and R° are each t 0 independently hydrogen or (C,-C,~Ikyl; or G and G' are taken together and are (C,-C,)alkytene and R6, R', R° and GZ are hydrogen; or G' and Gz are taken together and are (C,-C3)alkylene and R6, R', R' and G are hydrogen;
1~ qis0orl;
X is a covalent bond, -(C=NR'°)-, oxycarbonyl, vinylenylcarbonyl, oxy(C,-C,)alkylenylcarbonyl, (C,-C,)alkylenyicarbonyl, (C,-C,~Ikenylcart~onyl, thio(C,-C,)aikylenytcarbonyl, vinylenytsulfonyl, sulfinyl-(G,-C,~lkylenylcarbonyl, sulfonyf-(C,-C,)alkylenylcarbonyl or carbonyl(C°-C,)alkylenylcarbonyl; wherein said oxy(C,-20 C,)alkylenylcarbonyl, (C,-C,)alkyfenyicarbonyl, (C,-C,)atkenylcart~onyl and thio(C,-C,)aikyienyicarbonyl in the definition of X are each optionally and independently substituted with up to two (C,-C,)alkyl, benzyl or Ar said vinytenylsulfonyl and said vinylenylcarbonyl in the definition of X are optionally substituted independently on one or two vinyienyl carbons with (C,-C,)alkyl, benzyf or Ar; and said carbonyl(C°-25 C,)alkytenylcarbonyl in the deflri~tion of X is optionally substituted indepedently with up to three (C,-C,)alkyl, benzyl or Ar, R'° is hydrogen or (C,-C,~tkyl;
R' is (C,-C,)cydoalkyl, Ar'-(C°-C~)alkylenyl or (C,-C6~Ikyl optionally substituted with up to five fluoro; provided that when q = 0 and X is a covalent bond, oxycarbonyl or 30 (C,-C,~Ikylenylcarbonyl, then R' is not (C,-Ca~lkyl;
Ar and Ar' are independently a fully saturated, partially saturated or fully unsaturated five- to eight-membered ring optionally having up to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicydic ring consisting of two WO 00159510 PCT/IB00/00~96 fused independently partially saturated, fully saturated or fully unsaturated t'ave- to , seven-membered rings, taken independently, opttonalty having up to four heteroatoms 1 selected independently from riatrogen, sulfur and oxygen, or a tricydic ring consisting of three fused independently partially saturated, ftally saturated or fully unsaturated fare to seven membered rings, taken independently, optionally having up to tour heteroatoms selected independently, from nitrogen, sulfur and oxygen, said partially saturated, fully saturated ring or fully unsaturated monocydic ring, bicydic ring or tricydic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur .
Ar and Ar' are optionally independently substituted on carbon or nitrogen,1on one ring if the moiety is monocydic, on one or both rings if the moiety is bicydic, or on one, two or three rings if the moiety is tricydic, with up to a total of four substituents independently selected from R", R'2, R" and R"; wherein R", R'Z, R" and R" are each taken separately and are each independently halo, formyl, (C,-C6~Ikoxycarbonyl, (C,-C6)alkylenyloxycarbonyl, (C,-C')alkoxy-(C,-C,)alkyl, C(OH)R'SR'6, naphthyl, phenyl, tmidazolyl, pycidyl, triazolyl, morpholinyl, (Co-C')alkylsulfamoyl, N-(Co-C,)alkylcarbamoyl, N,N-di-(C,-C,)alkylcarbamoyl, N-phenytcarbamoyl, N-(C,-C,)alkyl-N-phenylcarbamoyl, N,N-Biphenyl cari~amoyl, (G,-C')alkylcarbonylamido, (C,-C,,)cydoatkylcarbonylamido, phenylcarbonylamido, piperidinyl, pyrrolidinyl, piperazinyl, cyano, benzimidazolyf, amino, anitino, pyrimidyl, oxazolyl, isoxazolyt, tetrazolyl, thienyl, thiazolyl, berazothiazolyl, pyrrolyl, pyrazolyl, tetrahydroquinolyl, tetrahydroisoquinolyf, benzoxazolyl, pyridazinyl, pyridytoxy, pyridylsutfanyl, furanyl, 8-(C,-C')atky(-3,8-diaza[3.2.1)bicydooctyl, 3,S~iioxo-1,2,4-triazinyl, phenoxy, thiophenoxy, (C,-C,)alkylsulfanyl, (C,-C,)altrylsulfonyl, (Cs-C,)cydoalkyl, (C,-C,~Ikyl optionally substituted with up to flue fluoro or (C,-C'~Ikoxy optionally substituted with up to five fluoro; said naphthyl, phenyl, pyaidyl, piperidinyl, benzimidazolYl, pyrimidyl, thienyl, benzothiazolyl. PY~IYI.
tetrahydroquinotyl, tetrahydroisoquinolyl, benzoxazoiyl, pyridazinyl, pyridyloxy, pyridylsutfanyf, furanyl, thiophenoxy, anilino and phenoxy in the definition of R", R'2, R" and R" are optionally substituted with up to three substituents independently selected fiom hydroxy, halo, hydroxy-(C,-C')atkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C4)alkyl optionally substituted with up to fare fluoro and (C,-C')alkoxy optionally substituted with up to five fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazoiyi and pyrazolyl in .the definition of WO 00/59510 PfrTIIB00/00296 R", R'=, R" and R" are optionally substituted with up to two substituents independently selected from hydroxy, halo, hydroxy-(C,fC,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to flue fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R", R'z, R" and R" is optionally substituted with up to two substituents independently selected from (C,-C,)alkyl; said pyrrolidinyl in the definition of R", R'2, R'a and R" is optionally substituted with up to two substituents independently selected from hydroxy, hydroxy-(C,-C3)alkyl, (C,-C,)alkoxy-(C,-C,)afkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five filuoro; said piperazinyl in the definition of R", R'2, R" and R" is optionally substituted with up to three substituents independently selected from (C,-C,~lkoxy-(C,-C,~lkyf;
hydroxy-(C,-C3)alkyl, phenyl, pyridyl, (Co-C,~Ikylsuffamoyl, (C,-C,)alkyl optionally~substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to ftve ftuoro: said triazolyl in the deftnition of R", R'Z, R" and R" is optionally substituted with hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,~Ikyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said tetrazofyl in the definition of R", R'2, R" and R" is optionally substituted with hydroxy-(C2-C3~Ikyi or (C,-C,~Ikyl optionally substituted with up to five fluoro;
and said phenyl and pyridyl which are optionally substituted on piperazine in the definition of R", R'2, R" and R" are optionally substituted with up to three hydroxy, halo, hydroxy-(C,-C,)atkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)atkyl optionally substituted with up to fwe fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; or R" and R'~ are taken together on adjacent carbon atoms and are -CH~OC(CH,)20CH~- or -O-(CHZ)p-O-, and R" and R" are taken separately and are each independently hydrogen or (C,-C,)alkyl;
pisl,2or3;
R'S and R'6 are taken separately and are each independently hydrogen, (C,-C,~Ikyl optionally substituted with up to five fluoro; or R's and R'a are taken separately and R's is hydrogen and R'° is (C,-C6)cycloalkyl, hydroxy-(C,-C~)alkyl, phenyl, pyridyl, PYn~dY<. thienyl, furanyl. thiazolyl, oxazolyl, imidazolyl, benzothiazolyl or benzoxazolyl; or R's and R'6 are taken together and are (C~-C6~lkylene;
wo oois9sio pc~r~sooroo2~
G', G, and GS are taken separately and are each hydrogen; r is 0: R'°
is hydrogen, (C,-C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C4~lkoxy-(C,-C4~Ikyl, hydroxy-(C,-C,)alky! or phenyl optionally independently substituted with up tv three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,~Ikyl or (C,-C,~tkoxy, wherein said (C,-C,~tky! in the definition of R6 and said (C,-C,)atkoxy in the definition of R°are optionally and independently substituted with up to five ttuoro; and R'° and, R~° are each independently (C,-C,)alkyl; or G', G' and Gs are taken separately and are each hydrogen; r is 1; R'°
is hydrogen, (C,-C,)alkyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkoxy-(C,-C,)alkyl, hydroxy-(C,-C,)atkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-G,)alkoxy-(C,-C,)alkyi, (C,-C,)alkyl or (C,-C,)atkoxy, wherein said (C,-C,)alkyl in the definition of R° and said (C,-C,)alkoxy in the definition Qf R° are optionally and independently substituted with up to five fluoro; and R'° and R'° are each independently hydrogen or (C,-C,)alkyl; or G' and G' are taken together and are (C,-C,)alkylene; r is 0 or 1; and R'°, R", R~° and G5 are hydrogen; or G' and G5 are taken together and are (C,-C3)alkylene; r is 0 or 1; and R'°, R'°, R~° and G' are hydrogen; , R" is S02NRZ'R~, CONR2'R~, (C,-CB)atkoxycartionyl, (C,-C6)alkyicarbonyl, At=-carbonyl, (C,-C°)alkylsulfonyl, (C,-C°~Ikylsul~nyl, ArZ-sulfonyl, Are-sufinyl and (C,-C°)atkyl, R2' and R~ are taken separately and are each independently selected from hydrogen, (C,-Cs)alkyl, (C,-G,k,Ydoalkyl and Arz-(Co-C,~Ikylenyl: or RZ' and R~ are taken together with the nitrogen atom to which they are attached to form aze6dinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicycto[322]nonanyl, azabicydoj22.1]hepiyl, 6,7-dihydro-SH-dibenzojc,e]azepinyl,1,2,3,4-tetrahydro-isoquinolyl or 5.6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the definition of RZ' and R~ is optionally substituted independently with one substituent selected from hydroxy, amino, hydroxy-(C,-C,)afkyl, (C,-C,)atkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said pyrrolidinyl, piperidinyf, azepinyl in the definition of R~' and R'~ are optionally subst~rted independently with up to two substituents independently selected from trydroxy, pCTIIB00100296 WO 00!59510 amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl. (C,-C,~aikyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of RZ' and R~ is optionally substituted with up to two substituents independent#y selected from hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said piperazinyl in the definition of.R=' and R~ is optionally.substituted independently with up to three substituents independently selected from phenyl, pyridyl, pyrimidyl, (C,-C,)alkoxycarbonyl and (C,-C,~Ikyl optionally substituted with up to five fluoro; said 1,2.3.4-tetrahydro-isoquinolyl and said 5,6,7,8-tetrahydropyrido[4,3-djpyrfmidyl in the definition of R~' and R~ are optionally substituted independently with up to three substituents independently selected from hydroxy, amino, halo; hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and ~(C,-C,)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-SH~ibenzo(c,eJazepinyl in the defnition of RZ' and R~ is optionally substituted with up to four substituents independently selected from hydroxy, amino, halo, hydroxy-(C,-C,)alkyt, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to five fluoro; said pyrimidyl, pytidyl and phenyl which are optionally substituted on said piperazine in the definition of R~' and R~ is optionally substituted with up to three substituents selected from hydroxy, amino, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C,-C,)alkoxy optionally substituted with up to flue fluoro;
Ar2 is independently defined as set forth for Ar and Ar' above;
said Are is optionally independently substituted as set forth for Ar and Ar' above;
R~' is CONR'~R~ or SO=R~R~, wherein R~ is hydrogen (C,-C,)alkyl or Ar'-(Co-C,)alkylenyt and R~° is Ar'-(C°-C,)alkylenyl; provided that when Ar-' is phenyl, naphthyl or biphenyl, then Ra cannot be CONR~R~ where Rte' is hydrogen or Ar' and R~° is Ar';
R~' is hydrogen, (C,-C,)alkyl, (C,-C,)alkoxycarbonyl. (C,rC,)alkoxy-(C,-C,)alkyl, hydroxy-(C,-C,)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C.)alkyl or (C,-C.)alkoxy. wherein said (C,-C,)alkyl in the definition of R° and said (C,-C,~Ikoxy in the definition of R6 are optionally and independently substituted with up to five fluoro;
WO 00!59510 -fi6-Ar' is independently defined as set forth for Ar and Ar' above;
said A~ is optionally independently substituted as set forth for Ar and Ar' above;
R~' is hydrogen or (C,-C,)alkyl;
R~° and R~ are each independently hydrogen, hydroxy, halo, hydroxy-(C,-C,)alkyl, .
(C,-C,)alkoxy-{C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro, (C,-C,)alkoxy optionally substituted with up to five fluoro, phenyl, pyridyl, pyrimidyl, thienyl, furanyl, thiazofyl, oxazolyl, phenoxy, thiophenoxy, SOzNR'°R", CONR'°R" or NR'°R";
said thienyl, pyrimidyl, furanyl, thiazolyl and oxazofyl in the definition of R~° and R~ are optionally substituted by up to two hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C;-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said.phenyl, pyridyl, phenoxy and thiophenoxy in the definition of R~° and R~ are optionally substituted by up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)a~koxy-(C,-C,)alkyf, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
R'° and R" are each independently hydrogen, (C,-C,)alkyl, (C'-C,kydoalkyl or phenyl, said phenyl is optionally substituted with up to three hydroxy, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,~Ikoxy optionally substituted with up to flue fluoro; or R'° and R" are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; said pyrrolidinyl and piperidinyl in the definition of R'° and R" are optionally substituted with up to two hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)allcyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said indolinyl and piperazinyl in the definition of R'° and R" are optionally substituted with up to three hydroxy, amino, hydroxy-(C,-C,~Ikyl, (C,-C,)alkoxy-(C,-C,~Ikyl, (C,-C,)alkoxycarbonyl, (C,-C,)alkyl optionally substituted with up to flue fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R'° and R" is optionally substituted with up to two substituents independently selected from hydroxy-(C,-C,)alkyl, (C,-C,~Ikoxy-{C,-C,)alkyl, (C,-C,~lkyl optionally substituted with up to five fluoro and tC,-C,)alkoxy optionally substituted with up to five fluoro;
A is N optionally substituted with hydrogen or (C,-C,)alkyl and B is carbonyl;
or WO 00!59510 pCTIIB00100296 A is carbonyl and B is N optionally substituted with hydrogen or (C,-C,)alkyl;
R'~ is hydrogen or (C,-C,)alkyl;
R" is phenyl. PY~dYI. PY~midyl, thiazolyl. oxazolyl, benzyl, quinolyl.
isoquinolyl, phthaiizinyl, quinoxanlyl, benzothiazoyl, benzoxazoiyi, benzofuranyl or benzothienyl;
said phenyl, pyridyl, pyrimidyl, thiazoiyl, oxazolyl, benzyl; quinolyl.
isoquinolyl, phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl and benzothienyl in the definition of R" are optionally substituted with up to three phenyl, ptienoxy, NR"R", halo, hydroxy, hydroxy-~C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to 5ve fluoro;
R" and R's are each~independently hydrogen, (G,-C, alkyl), phenyl or phenyfsulfonyl;
said phenyl and phenytsulfonyl in the definition of R" and R's are optionally substituted with up to three halo, hydroxy, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to flue fluoro;
D is CO, CHOH or CH2;
EisO,NHorS;
R'~ and R" are taken separately and are each independently hydrogen, halo, cyano, hydroxy, amino, (C,-C6)alkylamino, di-(C,-Cs)alkylamino, pyn'olidino, piperidino, morphoiino, (C,-C,~Ikoxy-(C; C,)alkyl, hydroxy-(C,-C,)alkyl, A~', (C,-C,~Ikyl optionally substituted with up to five tluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
R'°, R~ and R'° are each independently hydrogen or (C,-C,~alkyl;
Ar is phenyl, furanyl, thienyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl;
said Ar" being optionally substituted with up to three hydroxy, (C,-C,)alkoxy-(C,-C,)alkyl, halo, hydroxy-(C,-C,)alkyi, 7(C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,~Ikoxy optionally substituted with up to five fluoro; or R'~ and R" are taken together on adjacent carbon atoms and are -O-(CH~~-O-;
tisl,2or3;
Y is (Cz-Cs~lkylene;
R", R's and R's are each independently hydrogen or (C,-C,~Ikyl;
m and n are each independently i, 2 or 3, provided that the sum of m and n is 2, 3 or kis0,1,2,3or4;
Y' is a covalent bond, carbonyl, sulfonyl or oxycarbonyl;
R" is (C3-C,)cydoalkyl, Ars-(Co-C,)alkylenyl, NR"R'° or (C,-C6)alkyl optionally substituted with one to five fluoro; provided that when Y' is a covalent bond or oxycarbonyi, then R" is not NR"R'°; , ~ , R" and R'° are taken separately and are each independently selected from hydrogen, Ars, (C,-C6)alkyl and Ars-(Co-C,)alkylenyl; or , R" and R'° are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, azabicydo[3.2.2]nonanyl, azabicydo[2.2.1)heptyl, 1,2.3,4-tetrahydroisoquinolyl, 6,7-dihydro-5H-dibenzo[c.e]azepinyl or 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidy(;
said azetidinyl in the definition of R" and R'° are optionally substituted with one hydroxy, amino, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl.optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said pyrroiidinyl, piperidinyl and azepinyl in the definition of R"
and R'° are optionally substituted with up to two h~roxy, amino, hydroxy-(C, C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; said morpholinyl in the definition of R" and R'° is optionally substituted with up to tWo substituents independently selected from hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy-(C,-C,)alkyl, (C,-C,)alkyl optionally substituted with up to five fluoro and (C; C,)alkoxy optionally substituted with up to five fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and 5,6,7;8-tetrahydro[4,3-djpyrimidyl in the definition of R" and R'° are op6onalty substituted with up to three hydroxy, amino, halo, hydroxy-(C,-C,)alkyl, (C,-C,)alkoxy~(C,-C,)alkyl, (C,-C,)atkyl optionally substituted with up to five fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the defiti~ti~ of R"
and R'° are optionally substituted with up to four hydroxy, amino, halo, hydroxy-(C,-C.~I~. (C,-C.~Ikoxy-(C,-C.)alkyl. (C,-C:~Ikyl optionally substituted with up to fnre fluoro or (C,-C,)alkoxy optionally substituted with up to five fluoro;
Are is independently defined as set forth for Ar and Ar' above;
Ars is optionally independently substituted as set forth for Ar and Ar' above;
R'Z and R'~ are independently hydrogen, (C,-C,kydoalkyl; Are-(Co-C3)alkylenyl, A~°
(Cz-C,)alkenyl, A~-carbonyl or (C,-Cs)alkyl optionally substituted with up to five fiuoro;
Ar° is independently defined as set forth for Ar and Ar' above;
. ' WO 00/59510 PCT/IB00/00296 Ars is optionally indepenc)ently substituted as set forth for Ar and Ar' above; and R" and ~R"' are each independently hydrogen or (C,-C;~alkyl. ' A preferred group of compounds within the compound of formula 1° are those compounds wherein R°' is the acyl radical of ponaUesiat, tolrestai, zenarastat, zopolrestat, epalrestat, ZD5522 or sorbinil.
Espeaally preferred mutual ~prodrvgs of this invention are selected from (Er [4-oxo-3-(5-triouoromethyl-benzothiazol-2-ylmethyl~-3,4-dihydro-phthafazin-1-yl]-acetic acid 1 R-[4-(4-quinoxalin-2-yl-piperazin-1-yl}-pyrimidin-2-yl]-ethyl ester and (E~-[4-Oxo-3-(5-trifluoromethyl-benzothiazol-2-ylmethyl}-3,4-dihydro-phthalatin-'I-yl]-acetic aad 1 R-{4-[4-(3-thiophen-2-yl-acryloylrpiperazin-1-yl]-pyrimidin-2-yl}-ethyl ester.
This invention is also directed to intem~ediate compounds of the fotmula Z
Me Z
This invention is still further directed to intermediate compounds, designated Group AA, of the formula T1, ,oo Me ZZ
wherein R'°° is (C,-Ca~lkyl, benzyl or phenyl wherein said benzyl and phettyt are optionally substituted with up to three halo or (C,-C,~Ikyl.
A preferred group of compounds within Group AA, designated Group AB, are those compounds wherein R'°° is (C,-C,~Ikyl.
More preferred compounds within the Group AB are those cod wherein R'°° is n-butyl or ethyl.
This invention is still further directed to a compound of the formula Z~1, Rio, , , , N
Me N Me ~OCOR'°°
~- YYN
Me Zu wherein:
R'°° is (C,-Ca)alkyl, benzyl or phenyl wherein said benzyl and phenyl are optionally substituted with up to three halo or (C,-C,~tkyl: and R'°' is hydrogen or a suitable amine protecting group.
A preferred group of compounds of formula ZZZ, designated Group AC, are those compounds wherein R'°° is (C,-C,)alkyl and R'°' is benzyl or tert-butyloxycarbonyi. ' A preferred group of compounds within the Group AC are those compounds wherein R'°° is n-butyl or ethyl and R'°' is benzyl.
Another preferred group of compounds within the Group AC are those compuunds wherein R'°° is n-butyl or ethyl and R'°' is tert-butyloxycarbonyl.
This invention is also directed to a process for preparing a compound of the formula Z, OH
~N
~OH
~' YYN
Me Z
comprising:
_71_ a) reacting R-(+~-2-hycfroxy-propionamide with trieth~rioxonium ' tetrafluoroborate in a reaction inert solvent for 10 minutes; to 24 hours at 0 °C to ambient temperature to form the corresponding imidate;
b) reacting said corresponding imidate with anhydrous anunonia in a reaction inert solvent for 2 hours to 24 hours at 0 °C to ambient temperature to form R-(+~2-hydroxy-propionamidine hydrochloride; and c) reacting said R-(+)-2-hydroxy-propionanridine hydrochloride with ethyl 3-hydroxy-acrylate sodium salt and a suitable base in a n:action inert solvent to form said compound of formula Z .
This invention is also directed to a pham~aceutical composifwn, designated Composition AA, comprising a compound of fomwla !, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said c~mmpourd, and~a glycogen phosphorylase inhibitor (GPI), a prodrug of said GPI or a pharmaceutically acceptable salt of said GPI or said prodrug.
This invention is also directed to a Itit cx?r~tising:
a. a -compound of formula !, a prodnrg thereof or a pham~aceutically acceptable salt of said prodrug or said compound in a first unit dosage forth;
b. a glycogen phosphorylase inhibitor. (GPI), a prodrug thereof or a phamiaceuticaAy acceptable salt of said prodrug or said GPI in a second unit dosage form; and c. a container.
This invention is also directed to a method of treating or preventing diabetic complications in a mammal comprising administering to said mammal a pham~aoeutical composition of Composition AA.
This invention is also directed to a method of treating hyperglycemia in a mammal oorraprising administering to said mammal a phamvaoeuticat composition of Composition AA.
This invention is also directed to a method of treating ischemia in a mammal suffering from ischemia comprising administering to said mammal a pham~aceutical position of Composition AA.
This invention is also directed to a method of treating diabetes in a mammal ,, comprising adminstering to said mammal a phamiaoeutical composition of Composition AA.
This invention is also directed to a method of treating diabetic complications in a mammal comprising adminstering to said mammal a compound of formula i, a prodrug thereof or a pham~aceutically axeptable salt of said compound or said prodrug and a glycogen phosphorylase inhibitor (GPI), a prodnrg of said GPI or a pharmaceutically acceptable salt of said GPI or said prodnrg.
This invention is also directed to a method of treating hyperglycemia in a mammal comprising administering to said mammal a compound of fomurla I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a glycogen phosphorytase inhibitor (GP!), a prodnrg of said GPI or a pharmaceutically acceptable salt of said GPI or said prodcug.
This invention is also directed to a method of treating ischemia in a mammal comprising administering to said mammal a compound of formula 1, a prodrug f or a pharmaceutically acceptable salt of said compound or sad prodrug and a glycogen phosphorylase inhibitor (GPI), a prodrug of said GPI or a pharrnaoeuti~lyr acceptable salt of said GPI or said prodrug.
This invention is also directed to a method of treating diabetes ut a rtramrnal comprising administering to said mammal a compound of fom~ula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a glycogen phosphorylase inhibitor (GPI), a prodrug of said GP1 or a pham~aceutically acceptable salt of said GPI or said prodrug.
The subject invention also inGudes isotopically-labeled compounds, which are identical to those rented in Formula I, but for the fad that one or more at~ns are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention indude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as =fi,'H, "C, "C,'SN,'°C. ,W,'~P,'~P~'~S,'°I= and'~CI, respectively.
Compounds of the present invention, prodrugs thereof, and phamiaoeutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes andlor other isotopes of other atoms are within the scope of this invention. Certain pCTIIB00/00296 isotopicalfy-labeted compounds of the present invention; for example those into which radoactive isotopes such as'H and "C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e.,'H, and carbon-14, i.e., "C, isotopes are particularly preferred for their ease of preparation and detectability.
Further, substitution w'tth heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages re$ulting from greater metabolic stabifity~, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some arcumstances. Isotopically labeled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out.the procedures disclosed in the Schemes and lot: in the Examples and Preparations below, by substituting a readily available isotopicalfy labeled reagent for a non-isotopically labeled reagent.
The term "reduction" is intended to include partial prevention or prevention which, although greater than that which would result from taking no compound or from taking a placebo, is less than 100% in addition to substantially total prevention.
The term "damage resulting from ischemia" as employed herein refers to conditions directly associated with reduced blood flow to tissue, for example due to a dot or obstruction of blood vessels which supply blood to the subject tissue and which result, inter alia, in lowered oxygen transport to such tissue, impaired tissue perfom~ance, tissue dysfunction andlor necrosis. Alternatively, where blood flow or organ perfusion may be quantitatively adequate, the oxygen cartying capaaty of the blood or organ perfusion medium may be reduced, e.g., in hypoxic environment, such that oxygen supply to the tissue is knnrenrd, and impaired tissue perfom~ance, tissue dysfunction, and/or tissue necrosis ensues.
The term "treating", "treat" or "treatment" as used herein includes preventafrve (e.g., prophylactic) and palliative treatment.
By "pharmaceutically acceptable" it is meant the carrier, diluent, exapients, andlor salt must be compatible with the other ingredients of the formulation, and not deleterious to the reapient thereof.
The expression "prodnrg" refers to compounds that are drug precursors which foIIoHring administration, release the drug in vivo via some chemical or physiological process (e:g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form).
This invention is further directed to compounds.which are mutual proiirugs of , aldose reductase inhibitors and sorbitol dehydrogenase inhibitors. By mutual prodnrg is meant a compound which contains two active components, in this case, an aldose reductase inhibitor and a sorbitol dehydrogenase, inhibitor, which, following administration, is deaved, releasing each individual active component. Such mutual prodrugs of an aldose reductase inhibitor and a sorbitol dehydrogenase inhibitor are formed under standard esterification conditions weft known to those skilled in the art.
By alkyiene is meant saturated hydrocarbon (straight drain or branched) wherein a hydrogen atom is removed from each of the temunal carbons. Exemplary of such groups (as'suming the designated length encompasses the particular example) are methytene, ethylene, propylene, butylene, pentylene, hexylene, hepiylene.
By halo is meant diloro, bromo, iodo, or fiuoro.
By alkyl is meant straight chain saturated hydrocarbon or branched saturated hydrocarbon. Exemplary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, seo butyl, tertiary butyl, pentyl, isopentyl, neopenlyl, tertiary pentys, 1-methylbutyl, 2 methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
By alkoxy is meant straight chain saturated alkyl or branched saturated alkyl bonded through an oxygen. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy .
It is to be understood that if a carbocydic or heterocydic moiety may be bonded or otherwise attached to a designated substrate through differing ring atoms without denoting a spedfic point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivatent nitrogen atom. For example, the term "pyridyl" means 2-, 3-, or 4-pyridyl. the term 'thienyl"
means 2-, or 3-thienyl, and so forth.
The expression °pharmaoeutically-acceptable salt" refers to nontoxic anionic salts containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, dtrate, gluconate: methanesutfonate and 4-toluene-sulfonate. Where rt~ore than one basic moiety exists the expression indudes multiple salts (e.g., di-salt). The expnsssion also refers to nontoxic cationic salts such as (but not limited to) sodium, potassium.
calcium, magnesium, ammonium or protonated benzathine (N,N'-dibenzylethyfenediamine), choiine, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methyl-glucamine), benethamine (N,-benzylphenethyiamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).
As used herein, the expressions "reaction inert solvent" and "inert solvent"
refers to a solvent or mixture of solvents which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
The chemist of ordinary skill will recognize that certain compounds of formula I
of this invention wilt contain one or more atoms which may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All such isomers and mixtures thereof are included in this invention. Compounds of formula t may be chiral. In such cases, the isomer wherein R' has the R configuration is preferred. Hydrates of the compounds of formula I of this invention are also included.
The chemist of ordinary skill in the art will also recognize that certain compounds of formula 1 of this invention can exist in tautomeric form, i.e., that an equilibrium exists between two isomers which are in rapid equilibrium with each other.
A common example of tautomerism is keto-snot tautomerism, i.e., H
O O
N~
F~camples of compounds which can exist as tautomers include hydroxypyridines, hydroxypym~idines and hydroxyquinolines. Other examples will be recognized by those skilled in the art. Ali such tautomers and mixtures thereof are included in this invention.
DMF means N,N-dimethylfom~amide. DMSO means dimethyl sulfoxide. THE
means tetrahydrofuran.
Whenever the structure of a cyclic radical is shown with a bond drawn from outside the ring to inside the ring, it will be understood by those of ordinary skill in the art to mean that the bond may be attached to any atom on the sing with an available site for bonding. If the cyclic radical is a bicydic or tricydic radical, then the bond may be attached to any atom on any of the rings with an available site for bonding. For example, , ~N ' represents any or all of the following radicals:
\ v \ W \ W
I
~N . I ~N / / N
N N ~ N
I\ ~ w N~N and I / / N
N
Other features and advantages will be apparent from the spedfication and claims which describe the invention.
In general the compounds of formula I of this invention can be made by processes which include processes known in the chemical arts, partiartarly in light of the description contained herein. Certain processes for the manufacture of the compounds of formula t of this invention are provided as further features of the invention and are illustrated by the following reaction schemes. Other processes are described in the experimental section.
Scheme 1 Lv R' R2 Rx ( ~N, ~- R'-H I ~N
~R~
1-y N R
WO OOI59510 pCT/IB00/00296 -n-Compounds of formula 1-3 (i.e., formula I) are prepared as set forth in Scheme 1, particularly as described below.
Compounds of formula 1-3 are prepared by the displacement reaction of a pyrimidine of the formula 1-1 where R' and R2 are defined herein. Lv is a leaving group preferably selected from fluoro, chloro, bromo, iodo, thiomethyf, methylsulfone.
or OSOz,J wherein J is (C,-C6}-lower alkyl, trifluoromethyl, pentafluoroethyl, phenyl optionally substituted with up to three (C,-C,)alkyl, vitro or halo. The leaving group Lv is displaced by~an amine of the formula 1-2 where R' is defined above. The reaction is conducted in the presence of a non,aqueous base, preferably an organic amine or an inorganic base. ?refer-ed organic amines include triethylamine, pyridine, dimethylaminopyridine and N,N'-diisopropylethylamine (Hunig's base). Preferred inorganic bases include alkaline metal carbonates and bicarbonates such as sodium or potassium carbonate and sodium or potassium bicarbonate. An espeaally preferred inorganic base is potassium carbonate. An espeaally preferred organic amine is triethylamine. Alternatively, an excess of the reacting amine 1-2 can be used as the base for this reaction. The reaction can be conducted in the absence of solvent or in a reaction inert solvent. Where used herein, "reaction inert solvent" refers to a solvent which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product Preferred reaction inert solvents include aqueous media, pyridine, (C,-C,~ioohol, (C~-CB)glycol, halocarbon, aliphatirJaromatic hydrocarbon, ethereal solvent, polar aprotic solvent, ketonic solvent, or combinations thereof. The reaction time ranges from 15 minutes to 3 days arid the reaction temperature ranges from 0 °C to 180 °C.
Conveniently, the reaction may be conducted at the retlux temperature of the solvent being used. The reaction is preferably conducted at ambient pressure. The term ambient pressure, where used herein, refers to the pressure of the room in which the reaction is being conducted. The term ambient temperature, where used herein, refers to the temperature of the room in which the reaction is being oonduded.
When R' .contains a hydroxy group, the hydroxyl group may or may not be protected. When the hydroxyl group is protected, the protecting group may be any suitable h~idroxyl protecting group. The conditions used to remove such optional hydroxyl protecting groups contained in R' in compounds of formula 1-3 are as follows. When the protecting group is an ester, removal of such ester protecting groups is conducted under basic conditions using inorganic hydroxides or carbonates, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide or potassium carbonate. The reaction is carried out in.a reactibn inert solvent, preferably an alcoholic solvent. Especially preferred is methanol or methanol in combination with co-solvents such as water, tetrahydrofuran, or dioxane. The reaction time ranges from minutes to 24 hours and the reaction temperature ranges from 0 °C to 100 °C or to the reflux temperature of the solvents) of use. Alternatively, ester cleavage may be accomplished under acidic conditions. It is preferred to utilize aqueous hydrochloric 10 acid, genefally 2 N to concentrated, with or without a co-solvent. When a co-solvent is used, dioxane or methanol are preferred. The reaction time ranges from 4 hours to 3 days and the reaction temperature ranges from 0 °C to 60 °C.
When the protecting group is an alkyl ether, removal of such alkyl ether protecting groups is conducted using well known dealkylative conditions. For 15 example, the alkyl ether may be cleaved by reaction with boron tribromide or diethylboron bromide in a reaction inert solvent, preferably a halocarbon solvent. It will be recognized by those skilled in the art that a buffer such as triethyiamine may faalitate the reaction. The reaction times range from 15 minutes to 24 hours and the reaction temperature ranges from 0 °C to 60 °C. tn addition, a benzyl ether protecting group can be removed via standard or transfer hydrogenolysis using a palladium catalyst such as palladium on carbon. The hydrogenolysis reaction is conducted under a hydrogen atmosphere at ambient pressure to 50 psi in a reaction inert solvent, preferably methanol. The hydrogen source may be hydrogen gas, ammonium formate or trialkylammonium fortnate or cydohexene. The reaction temperature ranges from room temperature to the reflux temperature of the solvent employed. The reaction time ranges from 15 minutes to 24 hours.
When a silyl ether protecting group is employed, removal of such silyl ether protecting groups is conducted under addic conditions, preferably with aqueous hydrochloric aad such as 1 N to 6 N hydrochloric acid. The de-protection may be carried out in the presence of a co-solvent such as methanol or tetrahydrofuran. The reaction time ranges from 2 hours to 48 hours and the reaction temperature ranges from 0 °C'to 100 °C. Alternatively, the silyl ether protecting group maybe removed via fluoride-mediated deprotection. fn this case, deprotection is conducted using tetrabutylammonium fluoride or one of a variety of hydrofluoric acid sources in a , reaction inert solvent. It is preferred to use ethereal sohrents such as diethyl ether, .
dioxane or tetrahydrofuran, with tetrahydrofuran being especially preferred.
The reaction time ranges from 2 hours to 48 hours and~the reaction temperatures range from 0°C to the reflux temperature of the solvent being used. Other methods for removal of the aforementioned protecting groups are well known to those skilled in the art or can be found in Greene, T. W.; Wuts, P. G. M., Protective Groups in Organic Synthesis, 2"° ed.; John Wiley and Sons Inc.: New York, 1991. Other suitable hydroxyl protecting groups and methods for their removal may be found also be found therein.
The method of ~ Scheme I is preferred when RS is R"'~ ~'~'~ °~ °
"'° °. Thus, compounds of formula 1-2 are reacted with compounds of formula 1-1. Compounds of fortnuia 1-where R' is R3'' ~'"'~ 0. ° °' ° are commercially available or can be prepared, by methods well known to those skilled in the art.
~ WO OOI59510 PCT/IB00100296 Scheme 2 O N R~°
R
~ac~d \
Rz; ~- , r R NHz "w"~ ~R -.
N
2-2 , , r.
Lv R
__ Rzs ~ Rx N
~Rz' N
H
2~T
Compounds of formula 2-7 are prepared as set forth in Scheme 2, particularly as descxibed below.
WO 00/59510 PCT/iB00/00296 Where R~' is H, ethyl i-benzyf-3-oxo-4-piperidine-carboxytate hydrochloride, the compound of formula 2-1, which is available from Aldrich, is condensed with compounds of formula 2-2 to give compounds of formula 2-3. The compounds of formula 2-1 where R~' is not H can be prepared according to methods well known to those skilled in the art The reaction is conducted in the presence of excess base including non-aqueous bases, organic amines and inorganic bases. Preferred organic amines include triethyiamine and pyridine. Preferred non-aqueous bases include alkaline metal (C,-C,)alkoxides. Preferred inorganic bases include potassium carbonate. The reaction is conducted in a reaction inert solvent. Preferred such solvents include (C,-G,)alcohols, aromatic or aliphatic hydrocarbons, polar aprotic solvents, halocarbons, and ethereal solvents. (C,-C,)Atcohots are espeaally preferred. The reaction time ranges from 2 hours to 3 days. The reaction temperature ranges from ambient temperature to the reflex temperature of the solvent being .
employed. The reaction is preferably run at ambient pressure but may be conducted at pressures up to 250 psi.
Compounds of formula 2-4 are prepared from compounds of formula 2-3 by converting a compound of formula 2-3 into an activated compound of formula 2-4 where Lv' is selected from fluoro, chtoro, bromo, iodo, trifluvromethanesulfonate, (C,-CB)alkylsulfonate, or phenylsutfonate, wherein said phenyl is optionally substituted with up to three (C,-C,)allcyl, halo or vitro. This reaction is accomplished by reading compounds of formula 2-3 with a chlorinating agent such as phosphorus oxychloride andlor phosphonrs pentachloride to provide compounds of formula 2-4 where Lv' is chtoro. This reaction is conducted at ambient pressure in the absence of solvent or in a reaction inert solvent, preferably a hatocarbon solvent at. temperatures ranging from ambient temperature to 180 °C. Treatment of the chforo compound thus fom~ed with the requisite mineral add provides a compound of formula 2~t where Lv' is bromo or iodo. A sutfonate of formula 2-4 is prepared by reaction of a compound of fomwla 2-3 with a sulfonic add chloride or anhydride in the presence of an organic amine base, preferably triethyiamine or pyridine. in certain cases recognized by those skilled in the art, it may be necessary to add a catalyst to the reaction, fn those cases, a preferted catatyst is 4-dimethyiaminopyridine. This reaction is conducted at ambient pressure in a reaction inert solvent, preferably pyridine, a halocarbon such as chloroform, dichloromethane or carbon tetrachloride, an aromatic or aliphatic hydrocarbon, an pC't'IIB00/00296 ethereal solvent, or combinations thereof. The reaction temperature ranges from -20°
C to 100 °C and the reaction time ranges from 15 minutes to 1 day.
Compounds of formula 2-5 wherein R~ is defined above are prepared from compounds of formula 2-4 by a reduction reaction or by displacement of Lv' with a nudeophile. The reduction is conducted with a reduang agent, preferably ammonium formate or hydrogen gas, in a reaction inert solvent. The reduction is conducted in the presence of a palladium catalyst at ambient pressure or under a hydrogen pressure of up to 50 psi. Preferred solvents include. (C,-C,}alcohols such as methanol and ethanol, and ether solvents such as diethyl ether, dioxane and tetrahydrofuran. The nucleophilic displacement reaction may be conducted by adding the nudeophile directly or by pre-forming the nudeophile separately or in situ from a nudeophile precursor. Preferred nucleophiies include organoaluminum, organoboron, organocopper, organotin, organozinc or Grignard reagent; R~-H; or, where R~' contains a hydroxyl or thiol group, the anion of Rte. The term "organo" in the terms organoaluminum, organoboron, organocopper, organotin and organozinc refers to an organic radical selected from Rte. It will be recognized by those s>u'lled in the art that transition-metal catalysts may be required to effect reaction in certain displacement reactions. When required, such transition metal catalysts may include palladium(0), palladium(//), nickel(0), and nidcel(II) complexes. Palladium(//) bis(diphenylphosphinobutane) dichloride is a preferred such catalyst.
Additionally, an aqueous or non-aqueous base may be required in the displacement reaction.
Preferred such bases include sodium carbonate, sodium hydride, triethyiamine and sodium tert-butoxide. The reaction is conducted at ambient pressure in a reaction inert solvent such as -a halocarbon, an aromatic or aliphatic hydrocarbon, an ether or a polar aprotic solvent or a combination thereof. In certain cases, a (C,-C,)alcohol is used as a solvent or co-solvent. The reaction temperature ranges from 20 °C to the reflux temperature of the solvent employed. The reaction time ranges from 1 hour to 3 days.
Compounds of formula 2-6 are prepared by removal of the benzyl protecting group from compounds of formuta 2-3 or 2-5. This transformation is accomplished using the freebase, or preferably the pre-formed hydrochloride or similar salt, under standard ortransfer hydrogenolysis conditions. The catalysts which may be used in the hydrogenofysis reaction include, but are not limited to, palladium on carbon, palladium hydroxide on carbon and platinum(IV) oxide.. The reaction is conducted in a reaction inert solvent, preferably methanol or ethanol and the reaction temperature ranges from room temperature to the reflux temperature of the solvent being employed. The hydrogen source is hydrogen gas, ammonium fom~ate, trialkyiammonium fomiate, or cyGohexene. The reaction time ranges from 15 minutes to 3 days. Generally the reaction i~ conducted at ambient pressure but pressures of up to 50 psi of hydrogen may be employed. Altemativeiy, if appropriate, the benzyl protecting group is removed in two steps via chloroformate-induced acylative dealkylation. This involves reaction with a chtorofom~ate derivative to form a carbamate followed by Geavage of the carbamate. While this reaction is preferably conducted with 1-chloroethyl chloroformate and sodium iodide catalysis, it will be recognized by those skilled in the art that catalysis may not be required 9n certain cases. The reaction is conducted at ambient~temperature in a reat~tion inert solvent such as a halocarbon, an aromatic or aliphatic hydrocarbon, a ketone, an ether or a potar aprotic solvent. The reaction temperature ranges from -78 °C to the reflux temperature of the solvent being employed and the reaction time ranges from 15 minutes to 1 day. Cleavage of the carbamate formed by reaction with 1-chloroethyl chloroformate is accomplished upon exposure to methanol or ethanol at ambient pressure to give compounds of formula 2-6 as a hydrochloride salt. The reaction proceeds at temperatures from room temperature to the ~reflux temperaturE of the solvent being employed and the reaction time ranges from 15 minutes to 1 day.
Deprotection conditions for other carbamates can be found in Greene, T. W.;
Wuts, P.
G. M. Protective Groups in Organic Synthesis, 2"° ed.; John Wiley and Sons Inc.: New York, 1991, pp 315-348.
Compounds of formula 2-7 are prepared from the displacement reaction of amine 2-G as described in Scheme 1, where the amine 2-6 is equivalent to R'-NH.
Alternatively, compounds of fomwia 2 7 where R~ is as defined above are prepared from compounds of formula 2-3 wherein R~° is OH according to the sequence outlined in Scheme 2a below, wherein the conditions are as set forth as described for Scheme 2.
pCTIIB00/00296 Scheme 2a O N R~°
NH
llacid ~ N
~~ Rze~NH2 ~, ~ R~ ~
N~
2-2 , z-i. 2-3 /
--.~ .
2a-1 Rze Rie R' 2a~ 2-7 Compounds of formula 2-2 which are used in Schemes 2 and 2a above are commeraally available or ace prepared according to methods well known to those skilled in the art, such as those described in March, J. Advanced Organic Chemistry, 3'° ed.; John wley and Sons.: New York,1985, p 359, 374.
2a 2 ' PCT/IBOOI00296
-8~
Scheme 3 ~~ ~a~
R'~ R"
v R + o ~ j.
Me OH
r ~ R
R -) R~7 ' '9 R R
N
H
O
R~ ~R~s ~- 3 2 3-5 N
hi Compounds of formula 3-5 are prepared as set forth in Scheme 3 above and more particularly as described below.
Compounds of formula 3-3 are prepared by condensing a compound of formula 3-'i with a compound of fomwia 3-2. Where R'° and R'°
are each H, the carnpound of formula 3-1 is 1-benryl-4-piperidone, which is commercially available pCTIIB00/00296 from Aldrich. Compounds of formula 3-2 are either coriamercially available or can be prepared according to methods well known to those skilled in the art"
particularly according to methods set forth in March, J. Advanced'Organic chemistry, 3'° ed.;
John Wiley and Sons Inc.: New York, 1985, pp 499-500. The reaction is conducted at ambient pressure in the presence of a secondary amine. generally an excess of the secondary amine, preferably pyrrolidine, piperidine, morpholine or diethytamine, is used. An especially preferred secondary amine is pyrrofidine. The reac#ion is conducted in a reaction inert solvent, preferably a (C,-C,)aioohol, an aromatic or aliphatic hydrocarbon, a polar aprotic solvent, a halocarbon or an ether.
An.especially preferred solvent is ethanol. The reaction time ranges from 2 hours to 3 days and the reaction temperature ranges from ambient temperature to the reflex temperature of the solvent being employed.
Compounds of the formula 3-4 are prepared by removal of the benzyl protecting group from compounds of formula 3-3. This transforma#ion is conducted in a manner analogous to the procedure set forth for the preparation of compounds of formula 2-6 above.
Compounds of formula 3-5 are prepared from the displacement reaction of amine 3-4 as described in Scheme 1, where the amine 3-4 is equivalent to R'-NH.
Scheme 3a Ray R w ---.-- R'°-~-- ,~--R's --N FZ ~N~ ~R~
R
3a-~ _ , 3-5 3a 2 pGT/IB00/00296 Compounds of formulas 3a-1 and 3a-2 are prepared as shown in Scheme 3a , , from compounds of formula 3-5. Thus, to prepare a compound of 3a-1, a compound of formula 3-5 is reduced with a common reduang agent, such as, for example, sodium borohydride, lithium aluminum hydride or diisobutylaluminum hydride.
Other reducing agents capable of effecting the reduction of a ketone to an alcohol are well known to those skilled in the art (e.g., Larodc, R. D. Comprehensive Or~janic.
.
Transformations, VCH Publishers, lnc.: New York, 1989, pp 527-547). Likewise, compounds of formula 3a-2 are prepared from compounds of formula 3-5 by reduction with reducing agents capable of redudng a ketone completety to a methyfene group. A preferred such reducing agent is aluminum tridiloridelborane-tert-butylamine complex. Other such reducing agents are well known to those skilled in the art (e.g., J. Org. Chem.1989, 54. 4350; Larodc, R. D. Compr~ehensiv~
Organic Transformations, VCH Publishers, Inc.: New York, 1989, pp 35-37). It will be recognized by those skilled in the art that the transformation of 3-5 to 3a-1 or 3a-2 can be conducted at different points in Scheme 3, depending upon the dynamics of the particular system.
Alternatively, compounds of formula 3-5 wherein R'° and R" are hydrogen can be prepared from 4-piperidone monohydrate monochloride in a manner analogous to the procedure described in Scheme 1, where the amine 3-6 is equivalent to R'-NH to give compounds of fom~ula 3-7. Compounds of formula 3-7 can be reacted with compounds of formula 3-2 in a manner analogous to the procedure set forth for the synthesis of compounds of formula 3-3 to afford compounds of formula 3-5.
pC'TIIBOOI00296 Scheme 4 ' o , co=at 'f' R~NHNHZ , , ' , N Rs~
I 4'Z
BoC A-'~
4-1 \ 6 , -f- alkyl~Lv~
OzEt N
R~ J
O I
R'2 ~ -~ R~NHNH~ BoC ' , N , 8oc 4-1a ~ ' 4-3 where A = NH and B = CO (C,-C,)alkyi-Lv~ 4~3 where A = N-alkyl and B = CO
or or M3 where A = CO and B = NH 4.3 where A = CO and 8 = N ~ alkyl R~ ' /
A-N
\ S /R'u A~N
N
R~
R~ ~ N N
N ./ \Rt H
4~
Compounds of formula 4-5 are prepared according to Scheme 4 and more particularly as described below.
Compounds of formula 4-3 are prepared by reacting a compound of formula 4-2 with a compound of formula 4-1 or 4-1 a. Compounds of formula 4-1 and 4-1 a are prepared according to methods well known to those skilled in the art. Where R'~ is hydrogen, 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3~thyl ester is condensed with a compound of formula 4-2 to afford a compound of formula 4-3.
Said .89 compounds of formula 4-2 are readily available from well known commercial"vendors, known in the literature, or are synthesized under standard conditions well known to those skilled in the art. Preferred conditions to prepare compounds of formula from a compound of formula 4-1 where A is CO and B is NH or from a compound of formula 4-1 a where A is NH and B is CO can be found in March, J. Advanced Organic Chemistry, 3'~ ed.; John wley and Sons Inc.: New York, 1985, p 1163. The reaction is conducted at ambient pressure in a reaction inert solvent. Preferred such solvents include aqueous media, a (C,-C,)alcohol, glacial acetic acid, an aromatic or aliphatic hydrocarbon, a polar aprotic solvent, a halocarbon and ethers or combinat'rons thereof. The reaction time ranges from 2 hours to 3 days and the reaction temperature ranges from ambient temperature to the reflux temperature of the solvent being used. An optional second step using aqueous or non-aqueous base may be employed in certain cases which will be recognized by those skilled in the,art. This second step is conducted at ambient pressure in a reaction inert solvent.
Preferred such solvents include aqueous media, a (C,-C,)ahhol, glaaal acetic acid, an aromatic or aliphatic hydrocarbon, a polar aprotic solvent, a halocarbon and ethers oT
combinations thereof. The reaction time ranges from 2 hours to 3 days and the reaction temperature ranges from ambient temperature to the reflux temperature of the solvent being used.
Compounds of formula 4-3 wherein B is CO and A is N-alkyl or wherein B is N-alkyl and A is CO are prepared by alkytation of compounds of formula 4-3 where B
is CO and A is NH or wherein B is NH and A is CO, respectively. The anion of those compounds of formula 4-3 is formed by reaction with an appropriate base.
Preferred such bases inGude sodium hydride and sodium hexamethyldisilazide, although other bases may be used where conditions warrant, as determined by the skilled person.
The reaction is conducted in a reaction inert solvent, preferably an ether such as tetrahydrofuran, diethyl ether, dioxane or diglyme or polar aprotic solvent such as dimethylfomlamide. The reaction proceeds at ambient pressure and at temperatures ranging from -100 °C to ambient temperature. The reaction times are from 10 minutes to 2 hours. Addition of (C,-C,)alkyl halides or (C,-C,~Ikylsulfonates such as mesylate, tosylate-or nosylate to the anion of 4-3 proceeds at ambient pressure and at temperatures ranging from -20 'C to 50 'C. The reaction times range from 10 minutes to 1 day.
Compounds of formula 4-4 are prepared form compounds of formula 4-3 , wherein A is N-alkyl and B is CO or A is CO and B is N-alkyl via acid-catalyzed , deprotection of the Boc carbamate under standard conditions, for example, hydrochloric acid or trifluoroacetic aad in a reaction inert solvent or in the absence of solvent. Such conditions are known to those skilled in the art. Exemplary conditions are disGosed in Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2"° ed.; John Wiley and Sons lnc.: New York, 1991, pp 327-330.
Compounds of formula 4-5 are. prepared by the displacement reaction of amine 4-4 as described in Scheme 1; where the amine ~ is equivalent to R'-H.
Scheme 5 H X~Ra / /
~N N
z ~z Re-X-Lv3 .f: ( ~G' ~ ~ Z~G~
S_1 ~G
N N
s-2 Prt i Prt H -°
R9-X-Lv' -t-Compounds of formula 5-4 where X is a covalent bond and G, G', GZ, q, R', R2, R6, R' and Ra are as defined above are prepared according to Scheme 5 above and particularly as described below.
Compounds of formula 5-3 are prepared by reaction of a compound of formula 5-1 with a compound of formula 5-2 where Prt is an optional amine protecting group selected from benzyl and C02R~°, where R°° is selected from (C,-C,~lkyl, (C,-C,)allyl, pCT/IB00/00296 trichloroethyl and benzyl substitutedby up to two (C,-C,)alkoxy. Compounds of formula 5-1 where Rg is Ar' and Lv' is halo, (C,-C,)alkytsulfide, (C,-C,)alkylsulfone, . , trifluoromethanesulfonate, (C,-C6)alkylsulfonate or phenyisulfonate, where said phenyl is optionally substituted with up to three halo, vitro or (C,-C,)alkyl are commercially available or are readily prepared according to methods well known to those skilled in the art. For example, to prepare compounds of formula 5-1 wherein Lv' is chloro, a compound of formula Ar'-OH, or the Ar'-(=O) tautomer thereof, is reacted with a chlorinating agent such as phosphorus oxychloride and/or phosphorus pentachloride.
This chlorinating reaction is conducted at ambient pressure in the absence of solvent ~ 0 or in a reaction inert solvent, preferably a halocarbon solvent, at temperatures ranging from ambient temperature to 180 °C. Treatment of the chloro compound with the requisite mineral acid provides compounds of formula 5-1 where Lv' is bromo or iodo.
Compounds of formula 5-1 wherein Lv' is trifluoromethanesutfonate, (C,- 1 Cs~lkylsulfonate or phenylsulfonate are prepared from a compound of formula Ar'-OH, or the Ar'-(=O) tautomer thereof, by reaction with a sulfonic acid chloride or anhydride in the presence of a base, preferably an organic amine such as triethylamine, N,N'-diisopropylethylamine, dimethytaminopyridine or pyridine.
In certain cases it wiU be recognized by those skilled in the art that a catalyst will be required to effect reaction. In those cases, a preferred catalyst is 4-dimethylaminopyridine. This reaction is conducted at ambient pressure in a reaction inert solvent such as pyridine, a halocarbon, an aromatic or aliphatic hydrocarbon, an ether, or a combination thereof. The reaction temperature ranges from -20 °C to 100 °C and the reaction time ranges from 15 minutes to 1 day. Compounds of formula 5-1 where Lv' is thiomethyl are prepared by reacting a compound of formula Ar'-SH, or the Ar'-(=S) tauLomer thereof, with methyl iodide or dimethylsuifate in the presence of an inorganic base, preferably potassium carbonate. These reactions are conducted at ambient pressure in a reaction inert solvent, preferably an ether or a polar aprotic solvent. An espeaalfy preferred polar aprotic solvent is dimethylfomiamide at a temperature ranging from 0 °C to 100 °C. Compounds of formula 5-1 where Lv' is methylsutfone are, prepared from a compound of formula 5-1 where Lv' is thiomethyl by oxidation thereof according to procedures well known to those skilled in the art, specifically~s set forth in March, J. Advanced Organic Chemistry, 3"°
ed:; John wley and Sons.: New York, 1985, pp 1089-1090.
pCTIIB00/00296 -92_ A representative set of compounds of formula 5-1 which are commercially available or which can be prepared according to methods analogous to a literature procedure inGude 4-chloropyridine (Aldrich, P.O. Box 355, Milwaukee, Wisconsin 53201, USA), 3-chlon~-6-methyl-pyridazine (Maybridge, c/o Ryan Saentific, 443 Long Point Road, Suite D, Mount Pleasant, South Carolina 29464, USA), 2-chloro-pyrazine (Aldrich), 2,6-dichloro-pyrazine (Aldrich), 3-chloro-2,5-dimethylpyrazine (Aidrich), 2,4-dichloro-pyrimidine (Aldrich), 4,6-dict~loro-pyrimidine (Atdrich), 4-chloro-2-methyl-pyrimidine CChem. Ber. 1904, 37, 3641 ), 4-c~loro-6-methyl-pyrimidine CChem.
Ber.
1899, 32, 2931 ), 4-chloro-2,6-dimethyl-pyrimidine (J. Am. Chem. Soc. 1946, 68, 1299), 4-chloro-2,6-bis(trifluoromethyl)-pyrimidine (J. Org. Chem.1961, 26,4504), 4-chloro-2-methylsulfanyl-pyrimidine (Aldrich), 4-~chloro-2-methoxymethyl-pyrimidine (US Patent 5 215 990), 1-chloro-isoquinoline (J. Am. Chem. Soc. 1946, 68, 1299), 2-chloro-quinoline (Aldrich), 4-chloro-quinazoline (J. Am. Chem. Soc. 1909, 39, 509); 2-chloro-quinoxaline (US Patent 2 537 870), 2-chloro-3-methyl-quinoxafine (Aldrich), 2,6,7-trichloro-quinoxaline (J. Chem. Soc., Chem. Commun. 1956, 4731 ), 4-chtoro-pteridine (J. Chem. Soc., Chem. Commun. 1954. 3832), 7-chloro-pteridine (J.
Chem.
Soc., Chem. Commun. 1954, 3832), and 6-chloro-9H-purine (Aldrich). Other compounds of formula 5-1 can be prepared using methods well known to those skilled in the art or by using methods analogous to those described in the foregoing references.
Compounds of formula 5-3 are prepared by the displacement reaction of a compound of formula 5-1 with an amine of the formula 5-2. The reaction is conducted in the presence of a non-aqueous base, prefeably an organic amine such as pyridine, 4~iimethylaminopyridine, triethylamine or N,N'-diisopropyiethyfamine; an inorganic base such as potassium or sodium carbonate or bicarbonate; o~ an alkaline metal alkoxide such as potassium t-butoxide. Alternatively, an excess of the reacting amine 5-2 can be used in lieu of the added base. In cases where the leaving group Lv' is unactivated, or in speafic cases which will be recognized by those skilled in the art, the use of a transition-metal catatyst such as palladium(0), palladium (II), nidcel(0) or nidcel(ll), along with phosphine-based ligands, such as 2,2'-bis(diphenytphosphino)-1,1'-binaphthyl (BINAP), may be required to effect reaction. More spedfic details concerning this reaction are available in the following references: J. Org.
Chem.1997, 62, 1264; J. Org. Chern: 1997, 62, 1568; SymLett 1997, 329. The reacfron can be conducted in the absence of solvent or in a reaction inert solvent. Preferabl2 reaction , , inert solvents inGude aqueous media, (C,-C,)alcohol, (CZ-C6)glycol, a halocarbon, an aliphatic or aromatic hydrocarbon, an ether, a polar aprotic solvent, a ketone, or combinations thereof. The reacfion time ranges from 15 minutes to 3 days and the reaction temperature ranges from 0 °C to 180 °C or to the reflux temperature of the solvent being used. The reactions are preferably conducted at ambient pressure.
In certain cases which will be recognized by those skilled in the art, transformations of existing functionality in Ar' of compound 5-3 may be necessary to produce compounds of formula 5-4. This pertains in particular to those cases where;
for example, R9~ in 5-3 contains an aromatic or heteroaromafic halide, (C, C,)alkylsulfonate or triflate. Said compounds of formula 5-3 wherein Ar' contains up to two substituents selected from halide, (C,-C,)alkylsulfonate or trii3ate, ray be converted to a compound of formula Ar' where said halide, (C,-C,)alkylsulfonate or triflate is transformed into another functional group by a reduction reaction or by a displacement reaction of said halide, (C,-C,)alkylsulfonate or triflate with a nuGeophile. The reduction reaction is conducted with a reduang agent, preferably ammonium fomzate or hydrogen gas, in a reaction inert solvent. The reduction is conducted in the presence of a palladium catalyst at ambient pressure or under a hydrogen pressure of up to 50 psi. Preferred solvents include (C,-C,)atcohots such as methanol and ethanol, and ether solvents such as diethyl ether, dioxane and tetrahydrofuran. The nucleophilic displacement reaction may be conducted by adding the nucleophile directly or by pre-forming the nucleophile separately or in situ from a nucleophile precursor. Preferred nuGeophiies include organoaluminum, organoboron, organocopper, organotin, organozinc or Grignard reagent; R"-oxide or R"-thioxide; or anilino where anilino is within the scope of R". It will be recognized by those slulled in the art that transition-metal catalysts may be required to effect reaction in certain displacement reactions. When required, such transition metal catalysts may include palladium(0), paNadium(II), nickel(0), and nidcel(II) complexes. Palladium(//) bis(diphenylphosphinobutane) dichloride is a preferred such catalyst.
Additionally, an aqueous or non-aqueous base may be required in the displacement reaction.
Preferred such bases inGude sodium carbonate, sodium hydride, triethylamine and sodium test-butoxide. The reaction is conducted at ambient pressure in a reaction inert solvent such as a halocarbon, an aromatic or aliphatic hydrocarbon, an ether or a polar aprotic solvent or a combination thereof. In certain cases, a (C,-C,)alcohol is used as a solvent or co-solvent. The reaction temperature ranges from -20 °C to the reflux temperature of the solvent employed. The reaction time ranges from 1 hour to 3 days.
Optional protecting groups which riiay be present in compounds of formula S-3 are removed according to methods set forth above, or according to methods well known to those skilled in the art, particularly as set forth in: Greene, T.
W.; Wuts, P.
G. M. Protective Groups in Organic Synthesis, 2"° ed.; John Wiley and Sons inc.: New York, 1991.
Compounds of formula 5~ are prepared from the displacement reaction of amine 5-3 as described in Scheme 1, where the amine 5-3 is equivalent to R'-NH. A
representative set of amines of formula 5-3 which are commercially available or which can be prepared by a literature procedure include 1-phenyl-piperazine (Aldrich), 1-, pyridin-2-yl-piperazine (Aldrich), 3-piperazin-1-yl-benzo[d)isoxazole (J. Med.
Chem.
1986. 29, 359), 3-piperazin-1-yl-benzo[d]isothiazole (J. Med. Chem. 1986, 29, 359), 2-piperazin-1-yl-quinoxaline (J. Med. Chem.1981, 24, 93), 1-naphthalen-2-yl-piperazine (cf. Tetrahedron Lett. 1994; 35, 7331 ), and 1-(3,5-dimethylphenyl)-piperazine (cf.
Tetrahedron Lett 1994, 35, 7331 ). Other compounds of formula 5-3 can be prepared using methods well khown to those skilled in the art or by using methods analogous to those described in the foregoing references.
Alternatively, compounds of formula 5~ can be prepared from reaction with compounds of formula 5-1 with compounds of formula 5-5 using conditions set forth above to prepare 5-3. Compounds of formula 5-5 can be prepared in a manner analogous to the method used to prepare compounds of formula 1-3.
Compounds of formula 5~ wherein X is oxycarbonyl, vinylenylcarbonyl, oxy(C,-C,)alkylenylcarbonyl, (C,-C,)alkylenylcarbonyl, (C,-C,)alkenylcarbonyl, thio(C,-C,)alkenylcarbonyl, vinylenylsulfonyl or carbonyl(Co-C,)alkylenylcarbonyl;
wherein said oxy(C,-C,)alkylenylcarbonyl, (C,-C,)alkylenylcarbonyl, (C,-C,~Ikenyicarbonyl, and thio(C3-C,)alkenytcart~ony! in the definition of X are each optionally and independently substituted with up to two (C,-C,)alkyl, benzyl, or Ar; said vinylenylsulfonyt and said vinylenylcarbonyl in the definition of X are each optionally and independently substituted with up to three (C,-C,)alkyl, benzyl, or Ar are also prepared according to Scheme 5 above and particularly as described below.
Compounds of formula 5-4 where X is as defined in the immediately preceding paragraph are prepared by reacting a compound of formula 5-5 with a compound of formula 5-1 where Rs is described above, X is as defined in the immediately preceding paragraph and Lv3 is chtoro. The reaction is conducted under anhydrous conditions in the presence of a non-aqueous base, which includes organic amines such as triethytamine, N,N'-diisopropylethylamine and pyridine and derivatives thereof, The reaction is generally conducted in a reaction inert solvent. Preferred solvents include haiocarbon, aliphatic or aromatic hydrocarbon, ethers, ethyl acetate, pyridine and combinations thereof. The reaction time ranges from 15 minutes to 24 hours and the ,.
reaction temperature ranges from 0 °C to 80 °C or to the reflux temperature of the solvent being used. The reactions are preferably conducted at from 0 'C to ambient temperature and at ambient pressure. Removal of optional protecting groups is carried out as described in Scheme I.
Compounds of formula 5-4 wherein X is vinylenylcarbonyl, oxy(C,-C,~Ikylenyicarbonyl, (C,-C,~Ikylenylcarbonyl, (C,-C,)alkenylcarbonyl, thio(Cz-C,)alkenylcarbonyl, or carbonyl(Co-C,~ifcylenyfcarbonyl ; wherein said oxy(C,-C,)alkylenylcarbonyl, (C,-C,)atkylenylcarbonyl, (C,-C,)atkenylcarbonyl, and thio(C=-C,)alkenylcarbonyl in the definition of X are each optionally and independently substituted with up to finro (C,-C,)alkyl, benryl, or Ar; and said vinylenylcarbonyl in the definition of X are each optionally and independently substituted with up to three (C,-C,)alkyl, benzyt, or Ar are also prepared according to Scheme 5 avove and particularly as described below.
Compounds of formula 5-4 are prepared by reacting a compound of fomnuta 5-5 with a compound of formula RQ-X-Lv' where R° is described above, X is as defined in the immediately preceding paragraph and Lv' is OH. The reaction is conducted in the presence of coupling agents, preferably dicydohexylcarbodiimide or 1-(3-dimethylaminopropyl~3-ethylcarbodiimide hydrochloride as described in J:
Artier.
Chem. Soc.1996, 178, 4952. The reaction is conducted in a reaction inert solvent Preferred solvents include halocarbon, aliphatic or aromatic hydrocarbon and ethers.
Espeaally preferred solvents include dichloromethane and chloroform. Other coupling agents that can be used are well known to those skilled in the art and include, but are not limited to, various phosphine reagents, ethyl chlorofom~ate, and N-hydroxysucanimide. These reagents and procedures are described in "Compendium pCTIIB00100296 _gg_ of Organic Synthetic Methods" (Ed., I. T. Harrison and_ S. Harrison, John ~ley &
Sons). Specific references include the following: J. Org. Chem,~1971, 36, 1305; BuIL
Soc. Chim. Fr., 1971, 3034; Bull. Chem. Soc. Japan, 1971, 44, 1373;
Tetrahedron Lett., 1973, 28, 1595; Tetrahedron Letf., 1971, 26, 2967, and J. Med. Chem., 1968, 17, 534. Removal of optional protecting groups is carried out as described in Scheme Compounds of formula 5~ wherein X is a covalent bond and Rs is (C,-C,)cycloalkyl or Ar'-(C,-C3)alkylenyl are also prepared according to Scheme 5 above and particularly as described below.
Compounds of formula 5-4 wherein X is a covalent bond and R9 is (C,-C,)cydoalkyl or Ar'-{C,-C,)alkylenyl are prepared by reacting a compound of formula 5-1 wherein X is a covalent bond, R9 is (C3-C,)cydoalkyl or Ar'-(C,-C,)alkylenyl and Lv' is halo, methanesulfonate, p-toluenesulfonate or trifluoromethanesulfonate. The reaction is conducted under anhydrous conditions in the presence of a non-aqueous base, which inGudes organic amines such as triethylamine, N,N'-diisopropylethylamine and pyridine and derivatives thereof. The reaction is conducted in a reaction inert solvent. Preferred solvents for the reaction include halocatbons, aliphatic or aromatic hydrocarbons, ethers, ethyl acetate, pyridine and combinations thereof. The reaction time ranges from 15 minutes to 24 hours and the reaction temperature ranges from -20 °C to 80 °C or to the reflux temperature of the solvent being used. The reactions are preferably conducted at ambient temperature of the solvent being used and at 'ambient pressure. Removal of optional protecting groups is conducted as set forth in Scheme I.
Scheme 6 H HN Rn Rsz ~
/ ~NHz N
z~G, ~ ( z~G' .acid + Lv6~0 ~G ~ ~ G_ N a I i R" R'z Prt 5_2 Prt O O
6-zd R"
Ru a N
~N
TzN
( z~ G, N
I
Prt &3 6rt R"
HN
H ~NHz / ~ Rsx N N .2CId N _ ( z)c G, ( z) x , / N
N
N -.a N ( z)a z~
z R / ~ Rz / N N
N~Rs N"R' Rz / N
N R' Compounds of formula 6-5 wherein G, G', G~, q, R', RZ, 'R6, R' and R°
are as defined above are prepared as set forth in Scheme 6 above and particularly as described below.
Compounds of formula 6-1 are prepared from an amine of the formula 5-2 where Prt is an optional amine protecting group selected from benzyl and C02R~°, where R~° is selected from (C,-C,)atkyl, (C,-C,)allyl, trichloroethyl and benzyl substituted with up to two (C,-C,)aikoxy. The preferred procedure for preparing ' pCT/IB00100296 compounds of formula 6-1 can be found in Tetrahedron Left. 1993, 48, 7767 or J. Org.
Chem 1997, 62, 1540. ' Compounds of formula 6-3 are prepared by condensation of ~diketones or ~3-ketoesters of the formula 6-2b, where R" and.R'Z aye independently substituted as set forth above, or compounds of the formula 6-2a where Lv' is, for example, hydroxy, chloro or dimethylamino with guanidines of the formula 6-1. The reaction is conducted in the presence of an aqueous or non-aqueous base, preferably potassium or sodium hydroxide, potassium or sodium (C,-C,~alkoxide, triethylamine, pyridine, 4-dimethylaminopyridine, potassium or sodium carbonate or potassium or sodium bicarbonate. The reaction is conducted in a reaction inert solvent, preferably aqueous media, a (C,-C,)alcohol, a (CZ-C6)dialcohol, an aroma#ic hydrocarbon, a polar aprotic solvent, or combinations thereof. The reaction time ranges from 2 hours to 3 days and the reaction temperature ranges from room temperature to reflux of the solvent employed. The reaction is preferably run at ambient pressure, but may be conducted at pressures up to 250 psi.
Removal of of optional protecting groups in compounds of formula 6-3 to afford compounds of formula 6-4 is accomplished as set forth above.
Compounds of formula 6-5 are prepared from the displacement reaction of amine 6-4 as described in Scheme 1, where the amine 6-4 is equivalent to R'-NH.
Alternatively, compounds of formula 6-5 are prepared from compounds of formula 5-5 by formation of a compound of formula 6-6, or by reaction with compounds of formula 6-2a or 6-2b under the conditions outlined above in Scheme 6 Removal of optional protecting groups is conducted as described in Scheme 1.
Compounds of fomlula 5-5 are prepared as set forth above.
_99_ Scheme 7 H
N
.~. HNRx~R~
R~ " 7.3 / ~N
\
N~R' 7-0 7.~ 1 . .
H
TN R~
x),~°~G4 Rx,NCO
G ~-0 N
or Rx / N ---.r O R' N- _R' ~ x, Ct NR R
7.4 Compounds of formula 7-4 wherein G', G', G5, r, R', R2, R'°, R'9 and R~° are defined as set forth above are prepared as set forth in Scheme 7 and particulariy as described below.
Compounds of formula 7-1 are prepared by reaction of an amine of the formula 7-0 with phosgene or a phosgene equivalent such as triphosgene.
Compounds of 7-1 wherein the chloro group is replaced by an imidazolyl group are also useful in this reaction. Such compounds are prepared by reaction of an amine of formula 7-0 with carbonyl diimidazole. The reaction is conducted under anhydrous conditions in the presence of a nonaqueous base. Preferred such bases indude triethylamine and other tertiary 'amines and pyridine and' derivatives thereof. The reaction is conducted in a reaction inert solvent at -78 ~°C to 80 °C or at the reflux temperature of the solvent being used for 15 minutes to 24 hours. Preferred solvents for this reaction indude a halocarbon, an aliphatic or aromatic hydrocarbon, an ether, ethyl acetate, pyridine and combinations thereof. The reactions are preferably conducted at from 0 °C to ambient temperature and at ambient pressun:.
Compounds of formula 7-4 are prepared by reaction of carbamoyl chlorides of the formula 7-1 with amines of the formula 7-3, where R2' and R~ are defined above.
The reaction can be conducted in the absence of solvent, or in a reaction inert i0 solvent. Preferred such solvents indude aqueous media, a (C,-C,)aloohol, a (C2-C6)dialcohol, an aromatic or aliphatic hydrocarbon; a halocarbon, an ether, a polar aprotic solvent, a ketone, pyridine or combinations thereof. The reaction time ranges from 15 minutes to 3 days and the reaction temperature ranges from 0 °C to the reflux temperature of the solvent being used. 'The reaction is preferably conducted at ambient pressure. It will be recognized by those skilled in the art that addition of a base may be required to effect reaction. In those cases, preferred bases indude potassium or sodium hydroxide, triethyiamine and other tertiary amines, pyridine and its derivatives and inorganic bases such as sodium or potassium carbonate and sodium or potassium bicarbonate. Removal of optional hydroxyl protecting groups contained in R' is canied out according to methods set forth in Scheme 1.
Attematively, compounds of formula 7-4 are prepared from compounds of formula 7-0 by reaction with isocyanates of the formula 7-6 or with carbamoyl chlorides of the formula 7-8. Said isocyanates are commer~cialiy available, known in the literature, or synthesized under standard conditions known to those skilled in the art, particularly as described in March, J. Advanced Organic Chemistry, 3"° ed.; John Whey and Sons Inc.: New York, 1985, p 1166. A preferred method of forming such isocyanates is the Curtius rearrangement of a suitable aryl azide. Said carbamoyl chlorides are synthesized using methods analogous to that described for the preparation of vompounds of formuta 7-1 in Scheme 7. Removal of optional hydroxyl protecting groups contained in R' is carried out according to methods set forth in Scheme 1.
WO 00/59510 PG"TIIB00100296 Compounds of formula I containing the radicaLR'' are prepared according to the procedures set forth in Scheme 7 using the corresponding starting materials and reagents.
Scheme 8 Rze I \ ~ HCHO ,, ,.
R
Rr ,- Rze NHz Rz9 RZs 8-1a ~
Rr or Rze N
I \ ~ H
R 8.2 NHz 8~5 8-1b Rr ~ --N
Prt Prt Compounds of formula 8-5 are prepared as set forth in Scheme 8 and particularly as described below.
Compounds of formula 8-2 are readily prepared from commercially available phenethyiamines of formula 8-1 a and formaldehyde or an aidehyde of the formula R~'-CHO under Pictet-Spengler conditions. The Pictet-Spengler reaction is reviewed in Chem. Rev.1995, 95,1797. A similar route route to 1,2,3,4-tetrahydroiso4uinolines using the Bischler Napiecalski reaction, as disclosed in March, J. Advanced Organic Chemistry, 3'~ ed.; ,fohn Wiiey and Sons.: New York, 1985, 495, followed by standaM
reduction of the imine formed may also be employed.
pCfIIB00100296 Compounds of formula 8-4 are prepared from compounds of formula 8-3 by aromatic electrophilic substitution using the appropriate~electrophile. A
genera!
reference for this type of reaction can be found in March, J. Advanced Organic Chemistry, 3'° ed.; John Wiley and Sons.: New York, 1985, 4.47-511.
Compounds of formula 8-2 are also prepared by removal of the protecting group from a compound of formula 8-4. Preferably the protecting group is trifluoroacetamide which may be removed under basic conditions using inorganic hydroxides or carbonates in a reaction inert solvent. Suitable suds solvents include (C,-C,)aicohols and preferably methanol. Optionally, one or more co-solvents, preferably selected from water, tetrahydrofuran and dioxane may be employed.
The reaction time ranges from 15 minutes to 24 hours.and the reaction temperature ranges from 0 °C to 100 °C or to the reflux temperature of the solvent or solvent system being used. The reaction is preferabfy'conducted at ambient temperature.
Other conditions for deprotection of trifluoroacetamides and deprotection conditions for other suitable protecting groups can be found in Greene, T. W.; Wuts, P.
G. M.
Profective Groups in Organic Synthesis, 2"° ed.; John Wiley and Sons Inc.: New York, 1991.
Compounds of formula 8-4 are prepared by, adding a protecting group to compounds of fon'nuta 8-2. Preferably the protecting group is trifluoroacetamide or tert-butoxycarbonyl (BOC). The protecting group is attached by reaction of a compound of formula &2 with trifluoroacetyl chloride or di-tart-butyl dicarboriate or an equivalent thereof in the presence of a base, preferably triethylamine or pyridine. The reaction is conducted in a reaction inert solvent. Preferred such solvents indude ethers such as tetrahydrofuran, diethyl ether, dioxane or dimethoxyethane; a halocafion such as dichloromethane, chloroform or carbon tetrachloride; and aromatic or aliphatic hydrocarbons such as benzene, toluene or hexanes. The reaction bme ranges from 15 minutes to 3 days and the reaction temperature ranges from 0 °C to the reflux temperature of the solvent being used. The reaction is preferably conducted at ambient pressure. Other conditions for protection of amines with trifluoroacetamides or tart-butoxycarbonyl groups as welt as other suitable protecting groups can be found in Greene, T. W.; Wuts, P. G. M. Prr~tecfive Groups in Organic Synfhesis, 2"° ed.; John Wiley and Sons Inc.: New York, 1991:-Manipulation of the substituents R'° and R~ is cartied out to provide isoquinolines with altered substitution. Preferably, transition metal-catalyzed cross- , coupling of a compound of formula 8-4 where R~° or R~' is bromide or triflate is employed to afford compounds of formula 8-4 wherein R~° or R~' are as set forth above. This reaction is conducted according to methods well known to those skilled in the art, particularly as set forth in TetrBhedron,1998, 54, 263 far Stille and Siizuki Reactions and in Acc. Chem. Res.1998, 31, 805 for Buchwald Amination Reactions.
Compounds of formula 8-5 are prepared from the dispia<:ement reaction of amine 8-2 as described in Scheme 1, where the amine 8-2 is equivalent to R'-NH.
Scheme 9 O
COi~t , , HCI
NH
acid RZe~N
/ Hz
Scheme 3 ~~ ~a~
R'~ R"
v R + o ~ j.
Me OH
r ~ R
R -) R~7 ' '9 R R
N
H
O
R~ ~R~s ~- 3 2 3-5 N
hi Compounds of formula 3-5 are prepared as set forth in Scheme 3 above and more particularly as described below.
Compounds of formula 3-3 are prepared by condensing a compound of formula 3-'i with a compound of fomwia 3-2. Where R'° and R'°
are each H, the carnpound of formula 3-1 is 1-benryl-4-piperidone, which is commercially available pCTIIB00/00296 from Aldrich. Compounds of formula 3-2 are either coriamercially available or can be prepared according to methods well known to those skilled in the art"
particularly according to methods set forth in March, J. Advanced'Organic chemistry, 3'° ed.;
John Wiley and Sons Inc.: New York, 1985, pp 499-500. The reaction is conducted at ambient pressure in the presence of a secondary amine. generally an excess of the secondary amine, preferably pyrrolidine, piperidine, morpholine or diethytamine, is used. An especially preferred secondary amine is pyrrofidine. The reac#ion is conducted in a reaction inert solvent, preferably a (C,-C,)aioohol, an aromatic or aliphatic hydrocarbon, a polar aprotic solvent, a halocarbon or an ether.
An.especially preferred solvent is ethanol. The reaction time ranges from 2 hours to 3 days and the reaction temperature ranges from ambient temperature to the reflex temperature of the solvent being employed.
Compounds of the formula 3-4 are prepared by removal of the benzyl protecting group from compounds of formula 3-3. This transforma#ion is conducted in a manner analogous to the procedure set forth for the preparation of compounds of formula 2-6 above.
Compounds of formula 3-5 are prepared from the displacement reaction of amine 3-4 as described in Scheme 1, where the amine 3-4 is equivalent to R'-NH.
Scheme 3a Ray R w ---.-- R'°-~-- ,~--R's --N FZ ~N~ ~R~
R
3a-~ _ , 3-5 3a 2 pGT/IB00/00296 Compounds of formulas 3a-1 and 3a-2 are prepared as shown in Scheme 3a , , from compounds of formula 3-5. Thus, to prepare a compound of 3a-1, a compound of formula 3-5 is reduced with a common reduang agent, such as, for example, sodium borohydride, lithium aluminum hydride or diisobutylaluminum hydride.
Other reducing agents capable of effecting the reduction of a ketone to an alcohol are well known to those skilled in the art (e.g., Larodc, R. D. Comprehensive Or~janic.
.
Transformations, VCH Publishers, lnc.: New York, 1989, pp 527-547). Likewise, compounds of formula 3a-2 are prepared from compounds of formula 3-5 by reduction with reducing agents capable of redudng a ketone completety to a methyfene group. A preferred such reducing agent is aluminum tridiloridelborane-tert-butylamine complex. Other such reducing agents are well known to those skilled in the art (e.g., J. Org. Chem.1989, 54. 4350; Larodc, R. D. Compr~ehensiv~
Organic Transformations, VCH Publishers, Inc.: New York, 1989, pp 35-37). It will be recognized by those skilled in the art that the transformation of 3-5 to 3a-1 or 3a-2 can be conducted at different points in Scheme 3, depending upon the dynamics of the particular system.
Alternatively, compounds of formula 3-5 wherein R'° and R" are hydrogen can be prepared from 4-piperidone monohydrate monochloride in a manner analogous to the procedure described in Scheme 1, where the amine 3-6 is equivalent to R'-NH to give compounds of fom~ula 3-7. Compounds of formula 3-7 can be reacted with compounds of formula 3-2 in a manner analogous to the procedure set forth for the synthesis of compounds of formula 3-3 to afford compounds of formula 3-5.
pC'TIIBOOI00296 Scheme 4 ' o , co=at 'f' R~NHNHZ , , ' , N Rs~
I 4'Z
BoC A-'~
4-1 \ 6 , -f- alkyl~Lv~
OzEt N
R~ J
O I
R'2 ~ -~ R~NHNH~ BoC ' , N , 8oc 4-1a ~ ' 4-3 where A = NH and B = CO (C,-C,)alkyi-Lv~ 4~3 where A = N-alkyl and B = CO
or or M3 where A = CO and B = NH 4.3 where A = CO and 8 = N ~ alkyl R~ ' /
A-N
\ S /R'u A~N
N
R~
R~ ~ N N
N ./ \Rt H
4~
Compounds of formula 4-5 are prepared according to Scheme 4 and more particularly as described below.
Compounds of formula 4-3 are prepared by reacting a compound of formula 4-2 with a compound of formula 4-1 or 4-1 a. Compounds of formula 4-1 and 4-1 a are prepared according to methods well known to those skilled in the art. Where R'~ is hydrogen, 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3~thyl ester is condensed with a compound of formula 4-2 to afford a compound of formula 4-3.
Said .89 compounds of formula 4-2 are readily available from well known commercial"vendors, known in the literature, or are synthesized under standard conditions well known to those skilled in the art. Preferred conditions to prepare compounds of formula from a compound of formula 4-1 where A is CO and B is NH or from a compound of formula 4-1 a where A is NH and B is CO can be found in March, J. Advanced Organic Chemistry, 3'~ ed.; John wley and Sons Inc.: New York, 1985, p 1163. The reaction is conducted at ambient pressure in a reaction inert solvent. Preferred such solvents include aqueous media, a (C,-C,)alcohol, glacial acetic acid, an aromatic or aliphatic hydrocarbon, a polar aprotic solvent, a halocarbon and ethers or combinat'rons thereof. The reaction time ranges from 2 hours to 3 days and the reaction temperature ranges from ambient temperature to the reflux temperature of the solvent being used. An optional second step using aqueous or non-aqueous base may be employed in certain cases which will be recognized by those skilled in the,art. This second step is conducted at ambient pressure in a reaction inert solvent.
Preferred such solvents include aqueous media, a (C,-C,)ahhol, glaaal acetic acid, an aromatic or aliphatic hydrocarbon, a polar aprotic solvent, a halocarbon and ethers oT
combinations thereof. The reaction time ranges from 2 hours to 3 days and the reaction temperature ranges from ambient temperature to the reflux temperature of the solvent being used.
Compounds of formula 4-3 wherein B is CO and A is N-alkyl or wherein B is N-alkyl and A is CO are prepared by alkytation of compounds of formula 4-3 where B
is CO and A is NH or wherein B is NH and A is CO, respectively. The anion of those compounds of formula 4-3 is formed by reaction with an appropriate base.
Preferred such bases inGude sodium hydride and sodium hexamethyldisilazide, although other bases may be used where conditions warrant, as determined by the skilled person.
The reaction is conducted in a reaction inert solvent, preferably an ether such as tetrahydrofuran, diethyl ether, dioxane or diglyme or polar aprotic solvent such as dimethylfomlamide. The reaction proceeds at ambient pressure and at temperatures ranging from -100 °C to ambient temperature. The reaction times are from 10 minutes to 2 hours. Addition of (C,-C,)alkyl halides or (C,-C,~Ikylsulfonates such as mesylate, tosylate-or nosylate to the anion of 4-3 proceeds at ambient pressure and at temperatures ranging from -20 'C to 50 'C. The reaction times range from 10 minutes to 1 day.
Compounds of formula 4-4 are prepared form compounds of formula 4-3 , wherein A is N-alkyl and B is CO or A is CO and B is N-alkyl via acid-catalyzed , deprotection of the Boc carbamate under standard conditions, for example, hydrochloric acid or trifluoroacetic aad in a reaction inert solvent or in the absence of solvent. Such conditions are known to those skilled in the art. Exemplary conditions are disGosed in Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2"° ed.; John Wiley and Sons lnc.: New York, 1991, pp 327-330.
Compounds of formula 4-5 are. prepared by the displacement reaction of amine 4-4 as described in Scheme 1; where the amine ~ is equivalent to R'-H.
Scheme 5 H X~Ra / /
~N N
z ~z Re-X-Lv3 .f: ( ~G' ~ ~ Z~G~
S_1 ~G
N N
s-2 Prt i Prt H -°
R9-X-Lv' -t-Compounds of formula 5-4 where X is a covalent bond and G, G', GZ, q, R', R2, R6, R' and Ra are as defined above are prepared according to Scheme 5 above and particularly as described below.
Compounds of formula 5-3 are prepared by reaction of a compound of formula 5-1 with a compound of formula 5-2 where Prt is an optional amine protecting group selected from benzyl and C02R~°, where R°° is selected from (C,-C,~lkyl, (C,-C,)allyl, pCT/IB00/00296 trichloroethyl and benzyl substitutedby up to two (C,-C,)alkoxy. Compounds of formula 5-1 where Rg is Ar' and Lv' is halo, (C,-C,)alkytsulfide, (C,-C,)alkylsulfone, . , trifluoromethanesulfonate, (C,-C6)alkylsulfonate or phenyisulfonate, where said phenyl is optionally substituted with up to three halo, vitro or (C,-C,)alkyl are commercially available or are readily prepared according to methods well known to those skilled in the art. For example, to prepare compounds of formula 5-1 wherein Lv' is chloro, a compound of formula Ar'-OH, or the Ar'-(=O) tautomer thereof, is reacted with a chlorinating agent such as phosphorus oxychloride and/or phosphorus pentachloride.
This chlorinating reaction is conducted at ambient pressure in the absence of solvent ~ 0 or in a reaction inert solvent, preferably a halocarbon solvent, at temperatures ranging from ambient temperature to 180 °C. Treatment of the chloro compound with the requisite mineral acid provides compounds of formula 5-1 where Lv' is bromo or iodo.
Compounds of formula 5-1 wherein Lv' is trifluoromethanesutfonate, (C,- 1 Cs~lkylsulfonate or phenylsulfonate are prepared from a compound of formula Ar'-OH, or the Ar'-(=O) tautomer thereof, by reaction with a sulfonic acid chloride or anhydride in the presence of a base, preferably an organic amine such as triethylamine, N,N'-diisopropylethylamine, dimethytaminopyridine or pyridine.
In certain cases it wiU be recognized by those skilled in the art that a catalyst will be required to effect reaction. In those cases, a preferred catalyst is 4-dimethylaminopyridine. This reaction is conducted at ambient pressure in a reaction inert solvent such as pyridine, a halocarbon, an aromatic or aliphatic hydrocarbon, an ether, or a combination thereof. The reaction temperature ranges from -20 °C to 100 °C and the reaction time ranges from 15 minutes to 1 day. Compounds of formula 5-1 where Lv' is thiomethyl are prepared by reacting a compound of formula Ar'-SH, or the Ar'-(=S) tauLomer thereof, with methyl iodide or dimethylsuifate in the presence of an inorganic base, preferably potassium carbonate. These reactions are conducted at ambient pressure in a reaction inert solvent, preferably an ether or a polar aprotic solvent. An espeaalfy preferred polar aprotic solvent is dimethylfomiamide at a temperature ranging from 0 °C to 100 °C. Compounds of formula 5-1 where Lv' is methylsutfone are, prepared from a compound of formula 5-1 where Lv' is thiomethyl by oxidation thereof according to procedures well known to those skilled in the art, specifically~s set forth in March, J. Advanced Organic Chemistry, 3"°
ed:; John wley and Sons.: New York, 1985, pp 1089-1090.
pCTIIB00/00296 -92_ A representative set of compounds of formula 5-1 which are commercially available or which can be prepared according to methods analogous to a literature procedure inGude 4-chloropyridine (Aldrich, P.O. Box 355, Milwaukee, Wisconsin 53201, USA), 3-chlon~-6-methyl-pyridazine (Maybridge, c/o Ryan Saentific, 443 Long Point Road, Suite D, Mount Pleasant, South Carolina 29464, USA), 2-chloro-pyrazine (Aldrich), 2,6-dichloro-pyrazine (Aldrich), 3-chloro-2,5-dimethylpyrazine (Aidrich), 2,4-dichloro-pyrimidine (Aldrich), 4,6-dict~loro-pyrimidine (Atdrich), 4-chloro-2-methyl-pyrimidine CChem. Ber. 1904, 37, 3641 ), 4-c~loro-6-methyl-pyrimidine CChem.
Ber.
1899, 32, 2931 ), 4-chloro-2,6-dimethyl-pyrimidine (J. Am. Chem. Soc. 1946, 68, 1299), 4-chloro-2,6-bis(trifluoromethyl)-pyrimidine (J. Org. Chem.1961, 26,4504), 4-chloro-2-methylsulfanyl-pyrimidine (Aldrich), 4-~chloro-2-methoxymethyl-pyrimidine (US Patent 5 215 990), 1-chloro-isoquinoline (J. Am. Chem. Soc. 1946, 68, 1299), 2-chloro-quinoline (Aldrich), 4-chloro-quinazoline (J. Am. Chem. Soc. 1909, 39, 509); 2-chloro-quinoxaline (US Patent 2 537 870), 2-chloro-3-methyl-quinoxafine (Aldrich), 2,6,7-trichloro-quinoxaline (J. Chem. Soc., Chem. Commun. 1956, 4731 ), 4-chtoro-pteridine (J. Chem. Soc., Chem. Commun. 1954. 3832), 7-chloro-pteridine (J.
Chem.
Soc., Chem. Commun. 1954, 3832), and 6-chloro-9H-purine (Aldrich). Other compounds of formula 5-1 can be prepared using methods well known to those skilled in the art or by using methods analogous to those described in the foregoing references.
Compounds of formula 5-3 are prepared by the displacement reaction of a compound of formula 5-1 with an amine of the formula 5-2. The reaction is conducted in the presence of a non-aqueous base, prefeably an organic amine such as pyridine, 4~iimethylaminopyridine, triethylamine or N,N'-diisopropyiethyfamine; an inorganic base such as potassium or sodium carbonate or bicarbonate; o~ an alkaline metal alkoxide such as potassium t-butoxide. Alternatively, an excess of the reacting amine 5-2 can be used in lieu of the added base. In cases where the leaving group Lv' is unactivated, or in speafic cases which will be recognized by those skilled in the art, the use of a transition-metal catatyst such as palladium(0), palladium (II), nidcel(0) or nidcel(ll), along with phosphine-based ligands, such as 2,2'-bis(diphenytphosphino)-1,1'-binaphthyl (BINAP), may be required to effect reaction. More spedfic details concerning this reaction are available in the following references: J. Org.
Chem.1997, 62, 1264; J. Org. Chern: 1997, 62, 1568; SymLett 1997, 329. The reacfron can be conducted in the absence of solvent or in a reaction inert solvent. Preferabl2 reaction , , inert solvents inGude aqueous media, (C,-C,)alcohol, (CZ-C6)glycol, a halocarbon, an aliphatic or aromatic hydrocarbon, an ether, a polar aprotic solvent, a ketone, or combinations thereof. The reacfion time ranges from 15 minutes to 3 days and the reaction temperature ranges from 0 °C to 180 °C or to the reflux temperature of the solvent being used. The reactions are preferably conducted at ambient pressure.
In certain cases which will be recognized by those skilled in the art, transformations of existing functionality in Ar' of compound 5-3 may be necessary to produce compounds of formula 5-4. This pertains in particular to those cases where;
for example, R9~ in 5-3 contains an aromatic or heteroaromafic halide, (C, C,)alkylsulfonate or triflate. Said compounds of formula 5-3 wherein Ar' contains up to two substituents selected from halide, (C,-C,)alkylsulfonate or trii3ate, ray be converted to a compound of formula Ar' where said halide, (C,-C,)alkylsulfonate or triflate is transformed into another functional group by a reduction reaction or by a displacement reaction of said halide, (C,-C,)alkylsulfonate or triflate with a nuGeophile. The reduction reaction is conducted with a reduang agent, preferably ammonium fomzate or hydrogen gas, in a reaction inert solvent. The reduction is conducted in the presence of a palladium catalyst at ambient pressure or under a hydrogen pressure of up to 50 psi. Preferred solvents include (C,-C,)atcohots such as methanol and ethanol, and ether solvents such as diethyl ether, dioxane and tetrahydrofuran. The nucleophilic displacement reaction may be conducted by adding the nucleophile directly or by pre-forming the nucleophile separately or in situ from a nucleophile precursor. Preferred nuGeophiies include organoaluminum, organoboron, organocopper, organotin, organozinc or Grignard reagent; R"-oxide or R"-thioxide; or anilino where anilino is within the scope of R". It will be recognized by those slulled in the art that transition-metal catalysts may be required to effect reaction in certain displacement reactions. When required, such transition metal catalysts may include palladium(0), paNadium(II), nickel(0), and nidcel(II) complexes. Palladium(//) bis(diphenylphosphinobutane) dichloride is a preferred such catalyst.
Additionally, an aqueous or non-aqueous base may be required in the displacement reaction.
Preferred such bases inGude sodium carbonate, sodium hydride, triethylamine and sodium test-butoxide. The reaction is conducted at ambient pressure in a reaction inert solvent such as a halocarbon, an aromatic or aliphatic hydrocarbon, an ether or a polar aprotic solvent or a combination thereof. In certain cases, a (C,-C,)alcohol is used as a solvent or co-solvent. The reaction temperature ranges from -20 °C to the reflux temperature of the solvent employed. The reaction time ranges from 1 hour to 3 days.
Optional protecting groups which riiay be present in compounds of formula S-3 are removed according to methods set forth above, or according to methods well known to those skilled in the art, particularly as set forth in: Greene, T.
W.; Wuts, P.
G. M. Protective Groups in Organic Synthesis, 2"° ed.; John Wiley and Sons inc.: New York, 1991.
Compounds of formula 5~ are prepared from the displacement reaction of amine 5-3 as described in Scheme 1, where the amine 5-3 is equivalent to R'-NH. A
representative set of amines of formula 5-3 which are commercially available or which can be prepared by a literature procedure include 1-phenyl-piperazine (Aldrich), 1-, pyridin-2-yl-piperazine (Aldrich), 3-piperazin-1-yl-benzo[d)isoxazole (J. Med.
Chem.
1986. 29, 359), 3-piperazin-1-yl-benzo[d]isothiazole (J. Med. Chem. 1986, 29, 359), 2-piperazin-1-yl-quinoxaline (J. Med. Chem.1981, 24, 93), 1-naphthalen-2-yl-piperazine (cf. Tetrahedron Lett. 1994; 35, 7331 ), and 1-(3,5-dimethylphenyl)-piperazine (cf.
Tetrahedron Lett 1994, 35, 7331 ). Other compounds of formula 5-3 can be prepared using methods well khown to those skilled in the art or by using methods analogous to those described in the foregoing references.
Alternatively, compounds of formula 5~ can be prepared from reaction with compounds of formula 5-1 with compounds of formula 5-5 using conditions set forth above to prepare 5-3. Compounds of formula 5-5 can be prepared in a manner analogous to the method used to prepare compounds of formula 1-3.
Compounds of formula 5~ wherein X is oxycarbonyl, vinylenylcarbonyl, oxy(C,-C,)alkylenylcarbonyl, (C,-C,)alkylenylcarbonyl, (C,-C,)alkenylcarbonyl, thio(C,-C,)alkenylcarbonyl, vinylenylsulfonyl or carbonyl(Co-C,)alkylenylcarbonyl;
wherein said oxy(C,-C,)alkylenylcarbonyl, (C,-C,)alkylenylcarbonyl, (C,-C,~Ikenyicarbonyl, and thio(C3-C,)alkenytcart~ony! in the definition of X are each optionally and independently substituted with up to two (C,-C,)alkyl, benzyl, or Ar; said vinylenylsulfonyt and said vinylenylcarbonyl in the definition of X are each optionally and independently substituted with up to three (C,-C,)alkyl, benzyl, or Ar are also prepared according to Scheme 5 above and particularly as described below.
Compounds of formula 5-4 where X is as defined in the immediately preceding paragraph are prepared by reacting a compound of formula 5-5 with a compound of formula 5-1 where Rs is described above, X is as defined in the immediately preceding paragraph and Lv3 is chtoro. The reaction is conducted under anhydrous conditions in the presence of a non-aqueous base, which includes organic amines such as triethytamine, N,N'-diisopropylethylamine and pyridine and derivatives thereof, The reaction is generally conducted in a reaction inert solvent. Preferred solvents include haiocarbon, aliphatic or aromatic hydrocarbon, ethers, ethyl acetate, pyridine and combinations thereof. The reaction time ranges from 15 minutes to 24 hours and the ,.
reaction temperature ranges from 0 °C to 80 °C or to the reflux temperature of the solvent being used. The reactions are preferably conducted at from 0 'C to ambient temperature and at ambient pressure. Removal of optional protecting groups is carried out as described in Scheme I.
Compounds of formula 5-4 wherein X is vinylenylcarbonyl, oxy(C,-C,~Ikylenyicarbonyl, (C,-C,~Ikylenylcarbonyl, (C,-C,)alkenylcarbonyl, thio(Cz-C,)alkenylcarbonyl, or carbonyl(Co-C,~ifcylenyfcarbonyl ; wherein said oxy(C,-C,)alkylenylcarbonyl, (C,-C,)atkylenylcarbonyl, (C,-C,)atkenylcarbonyl, and thio(C=-C,)alkenylcarbonyl in the definition of X are each optionally and independently substituted with up to finro (C,-C,)alkyl, benryl, or Ar; and said vinylenylcarbonyl in the definition of X are each optionally and independently substituted with up to three (C,-C,)alkyl, benzyt, or Ar are also prepared according to Scheme 5 avove and particularly as described below.
Compounds of formula 5-4 are prepared by reacting a compound of fomnuta 5-5 with a compound of formula RQ-X-Lv' where R° is described above, X is as defined in the immediately preceding paragraph and Lv' is OH. The reaction is conducted in the presence of coupling agents, preferably dicydohexylcarbodiimide or 1-(3-dimethylaminopropyl~3-ethylcarbodiimide hydrochloride as described in J:
Artier.
Chem. Soc.1996, 178, 4952. The reaction is conducted in a reaction inert solvent Preferred solvents include halocarbon, aliphatic or aromatic hydrocarbon and ethers.
Espeaally preferred solvents include dichloromethane and chloroform. Other coupling agents that can be used are well known to those skilled in the art and include, but are not limited to, various phosphine reagents, ethyl chlorofom~ate, and N-hydroxysucanimide. These reagents and procedures are described in "Compendium pCTIIB00100296 _gg_ of Organic Synthetic Methods" (Ed., I. T. Harrison and_ S. Harrison, John ~ley &
Sons). Specific references include the following: J. Org. Chem,~1971, 36, 1305; BuIL
Soc. Chim. Fr., 1971, 3034; Bull. Chem. Soc. Japan, 1971, 44, 1373;
Tetrahedron Lett., 1973, 28, 1595; Tetrahedron Letf., 1971, 26, 2967, and J. Med. Chem., 1968, 17, 534. Removal of optional protecting groups is carried out as described in Scheme Compounds of formula 5~ wherein X is a covalent bond and Rs is (C,-C,)cycloalkyl or Ar'-(C,-C3)alkylenyl are also prepared according to Scheme 5 above and particularly as described below.
Compounds of formula 5-4 wherein X is a covalent bond and R9 is (C,-C,)cydoalkyl or Ar'-{C,-C,)alkylenyl are prepared by reacting a compound of formula 5-1 wherein X is a covalent bond, R9 is (C3-C,)cydoalkyl or Ar'-(C,-C,)alkylenyl and Lv' is halo, methanesulfonate, p-toluenesulfonate or trifluoromethanesulfonate. The reaction is conducted under anhydrous conditions in the presence of a non-aqueous base, which inGudes organic amines such as triethylamine, N,N'-diisopropylethylamine and pyridine and derivatives thereof. The reaction is conducted in a reaction inert solvent. Preferred solvents for the reaction include halocatbons, aliphatic or aromatic hydrocarbons, ethers, ethyl acetate, pyridine and combinations thereof. The reaction time ranges from 15 minutes to 24 hours and the reaction temperature ranges from -20 °C to 80 °C or to the reflux temperature of the solvent being used. The reactions are preferably conducted at ambient temperature of the solvent being used and at 'ambient pressure. Removal of optional protecting groups is conducted as set forth in Scheme I.
Scheme 6 H HN Rn Rsz ~
/ ~NHz N
z~G, ~ ( z~G' .acid + Lv6~0 ~G ~ ~ G_ N a I i R" R'z Prt 5_2 Prt O O
6-zd R"
Ru a N
~N
TzN
( z~ G, N
I
Prt &3 6rt R"
HN
H ~NHz / ~ Rsx N N .2CId N _ ( z)c G, ( z) x , / N
N
N -.a N ( z)a z~
z R / ~ Rz / N N
N~Rs N"R' Rz / N
N R' Compounds of formula 6-5 wherein G, G', G~, q, R', RZ, 'R6, R' and R°
are as defined above are prepared as set forth in Scheme 6 above and particularly as described below.
Compounds of formula 6-1 are prepared from an amine of the formula 5-2 where Prt is an optional amine protecting group selected from benzyl and C02R~°, where R~° is selected from (C,-C,)atkyl, (C,-C,)allyl, trichloroethyl and benzyl substituted with up to two (C,-C,)aikoxy. The preferred procedure for preparing ' pCT/IB00100296 compounds of formula 6-1 can be found in Tetrahedron Left. 1993, 48, 7767 or J. Org.
Chem 1997, 62, 1540. ' Compounds of formula 6-3 are prepared by condensation of ~diketones or ~3-ketoesters of the formula 6-2b, where R" and.R'Z aye independently substituted as set forth above, or compounds of the formula 6-2a where Lv' is, for example, hydroxy, chloro or dimethylamino with guanidines of the formula 6-1. The reaction is conducted in the presence of an aqueous or non-aqueous base, preferably potassium or sodium hydroxide, potassium or sodium (C,-C,~alkoxide, triethylamine, pyridine, 4-dimethylaminopyridine, potassium or sodium carbonate or potassium or sodium bicarbonate. The reaction is conducted in a reaction inert solvent, preferably aqueous media, a (C,-C,)alcohol, a (CZ-C6)dialcohol, an aroma#ic hydrocarbon, a polar aprotic solvent, or combinations thereof. The reaction time ranges from 2 hours to 3 days and the reaction temperature ranges from room temperature to reflux of the solvent employed. The reaction is preferably run at ambient pressure, but may be conducted at pressures up to 250 psi.
Removal of of optional protecting groups in compounds of formula 6-3 to afford compounds of formula 6-4 is accomplished as set forth above.
Compounds of formula 6-5 are prepared from the displacement reaction of amine 6-4 as described in Scheme 1, where the amine 6-4 is equivalent to R'-NH.
Alternatively, compounds of formula 6-5 are prepared from compounds of formula 5-5 by formation of a compound of formula 6-6, or by reaction with compounds of formula 6-2a or 6-2b under the conditions outlined above in Scheme 6 Removal of optional protecting groups is conducted as described in Scheme 1.
Compounds of fomlula 5-5 are prepared as set forth above.
_99_ Scheme 7 H
N
.~. HNRx~R~
R~ " 7.3 / ~N
\
N~R' 7-0 7.~ 1 . .
H
TN R~
x),~°~G4 Rx,NCO
G ~-0 N
or Rx / N ---.r O R' N- _R' ~ x, Ct NR R
7.4 Compounds of formula 7-4 wherein G', G', G5, r, R', R2, R'°, R'9 and R~° are defined as set forth above are prepared as set forth in Scheme 7 and particulariy as described below.
Compounds of formula 7-1 are prepared by reaction of an amine of the formula 7-0 with phosgene or a phosgene equivalent such as triphosgene.
Compounds of 7-1 wherein the chloro group is replaced by an imidazolyl group are also useful in this reaction. Such compounds are prepared by reaction of an amine of formula 7-0 with carbonyl diimidazole. The reaction is conducted under anhydrous conditions in the presence of a nonaqueous base. Preferred such bases indude triethylamine and other tertiary 'amines and pyridine and' derivatives thereof. The reaction is conducted in a reaction inert solvent at -78 ~°C to 80 °C or at the reflux temperature of the solvent being used for 15 minutes to 24 hours. Preferred solvents for this reaction indude a halocarbon, an aliphatic or aromatic hydrocarbon, an ether, ethyl acetate, pyridine and combinations thereof. The reactions are preferably conducted at from 0 °C to ambient temperature and at ambient pressun:.
Compounds of formula 7-4 are prepared by reaction of carbamoyl chlorides of the formula 7-1 with amines of the formula 7-3, where R2' and R~ are defined above.
The reaction can be conducted in the absence of solvent, or in a reaction inert i0 solvent. Preferred such solvents indude aqueous media, a (C,-C,)aloohol, a (C2-C6)dialcohol, an aromatic or aliphatic hydrocarbon; a halocarbon, an ether, a polar aprotic solvent, a ketone, pyridine or combinations thereof. The reaction time ranges from 15 minutes to 3 days and the reaction temperature ranges from 0 °C to the reflux temperature of the solvent being used. 'The reaction is preferably conducted at ambient pressure. It will be recognized by those skilled in the art that addition of a base may be required to effect reaction. In those cases, preferred bases indude potassium or sodium hydroxide, triethyiamine and other tertiary amines, pyridine and its derivatives and inorganic bases such as sodium or potassium carbonate and sodium or potassium bicarbonate. Removal of optional hydroxyl protecting groups contained in R' is canied out according to methods set forth in Scheme 1.
Attematively, compounds of formula 7-4 are prepared from compounds of formula 7-0 by reaction with isocyanates of the formula 7-6 or with carbamoyl chlorides of the formula 7-8. Said isocyanates are commer~cialiy available, known in the literature, or synthesized under standard conditions known to those skilled in the art, particularly as described in March, J. Advanced Organic Chemistry, 3"° ed.; John Whey and Sons Inc.: New York, 1985, p 1166. A preferred method of forming such isocyanates is the Curtius rearrangement of a suitable aryl azide. Said carbamoyl chlorides are synthesized using methods analogous to that described for the preparation of vompounds of formuta 7-1 in Scheme 7. Removal of optional hydroxyl protecting groups contained in R' is carried out according to methods set forth in Scheme 1.
WO 00/59510 PG"TIIB00100296 Compounds of formula I containing the radicaLR'' are prepared according to the procedures set forth in Scheme 7 using the corresponding starting materials and reagents.
Scheme 8 Rze I \ ~ HCHO ,, ,.
R
Rr ,- Rze NHz Rz9 RZs 8-1a ~
Rr or Rze N
I \ ~ H
R 8.2 NHz 8~5 8-1b Rr ~ --N
Prt Prt Compounds of formula 8-5 are prepared as set forth in Scheme 8 and particularly as described below.
Compounds of formula 8-2 are readily prepared from commercially available phenethyiamines of formula 8-1 a and formaldehyde or an aidehyde of the formula R~'-CHO under Pictet-Spengler conditions. The Pictet-Spengler reaction is reviewed in Chem. Rev.1995, 95,1797. A similar route route to 1,2,3,4-tetrahydroiso4uinolines using the Bischler Napiecalski reaction, as disclosed in March, J. Advanced Organic Chemistry, 3'~ ed.; ,fohn Wiiey and Sons.: New York, 1985, 495, followed by standaM
reduction of the imine formed may also be employed.
pCfIIB00100296 Compounds of formula 8-4 are prepared from compounds of formula 8-3 by aromatic electrophilic substitution using the appropriate~electrophile. A
genera!
reference for this type of reaction can be found in March, J. Advanced Organic Chemistry, 3'° ed.; John Wiley and Sons.: New York, 1985, 4.47-511.
Compounds of formula 8-2 are also prepared by removal of the protecting group from a compound of formula 8-4. Preferably the protecting group is trifluoroacetamide which may be removed under basic conditions using inorganic hydroxides or carbonates in a reaction inert solvent. Suitable suds solvents include (C,-C,)aicohols and preferably methanol. Optionally, one or more co-solvents, preferably selected from water, tetrahydrofuran and dioxane may be employed.
The reaction time ranges from 15 minutes to 24 hours.and the reaction temperature ranges from 0 °C to 100 °C or to the reflux temperature of the solvent or solvent system being used. The reaction is preferabfy'conducted at ambient temperature.
Other conditions for deprotection of trifluoroacetamides and deprotection conditions for other suitable protecting groups can be found in Greene, T. W.; Wuts, P.
G. M.
Profective Groups in Organic Synthesis, 2"° ed.; John Wiley and Sons Inc.: New York, 1991.
Compounds of formula 8-4 are prepared by, adding a protecting group to compounds of fon'nuta 8-2. Preferably the protecting group is trifluoroacetamide or tert-butoxycarbonyl (BOC). The protecting group is attached by reaction of a compound of formula &2 with trifluoroacetyl chloride or di-tart-butyl dicarboriate or an equivalent thereof in the presence of a base, preferably triethylamine or pyridine. The reaction is conducted in a reaction inert solvent. Preferred such solvents indude ethers such as tetrahydrofuran, diethyl ether, dioxane or dimethoxyethane; a halocafion such as dichloromethane, chloroform or carbon tetrachloride; and aromatic or aliphatic hydrocarbons such as benzene, toluene or hexanes. The reaction bme ranges from 15 minutes to 3 days and the reaction temperature ranges from 0 °C to the reflux temperature of the solvent being used. The reaction is preferably conducted at ambient pressure. Other conditions for protection of amines with trifluoroacetamides or tart-butoxycarbonyl groups as welt as other suitable protecting groups can be found in Greene, T. W.; Wuts, P. G. M. Prr~tecfive Groups in Organic Synfhesis, 2"° ed.; John Wiley and Sons Inc.: New York, 1991:-Manipulation of the substituents R'° and R~ is cartied out to provide isoquinolines with altered substitution. Preferably, transition metal-catalyzed cross- , coupling of a compound of formula 8-4 where R~° or R~' is bromide or triflate is employed to afford compounds of formula 8-4 wherein R~° or R~' are as set forth above. This reaction is conducted according to methods well known to those skilled in the art, particularly as set forth in TetrBhedron,1998, 54, 263 far Stille and Siizuki Reactions and in Acc. Chem. Res.1998, 31, 805 for Buchwald Amination Reactions.
Compounds of formula 8-5 are prepared from the dispia<:ement reaction of amine 8-2 as described in Scheme 1, where the amine 8-2 is equivalent to R'-NH.
Scheme 9 O
COi~t , , HCI
NH
acid RZe~N
/ Hz
9-1 or Compounds of formula 9-3 are prepared according to the generat procedures set forth in Scheme 2 starting from ethyl 1-benzyl-4-oxo-3-piperidine carboxylate hydrochloride (9-1 ). In certain cases, where R~' is H, N-tertbutoxycarbonyl-3-(dimethylaminomethylene~4-piperidone (9-2, Chemical Abstracts 121:157661 ) is used as the starting material.
' WO 00159510 Scheme 10 pCT/IB00100296 "O
a' N ~ .NHz O NYflR u~
\ ~ ~ R R
' H
+ ---.w J
N N
' , 10-3
' WO 00159510 Scheme 10 pCT/IB00100296 "O
a' N ~ .NHz O NYflR u~
\ ~ ~ R R
' H
+ ---.w J
N N
' , 10-3
10-1 10-2 R~
~N
a ' R \ _N Rs~ ay~N ~ N
N~~ N ~N R
Rs2! ,N ~ N ~ ~ N
'N ~ ~ R~ ' ~ ' ~ , 'NI
Cbz H ~N ~ R~
Compounds of formula 10-6 wherein R', RZ, R~ and R'~ are as defined above are prepared as set forth in Scheme 10 and more particutarty as described below.
Compounds of formula 10-2 where R9' is (C,-C,)alkyl are prepared by reacting a compound of fomwla 10-1, where Cbz is benzyloxycarbonyl, with an O-alkylating agent. A prefer-ed compound of formula 10-1 is 3-oxo-piperazine-1-carboxylic aad benzyi ester. A preferred O-alkyiating agent is triethyloxonium tetrafluoroborate. The reaction is conducted at ambient pressure in a reaction inert solvent.
Preferred solvents include an aromatic or aliphatic hydrocarbons, halocarbons and ethers.
Dichloromethane is especially preferred. The reaction time ranges from 2 hours to 3 days and the reaction temperature ranges from -100 °C to ambient temperature.
Corripounds of formula 10-4 are prepared by condensation of a compound of formula 10-2 with a compound of formula 10-3. Said compounds of formula 10-3 are commercially available, are known in the literature, or are readily prepared via standard amidation of hydrazine and an activated carboxylic aad, such as a carboxylic aad chloride. Such reactions are well known by those skilled in the art The condensation reaction is preferably run at ambient pressure, although higher pressures up to 250 psi may be employed if necessary. The reaction is conducted in a reaction inert solvent, preferably selected from (C,-C,)alcohols, aromatic or aliphatic hydrocarbons, polar aprotic media, halocarbons and ethers, or combination~'thereof.
The reaction is conducted at temperatures ranging from ambient temperature to °C. The reaction times are from 2 hours to 3 days.
Compounds of formula 10-5 are prepared form compounds of formula 10-4 via Lewis acid-catalyzed cleavage or hydrogenolysis of the~Cbz carbamate under standard conditions which are well known to those skilled in the art, particularly as set ..
forth in Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2"° ed.;
John Wiley and Sons Inc.: New York, 1991, pp 335-338.
Compounds of formula 10-6 are prepared from the displacement reaction of an amine of the formula 10-5 as described in Scheme 1, where the amine 10-5 is equivalent to R'-NH.
Scheme 11
~N
a ' R \ _N Rs~ ay~N ~ N
N~~ N ~N R
Rs2! ,N ~ N ~ ~ N
'N ~ ~ R~ ' ~ ' ~ , 'NI
Cbz H ~N ~ R~
Compounds of formula 10-6 wherein R', RZ, R~ and R'~ are as defined above are prepared as set forth in Scheme 10 and more particutarty as described below.
Compounds of formula 10-2 where R9' is (C,-C,)alkyl are prepared by reacting a compound of fomwla 10-1, where Cbz is benzyloxycarbonyl, with an O-alkylating agent. A prefer-ed compound of formula 10-1 is 3-oxo-piperazine-1-carboxylic aad benzyi ester. A preferred O-alkyiating agent is triethyloxonium tetrafluoroborate. The reaction is conducted at ambient pressure in a reaction inert solvent.
Preferred solvents include an aromatic or aliphatic hydrocarbons, halocarbons and ethers.
Dichloromethane is especially preferred. The reaction time ranges from 2 hours to 3 days and the reaction temperature ranges from -100 °C to ambient temperature.
Corripounds of formula 10-4 are prepared by condensation of a compound of formula 10-2 with a compound of formula 10-3. Said compounds of formula 10-3 are commercially available, are known in the literature, or are readily prepared via standard amidation of hydrazine and an activated carboxylic aad, such as a carboxylic aad chloride. Such reactions are well known by those skilled in the art The condensation reaction is preferably run at ambient pressure, although higher pressures up to 250 psi may be employed if necessary. The reaction is conducted in a reaction inert solvent, preferably selected from (C,-C,)alcohols, aromatic or aliphatic hydrocarbons, polar aprotic media, halocarbons and ethers, or combination~'thereof.
The reaction is conducted at temperatures ranging from ambient temperature to °C. The reaction times are from 2 hours to 3 days.
Compounds of formula 10-5 are prepared form compounds of formula 10-4 via Lewis acid-catalyzed cleavage or hydrogenolysis of the~Cbz carbamate under standard conditions which are well known to those skilled in the art, particularly as set ..
forth in Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2"° ed.;
John Wiley and Sons Inc.: New York, 1991, pp 335-338.
Compounds of formula 10-6 are prepared from the displacement reaction of an amine of the formula 10-5 as described in Scheme 1, where the amine 10-5 is equivalent to R'-NH.
Scheme 11
11-1 R'°
R~s Rs~
R'~ R"
E m E ~°
NwRso Rx ~R~
N
H
1.
11-3 , WO 00!59510 PCT/IB00/00296 Compounds of formula 11-4, wherein R', R2, R~, R", R'°; R'~ and R'° are as defined above are prepared as set forth in Scheme 11, and more particularly as described below:
Where R'~ and R'9 are hydrogen, 1-henry!-4-piperidone (3-1 ), available from Aldrich, is condensed with a compound of formula 11-1, which are either commercially available or well known to those skilled in the art, to give compounds of formula 11-2.
Where R'° and R'~ are not hydrogen, compounds of formula 3-1 can be prepared according to methods well known to those skilled in the art. The reaction is conducted at ambient pressure in the absence of solvent or in a reaction inert solvent:
Preferred solvents inGude (C,-C,)alcohols, aromatic or aliphatic hydrocarbons, polar aprotic solvents, halocarbons and ethers. The reacfion time ranges from 2 hours to 3 days and the reaction temperature ranges from ambient temperature to the reflux temperature of the solvent being employed. More specific conditions can be found in Indian J. Chem. 197fi, 14B, 984 and J. Chem. Soc., Perkin Trans. 1 1984, 2465.
Compounds of formula 11-3 are prepared by removal of the henry! protecting group from a compound of formula 11-2 in a manner analogous to the method employed for the preparation of compounds of 2-6 described above.
Compounds of formula 11-4 are prepared by the displacement reaction of an amine of the formula 11-3 as described in Scheme 1, where the amine 11-3 is equivalent to R'-H.
' WO 00/59510 PC'T/IB00100296 Scheme 12 fZn s ~N N
( Ha)r GaG~ , ( z)~sG~
G' N .(. R~~-Lv' N
RZ / N 12 2 . ~ RZ , / I
N R~ N~R~
R~s Rs~
R'~ R"
E m E ~°
NwRso Rx ~R~
N
H
1.
11-3 , WO 00!59510 PCT/IB00/00296 Compounds of formula 11-4, wherein R', R2, R~, R", R'°; R'~ and R'° are as defined above are prepared as set forth in Scheme 11, and more particularly as described below:
Where R'~ and R'9 are hydrogen, 1-henry!-4-piperidone (3-1 ), available from Aldrich, is condensed with a compound of formula 11-1, which are either commercially available or well known to those skilled in the art, to give compounds of formula 11-2.
Where R'° and R'~ are not hydrogen, compounds of formula 3-1 can be prepared according to methods well known to those skilled in the art. The reaction is conducted at ambient pressure in the absence of solvent or in a reaction inert solvent:
Preferred solvents inGude (C,-C,)alcohols, aromatic or aliphatic hydrocarbons, polar aprotic solvents, halocarbons and ethers. The reacfion time ranges from 2 hours to 3 days and the reaction temperature ranges from ambient temperature to the reflux temperature of the solvent being employed. More specific conditions can be found in Indian J. Chem. 197fi, 14B, 984 and J. Chem. Soc., Perkin Trans. 1 1984, 2465.
Compounds of formula 11-3 are prepared by removal of the henry! protecting group from a compound of formula 11-2 in a manner analogous to the method employed for the preparation of compounds of 2-6 described above.
Compounds of formula 11-4 are prepared by the displacement reaction of an amine of the formula 11-3 as described in Scheme 1, where the amine 11-3 is equivalent to R'-H.
' WO 00/59510 PC'T/IB00100296 Scheme 12 fZn s ~N N
( Ha)r GaG~ , ( z)~sG~
G' N .(. R~~-Lv' N
RZ / N 12 2 . ~ RZ , / I
N R~ N~R~
12-1 H Rxs N' Rz~
Rrj-Lv< ----~ N
12-2a Rz ~~N
N_ 'R' 12-1a 12-3a Compounds of formula 12-3 and 12-3a where R" and R~' are (C,-C6)alkoxycarbonyl, (C,-C6)alkylcarbonyl, Are-carbonyl, (C,-C6)alkylsulfonyl, Arz-sulfonyl, or Acs-sulfinyl are prepared according to Scheme 12 above and particularly as set forth below.
Compounds of formula 12-3 and 12-3a where R" and R~' are as defined in the immediately preceding paragraph are prepared by condensation with a compound of fortnuta 12-2 and 12-2a, wherein Lv' is chloro, respectively. Examples of compounds of formula 12-2 and 12-2a indude (C,-C6)alkoxyCOCI, (C,-C6)aIkyICOCI, Arz-COCI, (C,-C6)alkylSOZCI, Ar=-SOZCI, or Arz-SOC1. The reaction is conducted under anhydrous conditions in the presence of a non-aqueous base, which indudes organic amines such as triethylamine, N,N'-diisopropylethylamine and pyridine and derivatives thereof. The reaction is conducted in a reaction inert solvent. Preferred solvents for the reaction indude halocarbon, aliphatic or aromatic hydrocarbon, ethers, ethyl acetate, pyridine and combinations thereof. The reaction time ranges from 115 minutes to 24 hours and the reaction temperature ranges,from 0 °C to 80 °C or to the reflux temperature of the sotvent being used. The reactions are preferably conducted at from 0 °C to ambient temperature and at ambient. pressure. Removal of optional protecting groups is carried out as descxibed in Sd~eme i.
Compounds of formula 12-3 and 12-3a wherein R" and R~ are (C, CB)alkylcarbonyl or Ar2-carbonyl are also prepared according to Scheme 1~2 above and particularly as described below.
Compounds of fortnuta 12-3 and 12-3a wherein R" and R~' are (C,-C6)alkylcarbonyl or Arz-carbonyl are prepared by a condensation reaction with a compound of formula 12-2 or 12-2a, respectively, wherein Lv' is hydroxy in the presence of coupling agents such as dicydohexytcarbodiimide or 1-(3-dimethylaminopropyl}-3-ethyicarbodiimide hydrochloride. The reaction is conducted in a reaction inert solvent. Preferred solvents include halocarbon, aliphaticJaromatic hydrocarbons and ethers. Especially preferred solvents include dichloromethane and chloroform. Other coupling agents that can be used are weA knovm to those skilled in the art and include, but are not limited to, various phosphine reagents, ethyl chloroformate, and N-hydroxysucanimide. Removal of optional protecting groups is carried out as described in Scheme I.
Compounds of formula 12-3 where R" is (C,-C6)alkyyl are also prepared according to Scheme 12 and particularly as descxibed below.
Compounds of formula 12-3 where R" is (C,-CB~Ikyl are prepared by reacting a compound of formula i 2-i with a compound of formula 12-2 where R" is (C,-C,)alkyl and Lv'' is CI, Br, I, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy. The reaction is conducted under anhydrous conditions in the presence of a nonaqueous base, which includes organic amines such as triethylamine, Hunig's base and pyridine and derivatives thereof. The reaction is conducted in a reaction inert solvent. Prefetted solvents for the reaction include halocarbons, aliphatic or aromatic hydrocarbons, ethers, ethyl acetate, pyridine and combinations thereof. The reaction time ranges from 15 minutes to 24 hours and the reaction temperature ranges from ambient temperature to 80 °C or to the reflux temperatufe of the solvent being used. The reactions are preferably conducted at ambient temperature and pressure.
pGTIIB00/00296 -1 ~-The starting materials and reagents for the above described compounds are also readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used herein are related to, or are derived from, compounds found in nature, in which there is a large scientific interest and commerrcial need, and accordingly many such compounds are commeraally available or are reported in the literature or are easily prepared from other commonly available substances by methods which are reported in the literature.
The compounds of the instant invention inhibit the formation of sorbitol dehydrogenase and as such have utility in the treatment of diabetic complications inGuding but not limited to such complications as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic micxoangiopathy and diabetic macroangiopathy and diabetic cardiomyopathy. .The utility of the compounds of the present invention as medical agents in the treatment of diseases, such as are detailed herein in mammals (e.g., humans) for example, diabetic complications such as diabetic cardiomyopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic microangiopathy and diabetic maaoang'ropathy is demonstrated by the activity of the compounds of formula I of this invention in conventional assays.
Such assays also provide a means whereby the acFrvities of the compounds of formula I of this invention can be compared with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
Measurement of SDH Activity Male Sprague-Dawley rats (350-400 g) are used for these experiments.
Diabetes is induced in some of the rats by a tail vein in)ec~ion of streptozocin, 85 rng/kg. Twenty-four hours later, 4 groups of diabetic rats are given a single dose of the test compound of fomwla 1 of this invention (0.001 to 100 mglkg) by oral gavage.
Animals are sacrificed 4~ hours after dosing and blood and sciatic nerves are harvested. Tissues and cells are extracted with 6°~ perchloric acid.
Sorbitol in erythrocytes and nerves is measured by a modfication of the method of R. S. Ciements et al. (Saence,1_~6: 100?-8, 1969). Aliquots of tissue extracts are added to an assay system which has frnal oonoentrations of reagents of 0.033 M glyane, pH 9.4, 800 mM t3-nicotine adenine dinuGeotide, and 4 unitslml of sorbitol dehydrogenase. After incubation for 30 minutes at room temperature, sample fluorescence is determined on a fluorescence spectrophotometer with excitation at 366 nm and emission at 452 nm. After subtracting appropriate blanks, the amount of sorbitol in each sample is determined from a fmear regression of sorbitol standards processed in the same manner as the tissue extracts.
Fructose is determined by a rnodfication of the method descxibed by M.
Ameyama, Methods in Enzvmoloav, ~: 20-25 (1982). Resazurin is substituted for ferricyanide. Aliquots of tissue extracts are added to the assay system, which has final concentrations of reagents of 12 M citric add, pH 4.5,13 mM resazuriri, 3.3 units/ml of fructose dehydrogenase and 0.068% Triton X-100. After inarbation for 60 minutes at room temperature, sample fluorescence is detertrr>ined on a fluorescence spectrophotometer with exatation at 560 nm and emission at 580 nm. After subtracting appropriate blanks, the amount of fructose in each sample is determined from a linear regression of fructose standards processed in the same manner as the tissue extracts.
SDH activity is measured by a modfication of the method described by U.
Gerlach, Methodology of Enzymatic Analyses, edited by H. U. Bergmeyer, 3_,112-(1983). Aliquots of sera or urine are added to the assay system, which has final concentrations of reagents of 0.1 M potassium phosphate buffer, pH 7.4, 5 mM
NAO, 20 mM sorbi~l, and 0.7 unitslmi of sorbitol dehydrogenase. After inarbation for 10 minutes at room temperature, the average change in sample absorbanoe is detemuned at 340 nm. SDH activity was presented as milliOD"°
unitslminute (00"°
= optical density at 340 nm).
Any aldose reductase inhibitor may be used as the second compound (active agent) of this invention for combination therapies. The term aldose redudase inhibitor refers to compounds which inhibit the bioconversion of glucose to sorbitol catalyzed by the enzyme aldose redudase. Such inhibition is readily detemuned by those skilled in the art acoor~ding to standard assays (J.
Maione, Diabetes, X9:861-864,1980. "Red CeU Sorbitol, an Indicator of Diabetic Control").
A variety of aldose ~reductase inhibitors arse described and referenced below, however, other aldose reductase inhbitors wilt be known to those skilled in the art.
Also, common chemical USAN names or other designation are in parentheses WO 00/59510 pCTlB00/OOZ96 where applicable, together with reference to appropriate patent literature disdosing the compound. ' ' The activity of an aldose reductase inhibitor in ~a tissue can be determined by testing the amount of aldose reductase inhibitor that is required to lower tissue sorbitol {i.e., by inhibiting the further production of sorbitol consequent to bloddng aldose reductase) or lower tissue fructose (by inhibiting the produdfon of sorbitol consequent to blocking aldose reductase and consequently the production of fructose). While not wishing to be bound by any parircular theory or mechanism, it is believed that an aldose reductase inhibitor, by inhibiting aldose reductase, prevents or reduces ischemic damage as described hereinafter.
Accordingly, examples of aidose reductase inhibitors useful in the compositions and methods of this invention indude:
1. 3-(4-bromo-2-tluorobenzylr3,4-dihydro~-oxo-l-phthalazineacetic acid (ponalrestat, US 4,251,528);
2. N[[(5-trifluoromethyl~6-methoxy-1-naphthalenyl]thioxomethyl}-N-methyiglydne (toirestat, US 4,600,724); .
3. 5-[(Z,E)-~methylcinnamyiidene]-4-oxo-2-thioxo-3-thiazolideneacetic acid (epalrestat, US 4,464,382, US 4,791,126, US 4,831,045);
4. 3-(4-bromo-2-fluorobenzyl)-7-chioro-3,4-dihydro-2,4-dioxo-l (2H)-quinazolineacetic acid (zenarestat, US 4,734,419, and 4.883,800);
5. 2R,4R-6.7-dichloro-~-hydroxy-2-methytchroman-4-acetic acid (US
4.883,410);
6. 2R,4R-6,7-dichioro-6-fluoro~-hydroxy-2-methylchroman-4-acetic add (US 4,883,410);
7. 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine~-acetic add (US 4,771,050);
8. 3,4-dihydro-3-oxo-4~-((4,5,7-trifluoro-2-benzothiazoly!)methyt]-2H-~ ,4-benzothiazine-2-acetic add (SPR-210, U.S. 5,252,572);
9. N-[3,5-dimethyl-4-[(nitromethyl),suffonytjpheny(}-2-methyl-benzeneacetamide (ZD5522, U.S. 5,270,342 and U.S. 5,430,060);
10. (S-)-6-fluorospirojchroman~,4'-imidazolidine]-2,5'-dione (sorbinil, US
4,130,714);
' WO OOI59510 pCl'/~800/00296 11. d-2-methyl-6-fluoro-spiro(chroman~',4'-iwiidazolidirter2',5'-dione (US
4.540,704):
12. 2-fluoro-spiro(9H-fluorene-9,4'-imidazolidine~2',5'-dione (US
4,438,272);
Rrj-Lv< ----~ N
12-2a Rz ~~N
N_ 'R' 12-1a 12-3a Compounds of formula 12-3 and 12-3a where R" and R~' are (C,-C6)alkoxycarbonyl, (C,-C6)alkylcarbonyl, Are-carbonyl, (C,-C6)alkylsulfonyl, Arz-sulfonyl, or Acs-sulfinyl are prepared according to Scheme 12 above and particularly as set forth below.
Compounds of formula 12-3 and 12-3a where R" and R~' are as defined in the immediately preceding paragraph are prepared by condensation with a compound of fortnuta 12-2 and 12-2a, wherein Lv' is chloro, respectively. Examples of compounds of formula 12-2 and 12-2a indude (C,-C6)alkoxyCOCI, (C,-C6)aIkyICOCI, Arz-COCI, (C,-C6)alkylSOZCI, Ar=-SOZCI, or Arz-SOC1. The reaction is conducted under anhydrous conditions in the presence of a non-aqueous base, which indudes organic amines such as triethylamine, N,N'-diisopropylethylamine and pyridine and derivatives thereof. The reaction is conducted in a reaction inert solvent. Preferred solvents for the reaction indude halocarbon, aliphatic or aromatic hydrocarbon, ethers, ethyl acetate, pyridine and combinations thereof. The reaction time ranges from 115 minutes to 24 hours and the reaction temperature ranges,from 0 °C to 80 °C or to the reflux temperature of the sotvent being used. The reactions are preferably conducted at from 0 °C to ambient temperature and at ambient. pressure. Removal of optional protecting groups is carried out as descxibed in Sd~eme i.
Compounds of formula 12-3 and 12-3a wherein R" and R~ are (C, CB)alkylcarbonyl or Ar2-carbonyl are also prepared according to Scheme 1~2 above and particularly as described below.
Compounds of fortnuta 12-3 and 12-3a wherein R" and R~' are (C,-C6)alkylcarbonyl or Arz-carbonyl are prepared by a condensation reaction with a compound of formula 12-2 or 12-2a, respectively, wherein Lv' is hydroxy in the presence of coupling agents such as dicydohexytcarbodiimide or 1-(3-dimethylaminopropyl}-3-ethyicarbodiimide hydrochloride. The reaction is conducted in a reaction inert solvent. Preferred solvents include halocarbon, aliphaticJaromatic hydrocarbons and ethers. Especially preferred solvents include dichloromethane and chloroform. Other coupling agents that can be used are weA knovm to those skilled in the art and include, but are not limited to, various phosphine reagents, ethyl chloroformate, and N-hydroxysucanimide. Removal of optional protecting groups is carried out as described in Scheme I.
Compounds of formula 12-3 where R" is (C,-C6)alkyyl are also prepared according to Scheme 12 and particularly as descxibed below.
Compounds of formula 12-3 where R" is (C,-CB~Ikyl are prepared by reacting a compound of formula i 2-i with a compound of formula 12-2 where R" is (C,-C,)alkyl and Lv'' is CI, Br, I, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy. The reaction is conducted under anhydrous conditions in the presence of a nonaqueous base, which includes organic amines such as triethylamine, Hunig's base and pyridine and derivatives thereof. The reaction is conducted in a reaction inert solvent. Prefetted solvents for the reaction include halocarbons, aliphatic or aromatic hydrocarbons, ethers, ethyl acetate, pyridine and combinations thereof. The reaction time ranges from 15 minutes to 24 hours and the reaction temperature ranges from ambient temperature to 80 °C or to the reflux temperatufe of the solvent being used. The reactions are preferably conducted at ambient temperature and pressure.
pGTIIB00/00296 -1 ~-The starting materials and reagents for the above described compounds are also readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used herein are related to, or are derived from, compounds found in nature, in which there is a large scientific interest and commerrcial need, and accordingly many such compounds are commeraally available or are reported in the literature or are easily prepared from other commonly available substances by methods which are reported in the literature.
The compounds of the instant invention inhibit the formation of sorbitol dehydrogenase and as such have utility in the treatment of diabetic complications inGuding but not limited to such complications as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic micxoangiopathy and diabetic macroangiopathy and diabetic cardiomyopathy. .The utility of the compounds of the present invention as medical agents in the treatment of diseases, such as are detailed herein in mammals (e.g., humans) for example, diabetic complications such as diabetic cardiomyopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic microangiopathy and diabetic maaoang'ropathy is demonstrated by the activity of the compounds of formula I of this invention in conventional assays.
Such assays also provide a means whereby the acFrvities of the compounds of formula I of this invention can be compared with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
Measurement of SDH Activity Male Sprague-Dawley rats (350-400 g) are used for these experiments.
Diabetes is induced in some of the rats by a tail vein in)ec~ion of streptozocin, 85 rng/kg. Twenty-four hours later, 4 groups of diabetic rats are given a single dose of the test compound of fomwla 1 of this invention (0.001 to 100 mglkg) by oral gavage.
Animals are sacrificed 4~ hours after dosing and blood and sciatic nerves are harvested. Tissues and cells are extracted with 6°~ perchloric acid.
Sorbitol in erythrocytes and nerves is measured by a modfication of the method of R. S. Ciements et al. (Saence,1_~6: 100?-8, 1969). Aliquots of tissue extracts are added to an assay system which has frnal oonoentrations of reagents of 0.033 M glyane, pH 9.4, 800 mM t3-nicotine adenine dinuGeotide, and 4 unitslml of sorbitol dehydrogenase. After incubation for 30 minutes at room temperature, sample fluorescence is determined on a fluorescence spectrophotometer with excitation at 366 nm and emission at 452 nm. After subtracting appropriate blanks, the amount of sorbitol in each sample is determined from a fmear regression of sorbitol standards processed in the same manner as the tissue extracts.
Fructose is determined by a rnodfication of the method descxibed by M.
Ameyama, Methods in Enzvmoloav, ~: 20-25 (1982). Resazurin is substituted for ferricyanide. Aliquots of tissue extracts are added to the assay system, which has final concentrations of reagents of 12 M citric add, pH 4.5,13 mM resazuriri, 3.3 units/ml of fructose dehydrogenase and 0.068% Triton X-100. After inarbation for 60 minutes at room temperature, sample fluorescence is detertrr>ined on a fluorescence spectrophotometer with exatation at 560 nm and emission at 580 nm. After subtracting appropriate blanks, the amount of fructose in each sample is determined from a linear regression of fructose standards processed in the same manner as the tissue extracts.
SDH activity is measured by a modfication of the method described by U.
Gerlach, Methodology of Enzymatic Analyses, edited by H. U. Bergmeyer, 3_,112-(1983). Aliquots of sera or urine are added to the assay system, which has final concentrations of reagents of 0.1 M potassium phosphate buffer, pH 7.4, 5 mM
NAO, 20 mM sorbi~l, and 0.7 unitslmi of sorbitol dehydrogenase. After inarbation for 10 minutes at room temperature, the average change in sample absorbanoe is detemuned at 340 nm. SDH activity was presented as milliOD"°
unitslminute (00"°
= optical density at 340 nm).
Any aldose reductase inhibitor may be used as the second compound (active agent) of this invention for combination therapies. The term aldose redudase inhibitor refers to compounds which inhibit the bioconversion of glucose to sorbitol catalyzed by the enzyme aldose redudase. Such inhibition is readily detemuned by those skilled in the art acoor~ding to standard assays (J.
Maione, Diabetes, X9:861-864,1980. "Red CeU Sorbitol, an Indicator of Diabetic Control").
A variety of aldose ~reductase inhibitors arse described and referenced below, however, other aldose reductase inhbitors wilt be known to those skilled in the art.
Also, common chemical USAN names or other designation are in parentheses WO 00/59510 pCTlB00/OOZ96 where applicable, together with reference to appropriate patent literature disdosing the compound. ' ' The activity of an aldose reductase inhibitor in ~a tissue can be determined by testing the amount of aldose reductase inhibitor that is required to lower tissue sorbitol {i.e., by inhibiting the further production of sorbitol consequent to bloddng aldose reductase) or lower tissue fructose (by inhibiting the produdfon of sorbitol consequent to blocking aldose reductase and consequently the production of fructose). While not wishing to be bound by any parircular theory or mechanism, it is believed that an aldose reductase inhibitor, by inhibiting aldose reductase, prevents or reduces ischemic damage as described hereinafter.
Accordingly, examples of aidose reductase inhibitors useful in the compositions and methods of this invention indude:
1. 3-(4-bromo-2-tluorobenzylr3,4-dihydro~-oxo-l-phthalazineacetic acid (ponalrestat, US 4,251,528);
2. N[[(5-trifluoromethyl~6-methoxy-1-naphthalenyl]thioxomethyl}-N-methyiglydne (toirestat, US 4,600,724); .
3. 5-[(Z,E)-~methylcinnamyiidene]-4-oxo-2-thioxo-3-thiazolideneacetic acid (epalrestat, US 4,464,382, US 4,791,126, US 4,831,045);
4. 3-(4-bromo-2-fluorobenzyl)-7-chioro-3,4-dihydro-2,4-dioxo-l (2H)-quinazolineacetic acid (zenarestat, US 4,734,419, and 4.883,800);
5. 2R,4R-6.7-dichloro-~-hydroxy-2-methytchroman-4-acetic acid (US
4.883,410);
6. 2R,4R-6,7-dichioro-6-fluoro~-hydroxy-2-methylchroman-4-acetic add (US 4,883,410);
7. 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine~-acetic add (US 4,771,050);
8. 3,4-dihydro-3-oxo-4~-((4,5,7-trifluoro-2-benzothiazoly!)methyt]-2H-~ ,4-benzothiazine-2-acetic add (SPR-210, U.S. 5,252,572);
9. N-[3,5-dimethyl-4-[(nitromethyl),suffonytjpheny(}-2-methyl-benzeneacetamide (ZD5522, U.S. 5,270,342 and U.S. 5,430,060);
10. (S-)-6-fluorospirojchroman~,4'-imidazolidine]-2,5'-dione (sorbinil, US
4,130,714);
' WO OOI59510 pCl'/~800/00296 11. d-2-methyl-6-fluoro-spiro(chroman~',4'-iwiidazolidirter2',5'-dione (US
4.540,704):
12. 2-fluoro-spiro(9H-fluorene-9,4'-imidazolidine~2',5'-dione (US
4,438,272);
13. 2,7-di-fluoro-spiro(9H-fluorerie-9,4'-imidazolidine)-2',5'-dione (US
4,436,745, US 4,438,272);
4,436,745, US 4,438,272);
14. 2,7-di-fluoro-5-methoxy-spiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione (US 4,436,745, US 4,438,272);
15. 7-fluoro-spiro(5H-indenoljl,2-b]pyridine-5,3'-pyrrolidine~2,5'-dione (US
4,436,745, US 4,438,272);
4,436,745, US 4,438,272);
16. dais-fi'-chloro-2',3'-dihydro-2'-methyl-spiro-(imidazolidine-4,4'-4'H-pyrano(2,3-b)pyridine)-2,5-dione (US 4,980,357);
17. sp'iro(midazolidine-4,5'(6H)-quinoline]-2,5-dione-3'-chloro-7,'8'-dihydro-T-methyl-(5'-as) (US 5,066,659);
18. (2S,4S~6-fluoro-2',5'-dioxospiro(chroman-4,4'-imidazolidine)-2-carboxamide (US 5,4.47,946); and
19. 2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[soquinoline-4(1 H),3'-pymoiidine]-1,2',3,5'(2H)-tetrone (ARI-509, US 5,037,831 ).
Other aldose reductase inhibitors inGude compounds having formula ARI, Y
Z ~ ~ X
N
, ARI
or a phamiaoeutically acoeptabie salt thereof, wherein Z in the compound of formula ARI is O or S;
R' in the compound of formula ARI is hydroxy or a group capable of being removed in vivo to produce a compound of formula ARI wherein R' is OH; and X and Y in the compound of formula ARI are the same or different and are selected from hydrogen, trifluoromethyl, fluoro, and chloro.
WO 00159510 PCTIiB00100296 -t 13-A preferred subgroup within the above group of aldose reductase intribitors , indudes numbered compounds 1, 2, 3, 4, 5, 6, 9, 10, and 17, and the following compounds of Formula ARI:
Other aldose reductase inhibitors inGude compounds having formula ARI, Y
Z ~ ~ X
N
, ARI
or a phamiaoeutically acoeptabie salt thereof, wherein Z in the compound of formula ARI is O or S;
R' in the compound of formula ARI is hydroxy or a group capable of being removed in vivo to produce a compound of formula ARI wherein R' is OH; and X and Y in the compound of formula ARI are the same or different and are selected from hydrogen, trifluoromethyl, fluoro, and chloro.
WO 00159510 PCTIiB00100296 -t 13-A preferred subgroup within the above group of aldose reductase intribitors , indudes numbered compounds 1, 2, 3, 4, 5, 6, 9, 10, and 17, and the following compounds of Formula ARI:
20. 3,4-dihydro-3-(5-fluorobenzothiazol-2-ylmethyl}-4-oxophthalazin-1-yl-acetic add [R'=hydroxy; X=F; Y=HJ;
21. 3-(5,7-difluorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxopht~alazin-1-yiacetic acid [R'=hydroxy; X=Y=Fj;
22. 3-(5-chlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-yiacetic acid [R'=hydroxy; X=CI; Y=Hj; ,
23. 3-(5,7-dichlorobenzothiazol-2-ylmethyt)-3,4-dihydro~-oxophthaiazin-1-ylacetic add [R'=hydroxy; X=Y=CIJ;
24. 3,4-dihydro-4-oxo-3-(5-trifluoromethylbenzoxazol-2-ylmethyl)phthalazin-1-ylacetic acid [R'=hydroxy; X=CF3; Y=HJ;
25. 3,4-dihydro-3-(5-fiuorobenzoxazol-2-ylmethyl)~-oxophthalazin-1-yl-acetic add [R'=hydroxy; X=F; Y=HJ;
26. 3-(5,7-difluorobenzoxazol-2-yimethyl~3,4-dihydro-4-oxophthafazin-1-ylacetic add [R'=hydroxy; X=Y=F~;
27. 3-(5-chlorobenzoxazol-2-ylmethyl~3,4-dihydro~-oxophthalazin-1-yfacetic acid [R'=hydroxy; X=CI; Y=HJ;
28. 3-(5,7-dichforobenzoxazol-2-ylmethy1~3,4-dihydro-4-oxophthalazin-1-ylacetic add [R'=hydroxy; X=Y=CIJ; and
29. zopolrestat; 1-phthalazineacetic add, 3,4-dihydro-4-oxo-3-[[5 (trifluoromethyi}-2-benzothiazolyl]methyt]- [R'=hydroxy; X=trifluorornethyl;
Y=HJ.
In compounds 20-23, and 29 Z is S. fn compounds 24-28, Z is O.
Of the above subgroup, compounds 20-29 are more preferred with 29 espedalfy prefer-ed.
M espedally preferred aldose reductase inhibitor is 1-phthalazineacetic aad, 3,4-dihydro-4~xo-3-(j5-trifluoromethyl}-2-benzothiazolyl]methylj-.
The term "aryl radical of a carboxylic add aldose reductase inhibitor" refers to any of the above-mentioned aldose reductase inhbitors which contains a carboxylic add group in which the carboxylic add group is replaced with a carbonyl radical.
pG"fIIB00/00296 The aldose reductase inhibitor compounds of this invention are readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis, particularly in view of the pertinent patent specification descriptions.
An amount of the aldose reductase inhibitor of this invention that is effective for the activities of this invention may be used. Typically, an effective dosage for the aldose reductase inhibitors of this invention is in the range of about 0.1 mg/kglday.to 100 mg/kglday in single or divided doses, preferably 0.1 mglkglday to 20 mg/kg/day in single or divided doses.
Any sodium hydrogen ion exchange (NHE-1 ) inhibitor may be used as the second compound (active agent) of this invention for combination therapies.
The term NHE-1 inhibitor refers to compounds which inhibit the sodiumlproton (Na'IH') exchange transport system and hence are useful as a therapeutic or prophylactic agent for diseases caused or aggravated by the acceleration of the sodiumlproton (Na'/H') exchange transport system, for example, cardiovascular diseases [e.g., arteriosderosis, hypertension, arrhythmia (e.g. ischemic arrhythmia, arrhythmia due to myocardial infarction, myocardial stunning, myocardial dysfunction, artfiythmia after PTCA or after thrombolysis, etc.), angina pectoris, cardiac hypertrophy, myocardial infarction, heart failure (e.g. congestive heart failure, acute heart failure, cardiac hypertrophy, etc.), restenosis after PTCA, PTCI, shock (e.g. hemorrhagic shock, endotoxin shock, etc.)], renal diseases (e.g. diabetes mellitus, diabetic nephropathy, ischemic acute renal failure, etc.) organ disorders associated with ischemia or ischemic reperfusion [e.g. heart musde ischemic reperfusion assodated disorders, acute renal failure, or disorders induced by surgical treatment such as coronary artery bypass grafting (CABG) surgeries, vascular surgeries, organ transplantation, non-cardiac surgeries or percutaneous transluminal coronary angioplasty (PTCA)], oerebrovasarlar diseases (e.g. ischemic stroke, hemorrhagic stroke, etc.), cerebra ischemic disorders (e.g. disorders assodated with cerebral infarction, disorders caused after cerebral apoplexy as sequetae, or oerebrat edema. NHE-1 inhibitors can also be used as: an agent for myocardial protection during coronary artery bypass grafting (CABG) surgeries, vascular surgeries, percutaneous transluminal coronary angioplasty (PTCA), PTC1, organ transplantation, or non-cardiac surgeries. The utility of NHE-7 inhibitors as medical agents in the treatment of diseases, such as are detailed herein in mammals (e.g. humans) for example, myocardial protection during surgery or mycardial protection in patients presenting with ongoing cardiac or cerebral ischemic events or chronic cardioprotedion in patients with diagnosed coronary heart disease, or at risk for coronary heart disease, cardiac dysfunction or myocardial stunning is demonstrated by the activity of the compounds of formula ! of this , invention in conventional predinical cardioprotedyon assays [see the in viuo assay in Klein, H. et aL, Circulation 92:912-917 (1995); the isolated heart assay in Schotz, W.
et al., Cardiovascular Research 29:260-268 (1995); the antiarrhythmic assa~r in Yasutake M- et aL, Am. J. Physiol., 36:H2430-H24.40 (1994); the NMR assay in Kolke et al., J. Thorac. t:ardiovasc. Surg.112: 765-775 (1996)] and the additional in viUo and in vivo assays described below. Such assays also provide a means whereby the activities of the compounds of formula I of this invention can be compared with the activities of other known compounds. The results of these comparisons are useful for detemuning dosage levels in mammals, inducting humans, for the treatment of such diseases.
NHE-1 inhibitors are disclosed in U.S. Pat. No. 5,698,581, European Patent Application Publication No. EP 803 501 A1, International PatentAppCcation Publication Nos. WO 94/26709 and PCTIJP97/0465~0.
The NHE-1 inhibitors disclosed therein have utility in the combination of this invention. Said NHE-1 inhibitors can be prepared as disclosed therein.
Preferred NHE-1 inhibitors include compounds of the fom~ula NHE,:
Z" ~NHZ
Oi N~ Hz NHE
a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug, wherein Z in the compound of formula NHE is carbon oonned~ed and is a fnre-membered, diaza, diunsaturated ring having two contiguous rirtrogens, said ring optiortalfy mono-, di-, or tri-substituted with up to three subst~rents-independently selected from R'; Rz and R3 ;
wo oo~s9sio Pcr~sooiooz~
-~ 1 s Or Z in the compound of formula NHE carbon connected and is a five-membered, triaza, diunsaturated ring, said ring optionally mono- or di-substituted with up to two substituents independently selected from R' and R5;
wherein R', RZ, R3, R' and RS in the'compound of formula NHE are each independently hydrogen, hydroxy-(C,-C,)alkyl, (C,-C,)alkyl, (C,-C,)alkylthio, (C,-C,)cydoalkyl, (C,-C,)cydoalkyl(C,-C,)alkyl, (C,-C,)alkoxy, (C,-C,)alkoxy(C,-C,)alkyl, mono-N- or di-N,N-(C,-C,)alkylcarbamoyl, M or M(C,-C,)alkyl, any of said previous (C,-C,)alkyl moieties optionally having from one to nine fluorines; said (C,-C,)alkyl or (C,-C,)cycloalkyl op6onaliy mono-or di-substituted independently with hydroxy, (C,-C,)alkoxy, (C,-C,)alkylthio, (C,-C,)alkylsulfinyl, (C,-C,)alkylsulfonyl, (C,-C,)alkyl, mono-N- or di-N,N-(C,-C,)alkylcarbamoyl or mono-N- or di-N,N-(C,-C,)alkytaminosulfonyl; and said (C,-C,)cydoalkyl optionally having from one to seven tiuorines;
wherein M in the compound of formula NHE is a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicydic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
said M in the compound of formula NHE is optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicydic, on carbon or nitrogen with up to three substituents independently selected from R°, R' and R°, wherein one of R6, R' and R°
is optionally a partially saturated, fully saturated, or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen optionally substituted with (C,-C,~Ikyl and additionally R6, R' and R° are optionally hydroxy, vitro, halo, {C,-C,)alkoxy, (C,-C,)alkoxycarbonyl, (C,-C,~Ikyl, fomiyt, (C,-C,~Ikanoyl, (C,-C,~Ikanoyloxy, (C,-C,)alkanoylamino, (C,-C,)alkoxycarbonylamino, sulfonamide, (C,-C,)alkyisulfonamido, amino, mono-N- or di-N,N-(C,-C,)atkylamino, cartiamoyl; mono-N- or di-N,N-{C,-C,~lkylcarbamoyl, cyano, thioi. (C,-C,)alkylthio, (C,-C,)alkylsulfinyl, (C,-C,)alkylsulfonyi, mono-N-or di-,, N,N-(C,-C,)alkylaminosulfonyl, (CZ-C,)alkenyl, (CZ-C,)alkynyl or (C~-C,)cydoalkenyl, wherein said (C,-C,)alkoxy, (C,-C,)alkyl, (C,-C,~Ikanoyl, (C,-C,~Ikylthio.
mono-N- or di-N;N-(C,-C,)alkylamino or (C,-C,)cydoalkyl R6. R' and R°
substituents are optionally mono- substituted independently with hydroxy, (C,-C,)alkoxycarbonyl, (C,-C,)cydoalkyl, (C,-C,)alkanoyl, (C,-C,)alkanoylamino, (C,-C,)alkanoyloxy, (C;
C,)aikoxycarbonylamino, sulfonamido, (C,-C,)alkylsulfonamido, amino, mono-N-or di-N,N-(C,-C,)alkylamino, carbamoyl, mono-N- or di-N,N-(C,-C,)alkylcarbamoyl, cyano, 0 thiol, vitro, (C,-C,)alkylthio, (C,-C,)alkylsulfinyl; (C,-C,)alkylsulfonyl or mono-N- or di-N,N-(C,-C,)alkylaminosulfonyl or optionally substituted with one to nine fluorines.
Especially preferred NHE-1 inhibitors indude [1-(8-bromoquinolin-5-I -5-cydopropyl-1 H-pyrazofe-4-carbon y ) yt]guanidine; [1-(6-chloroquinotin-5-yl).
5-cydopropyl-1 H pyrazole-4-carbonyl]guanidine; [1-(indazol-7 ylr5-cyclopropyt-1H pyrazole-4-carbonyljguanidine; [1-(benzimidazol-5-y1~5-cydopropyt-1H pyrazole-4-carbonyf]guanidine; [1-(1-isoquinolyl~5-cydopropyl-1 H-pyrazoie-4-carbonyljguanidine; [5-~ydopropyl-1-(4-quinolinyl~
1 H-pyrazole-4-carbonyf]guanidine; [5-cydopropyl-1-(quinolin-S-yl)-1 H-pyrazole-4-carbonyf]guanidine; [5-cydopropyl-1-(quinolin-8-yl)-1 H-pyrazole~-carbonyl]guanidine; [1-(indazol-6-y1~5-ethyl-1 H pyrazole~-carbonyl]guanidine; [1-(indazol-5-yt}-5-ethyl-1H py~azole-4-carbonyl]guanidine; [1-(benzimidazol-5-yl)-5~thy1-7H pyrazote-4-carbonyQguanidine; [1-{1-methylbenzimidazol-6-y1~5-ethyl-1H-pyrazole~-carbony~guanidine; 1-(5-quinolinylr5-n-propyt-1H pyrazole-4-carbony(jguanidine; [1-(5-quinolinyl}-5-isopropyl-11+pyrazole~-carbonyl]guanidine; [b-ethyl-1-(6-quinolinyl)-1H-pyrazole-4-carbony(]guanidine; [1-{2-methylbenzimidazol-5-y1~5-ethyl-1H-Pyrazole~.
carbonyQguanidine; [1-(1,4-benzodioxan-6-yl~5~thyl-1H-pyrazole-4-carbony!]guanidine; [1-(benzotriazol-5-yl)-5-ethyl-1H-pyazole-4-carbonyQguanidine; [1-(3-chloroindazol-5-yl~5~thyl-1 H-pyrazole-4-ca(bonyl]guanidine; [1-(5-quinolinyl~5-butyl-1H-pyrazole-4-carbonyt]guanidine; [5-propyl-1-(6-quinolinyl~l H pyrazole-4-carbonyl]guanidine; [S-isopropyl-1-(6-quinoliny(~1 H pyrazole-4--11 &
carbonyl]guanidine: j1-(2-chloro-4-methylsulfonylphenylr5-cydopropy!-1H-' pyrazole-4-carbonyiJguanidine; [1-(2-chlorophenylj-5-cydopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-trifluoromethyl-~-fluorophenyl)-5-cydopropyl-1 H-pyrazote-4-carbonyQguanidine; j1-(2-brornophenyl)-5-cydopropyt-1H
pyrazole-4-carbonyl]guanidine; [1-(2-fluorophenyl)-5-cydopropyl-1H pyrazole-4-carbonyljguanidine; [1-(2-chioro-5-methoxyphenyl)-5-cydopropy!-1I+ .
pyrazole-4-carbonyljguanidine; [1-(2-chloro-4-methylaminosutfonylphenyl)-5-cyclopropyl-1H pyrazole-4-carbonylJguanidine; [1-(2,5~i~lorophenyl~5-cydopropyl-1 H-pyrazole-4-carbonyf]guanidine; [1-(2,3-dichlorophenyl}-5-cydopropyl-1H pyrazole-4-carbonyfjguanidine; [1-(2-chloro-5-aminocarbonylphenyl)-5-cydopropyl-1 H-pyrazole-4-carbonyljguanidine; [1-(2-chloro-5-aminosulfonytphenyl)-5-cydopropyl-i H-pyrazole-4-carbonylJguanidine; [1-(2-fluoro-6-trifluoromethylphenyl~5-cydopropyl-1H
pyrazole-4-carbonyiJguanidine; [1-(2-chloro-5-methylsulfonylphenyl~5-cydopropyl-1H pyrazole-4-carbonyljguanidine; [1-(2-chtoro-5-dimethylaminosulfonylphenyl~5-cydopropyl-1 H-pyr'azole-4-carbony(jguanidine; [1-(2-trifluoromethyf~-c~ilorophenyl~5-cyclopropyl-11-~
pyrazole-4-carbonytJguanidine; [1-(2-chlorophenyl~5-methyl-1H-pyrazole-4-carbonyl]guanidine; [5-methyl-1-(2-trifluoromethylphenyl)'1H-pyrazole-4-carbonytjguanidine; [5-ethyl-1-phenyl-1 H-pyrazole~-carbonyl]guanidine; [5-cydopropyl-1-(2-trifluoromethylphenyl)-1 H-pyrazole-4-carbonyljguanidine; [5-cydopropyl-1-phenyl-1 H-pyrazole-4-carbonyQguanidine; [5-cydopropyl-1-(2,6-dichiorophenyl~1 H-pyfazole-4-carbonyljguanidine or or a pharmaceutically acceptable salt thereof.
The preferred and especially preferred NHE-1 inhibitors disdosed in the above two paragraphs can be prepared according to methods set forth in International Patent Application No. PCTIlB99/002t76 or as set forth below, where the vartables in the following schemes and description refer only to the NHE-1 compounds.
WO 00/59510 PCT/IB00~00296 O O I ~ ' O O ~ \
R' N(H). / . R' I N~H> /
I_a NwOH t_b 1-c R~ R' COzH
N~H)w NI ~N ~ I O , , ~ \
~N~ ~Ni Rs Rs R' I NCH) /
I f I~ N~OH I-d SCHEME ll O R' is R\NH + N/'~ OR f ~ \\ N R' z~ N
I!- f 1a II-b O OR
It-c O
Rs HZN
-'120 SCHEME Iil Rs Rs N H) ~N~H) CICOC02R
R~
R~ ~ N
O v III-b R O ~ O NHZ
Rs N Rs N
OR ~ ~ N~NH
z N-N N-N
Ili-C 111-d SCHEME N
R~
S /N,~H) CICOC02R
~ N
Rs' _NH
a IV-a RS~NH
z iV-b Rs~N~N,--R'~ Rs j wN.~R, N' N
OR N
O O ~~NHx tV-c IV-d H.,N
WO 00/59510 pGTIIB001i100296 -t21 SCHEME V
O O
R''~~~OR
V-a O O
O O ~ .
R' ~ OR
R' ~ ~OR
R' NMe=
R' OEt V-c V-b RzNHNH2 R2NHNH2 V-d V-d R' COzR
NON R, R~
V~
' R' COZRH
NI . ~ R, N n (z Rs R
V_f . V-9 .122 SCHEME VI
Br R2 R' N~H~ ~ ,f" . RwN ~ R~
R ~ N C,OZEt RO "'~' N._ OEt Vha Vi-b , O
VI-c R~
RswN ~ R, N-N , O ~~NHz VI-d HzN
SCHEME VII
O OH
~,N Ra R NHNHZ ~- R3 \ N ROti N
Vii-a ~ ~ HCI
R N OH R ~OR
VII-c ~~O
Vil-b R' WO OOI59510 pCT/IB00/00296 SCHEME VIII , , , O O OLi R~NHNH2 VIII-d Rz LiN(SiMe~)2 Ri ' V(I
(COZR)z OR +
R' R' / Vlll-e Vllt-a O
Vtll-b OR R N
iN ~N NHZ
N~ I \O N~ I \O
R2 R' Rz R' ", VI11-d V111-f OR
N -.-' R'wNi ~ O R'N/ \ NH
s ~O
R= R' VIII-e RZ R~
VIII-g According to Scheme I, the Formula I-a compound, wherein R' is as described above for the compound of formula NHE, is dissolved or suspended in an aqueous alkali metal hydroxide solution (e.g. 1 N sodium hydroxide) along with sodium nitrite and the mixture is added to an aqueous aadic solution (e.g. 10% v/v sulfuric acrd) at a pH of about 0 at a temperature of about 0°C to about 5°C for about 30 min to about 1 hour. The resulting mixture is filtered to yield the Formula i-b oxime.
AitematNeiy, the Formula 1-a compound is dissolved in 1:1 acetic aadlpropionic acrd and soC~d sodium nitrite is added at about 0°C. The reaction mbct<rre is stirred at about 0°C for about 2 hours, then poured into ice water and the Fomwla !-b oxime is obtained by filtration.
The Fortnuia I-b compound is reacted with a Formula t-c cornpour~, vifierein R5 is as described above for the compound of formula NHE in a erotic solvent such as ethanol at a temperature of about 50°C to about 110°C .for about 10 min to about 1 hour to form the Formula I-d hydrazone. , , The Formula I-d hydrazone is cydized and hydrolyzed to the Formula I-a triazole in an alcoholic solvent such as 2-ethoxyethanol under basic conditions (e.g., potassium hydroxide) at a temperature of about 100 °C to about 175°C for about 1I2 hour to about 2 hours followed by addification to yield the Formula I-a triazole aad.
The Formula I-a aad is coupled with guanidine in the presence of a suitable coupling agent. A suitable coupling agent is one which transforms a carboxylic acid into a reactive speaes which fortes an amide linkage on readion with an amine.
The coupling agent may be a reagent which effects this condensation in a one pot process when mixed together with the carboxylic aad and guanidine.
Exemptary coupling reagents are 1-(3~imethylaminopropyl~3-ethylcarbodiimide hydrochloride-hydroxybenzotriazole (EDCIHBT), dicydohexylcarbodiimidelhydroxybenzotriazole(HBT), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), and diethylphosphoryfcyanide. The coupling is perfom~ed in an inert solvent, preferably an aprobc solvent at a temperature of about -20°C to about 50°C for about 1 to about 48 hours, in the presence of excess guanidine as base. Exemplary solvents include acetonitrile, dida~oromethane, dimethylfom~amide and chloroform or mixtures thereof.
The coupling agent may also be that agent which converts the carboxylic acid to an activated intermediate which is isolated and/or fom~ed in a first step and allowed to react with guanidine in a second step. Examples of such coupling agents and activated intermediates are thionyl chloride or oxalyl chloride to form the aad chloride, cyanuric fluoride to form an aad fluoride or an alkyl chlorofomiate such as isobutyl or isopropenyl chloroformate or propanephosphonic anhydride (propanephosphonic add anhydride, PPA) (with a tertiary amine base) to form a mixed anhydride of the carboxylic aad, or carbonyldiimidazote to form an acylimidazole. ff the coupling agent is oxaiyl chloride, it is advantageous to employ a small amount of dimethylforrrrarrode as cosolvent with another solvent (such as dichforomethane) to catalyze the formation of the acid chloride. This activated aad derivative may be coupled by mixing with excess guanidine in an appropriate solvent together with an appropriate base.
Appropriate solvent/base combinations are for example, dichloromethane, dimethylformamide or acetori~trile or mixtures thereof in the presence of excess WO OOI59510 PCTIIB~O/00296 guanidine as base. Other appropriate solvent/base combinations inGude water or a (C,-Cs~lcohot or a mixture thereof together with a cosplvent such as dichloromethane, tetrahydrofuran or dioxane and a base such as sodium, potassium or lithium hydroxide in sufficient quantity to consume the acid liberated in the reaction.
Use of these coupling agents and appropriate selection of solvents and temperatures are known to those skilled in the art or can be readily determined from the literature.
These and other exemplary conditions useful for coupling carboxylic aads are described in Houben-Weyl, Vol XV, part II, E. Wunsch, Ed., G. Theime Verlag,1974, Stuttgart: M. Bodansky, Prinapfes of Peptide Synthesis, Springer Verlag, 8eriin 1984;
and The Peptides, Analysis, Synthesis and Biology led: E. Gross and J.
Meienhofer), vols 1-5 (Academic Press, NY 1979-1983).
According to Scheme II, the Formula II-a primary amine wherein R5 is as described above for the compound of formula ~NHE is reacted with a Formula II-b a-diazo-p-keto-ester wherein R' is as described above for the compound of formula NHE, and R is lower alkyl, in the presence of titanium tetrachioride analogously to the method described in Eguchi S. ef al. Synthesis 7993, 793 to form the Formula II-c triazole carboxylic acrd ester. The Formula II-c ester is converted directly to the acylguanidine 11-d by reaction with guanidine in an,alcoholic solvent at a temperature of about 60 to about 110°C, preferably refluxing methanol, for a period of 8 to 20 hours. .
According to Scheme III, the Formula III-a compound wherein R' and Rs are as described above for the compound of formula NHE is treated with t-awesson's reagent (i.e., 2,4-bis(4-methoxyphenyl~l,3-dithia-2,4-diphosphetane-2,4-disulfide) in an aprotic solvent suds as dimethoxyethane at a temperature of about 20°C to about 120°C for about one to eight hours. The resulting thioamide is treated with an alkyla6ng agent such as methyl iodide in a polar, inert sohrent such as acetone, conveniently at ambient temperature for about eight hours to about forty-eight hours.
The resulting compound is reacted with anhydrous hydrazine in an alcohof~c solvent at a temperature of about 0°C to about 25°C for about one to eight hours to provide the Formula III-b compound (analogously as described in Doyle and Kurzer, Synthesis 1974, 583).
The Formula III-b compound is treated with a monoalkyloxalyl chloride in an aprotic solvent at a temperature of about 25°C to about 50°C for about one to eight -12s-hours to provide the Formula III-c carboxylic ester compound wherein R is lower alkyl.
The Formula III-c ester is directly coupled with guanidine in an alcoholic solvent at a temperature of about 60°C to about 110 °C, preferably refluxing methanol, for a period of eight to twenty hours, to prepare the Formula ~ , ttl-d triazole carbonyl guanidines.
According to Scheme N the Formula IV-a compound wherein R5 is as described above for the compound of formula NHE is treated with methyl iodide in an inert solvent, conveniently at ambient temperature for about four to twenty-four hours.
The resulflng compound is reacted with anhydrous R'-hydrazine (wherein R' is as described above for the compound of formula NHE) in an alcohofrc solvent at a temperature of about 0°C to about 25°C for about one to eight hours to provide the Formula N-b amidrazone compound (analogously as described in Doylg and ICurzer, Synthesis 1974, 583).
The Formula N-b compound is treated with a monoafkyloxalyl chloride in an aprotic solvent at a temperature of about 25°C to about 50°C for about one to eight hours to provide the Fortnuia IV-c carboxylic ester compound wherein R is lower alkyl.
The Fomzufa N-c ester is directly coupled with guanidine in an alcoholic solvent at a temperature of about 60°C to about 110°C, preferably refluxing methanol, for a period of eight to twenty hours to prepare the Formula N-d triazole carbonyl guanidines.
Aaoording to Scheme V the Formula V-a compound wherein R' is as described above for the compound of fonnuta NHE is combined with excess (CH,O)ZC(R')N(CH3)= (N,N-dimethy! amide dimethyl acetal) wherein R' is as described above for the compound of formula NHE, optionally in the presence of an aad catalyst such as p-toluenesulfonic aad at a temperature of about 90°C to about 110°C for about one to about two hours to prepare the Formula V-c compound above.
The Formula V-c compound is cyclized with a Fomurla V-d compound, wherein R2 is as described above for the compound of formula NHE, in an inert solvent such as ethanol at a temperature of about 20°C to about
Y=HJ.
In compounds 20-23, and 29 Z is S. fn compounds 24-28, Z is O.
Of the above subgroup, compounds 20-29 are more preferred with 29 espedalfy prefer-ed.
M espedally preferred aldose reductase inhibitor is 1-phthalazineacetic aad, 3,4-dihydro-4~xo-3-(j5-trifluoromethyl}-2-benzothiazolyl]methylj-.
The term "aryl radical of a carboxylic add aldose reductase inhibitor" refers to any of the above-mentioned aldose reductase inhbitors which contains a carboxylic add group in which the carboxylic add group is replaced with a carbonyl radical.
pG"fIIB00/00296 The aldose reductase inhibitor compounds of this invention are readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis, particularly in view of the pertinent patent specification descriptions.
An amount of the aldose reductase inhibitor of this invention that is effective for the activities of this invention may be used. Typically, an effective dosage for the aldose reductase inhibitors of this invention is in the range of about 0.1 mg/kglday.to 100 mg/kglday in single or divided doses, preferably 0.1 mglkglday to 20 mg/kg/day in single or divided doses.
Any sodium hydrogen ion exchange (NHE-1 ) inhibitor may be used as the second compound (active agent) of this invention for combination therapies.
The term NHE-1 inhibitor refers to compounds which inhibit the sodiumlproton (Na'IH') exchange transport system and hence are useful as a therapeutic or prophylactic agent for diseases caused or aggravated by the acceleration of the sodiumlproton (Na'/H') exchange transport system, for example, cardiovascular diseases [e.g., arteriosderosis, hypertension, arrhythmia (e.g. ischemic arrhythmia, arrhythmia due to myocardial infarction, myocardial stunning, myocardial dysfunction, artfiythmia after PTCA or after thrombolysis, etc.), angina pectoris, cardiac hypertrophy, myocardial infarction, heart failure (e.g. congestive heart failure, acute heart failure, cardiac hypertrophy, etc.), restenosis after PTCA, PTCI, shock (e.g. hemorrhagic shock, endotoxin shock, etc.)], renal diseases (e.g. diabetes mellitus, diabetic nephropathy, ischemic acute renal failure, etc.) organ disorders associated with ischemia or ischemic reperfusion [e.g. heart musde ischemic reperfusion assodated disorders, acute renal failure, or disorders induced by surgical treatment such as coronary artery bypass grafting (CABG) surgeries, vascular surgeries, organ transplantation, non-cardiac surgeries or percutaneous transluminal coronary angioplasty (PTCA)], oerebrovasarlar diseases (e.g. ischemic stroke, hemorrhagic stroke, etc.), cerebra ischemic disorders (e.g. disorders assodated with cerebral infarction, disorders caused after cerebral apoplexy as sequetae, or oerebrat edema. NHE-1 inhibitors can also be used as: an agent for myocardial protection during coronary artery bypass grafting (CABG) surgeries, vascular surgeries, percutaneous transluminal coronary angioplasty (PTCA), PTC1, organ transplantation, or non-cardiac surgeries. The utility of NHE-7 inhibitors as medical agents in the treatment of diseases, such as are detailed herein in mammals (e.g. humans) for example, myocardial protection during surgery or mycardial protection in patients presenting with ongoing cardiac or cerebral ischemic events or chronic cardioprotedion in patients with diagnosed coronary heart disease, or at risk for coronary heart disease, cardiac dysfunction or myocardial stunning is demonstrated by the activity of the compounds of formula ! of this , invention in conventional predinical cardioprotedyon assays [see the in viuo assay in Klein, H. et aL, Circulation 92:912-917 (1995); the isolated heart assay in Schotz, W.
et al., Cardiovascular Research 29:260-268 (1995); the antiarrhythmic assa~r in Yasutake M- et aL, Am. J. Physiol., 36:H2430-H24.40 (1994); the NMR assay in Kolke et al., J. Thorac. t:ardiovasc. Surg.112: 765-775 (1996)] and the additional in viUo and in vivo assays described below. Such assays also provide a means whereby the activities of the compounds of formula I of this invention can be compared with the activities of other known compounds. The results of these comparisons are useful for detemuning dosage levels in mammals, inducting humans, for the treatment of such diseases.
NHE-1 inhibitors are disclosed in U.S. Pat. No. 5,698,581, European Patent Application Publication No. EP 803 501 A1, International PatentAppCcation Publication Nos. WO 94/26709 and PCTIJP97/0465~0.
The NHE-1 inhibitors disclosed therein have utility in the combination of this invention. Said NHE-1 inhibitors can be prepared as disclosed therein.
Preferred NHE-1 inhibitors include compounds of the fom~ula NHE,:
Z" ~NHZ
Oi N~ Hz NHE
a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug, wherein Z in the compound of formula NHE is carbon oonned~ed and is a fnre-membered, diaza, diunsaturated ring having two contiguous rirtrogens, said ring optiortalfy mono-, di-, or tri-substituted with up to three subst~rents-independently selected from R'; Rz and R3 ;
wo oo~s9sio Pcr~sooiooz~
-~ 1 s Or Z in the compound of formula NHE carbon connected and is a five-membered, triaza, diunsaturated ring, said ring optionally mono- or di-substituted with up to two substituents independently selected from R' and R5;
wherein R', RZ, R3, R' and RS in the'compound of formula NHE are each independently hydrogen, hydroxy-(C,-C,)alkyl, (C,-C,)alkyl, (C,-C,)alkylthio, (C,-C,)cydoalkyl, (C,-C,)cydoalkyl(C,-C,)alkyl, (C,-C,)alkoxy, (C,-C,)alkoxy(C,-C,)alkyl, mono-N- or di-N,N-(C,-C,)alkylcarbamoyl, M or M(C,-C,)alkyl, any of said previous (C,-C,)alkyl moieties optionally having from one to nine fluorines; said (C,-C,)alkyl or (C,-C,)cycloalkyl op6onaliy mono-or di-substituted independently with hydroxy, (C,-C,)alkoxy, (C,-C,)alkylthio, (C,-C,)alkylsulfinyl, (C,-C,)alkylsulfonyl, (C,-C,)alkyl, mono-N- or di-N,N-(C,-C,)alkylcarbamoyl or mono-N- or di-N,N-(C,-C,)alkytaminosulfonyl; and said (C,-C,)cydoalkyl optionally having from one to seven tiuorines;
wherein M in the compound of formula NHE is a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicydic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
said M in the compound of formula NHE is optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicydic, on carbon or nitrogen with up to three substituents independently selected from R°, R' and R°, wherein one of R6, R' and R°
is optionally a partially saturated, fully saturated, or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen optionally substituted with (C,-C,~Ikyl and additionally R6, R' and R° are optionally hydroxy, vitro, halo, {C,-C,)alkoxy, (C,-C,)alkoxycarbonyl, (C,-C,~Ikyl, fomiyt, (C,-C,~Ikanoyl, (C,-C,~Ikanoyloxy, (C,-C,)alkanoylamino, (C,-C,)alkoxycarbonylamino, sulfonamide, (C,-C,)alkyisulfonamido, amino, mono-N- or di-N,N-(C,-C,)atkylamino, cartiamoyl; mono-N- or di-N,N-{C,-C,~lkylcarbamoyl, cyano, thioi. (C,-C,)alkylthio, (C,-C,)alkylsulfinyl, (C,-C,)alkylsulfonyi, mono-N-or di-,, N,N-(C,-C,)alkylaminosulfonyl, (CZ-C,)alkenyl, (CZ-C,)alkynyl or (C~-C,)cydoalkenyl, wherein said (C,-C,)alkoxy, (C,-C,)alkyl, (C,-C,~Ikanoyl, (C,-C,~Ikylthio.
mono-N- or di-N;N-(C,-C,)alkylamino or (C,-C,)cydoalkyl R6. R' and R°
substituents are optionally mono- substituted independently with hydroxy, (C,-C,)alkoxycarbonyl, (C,-C,)cydoalkyl, (C,-C,)alkanoyl, (C,-C,)alkanoylamino, (C,-C,)alkanoyloxy, (C;
C,)aikoxycarbonylamino, sulfonamido, (C,-C,)alkylsulfonamido, amino, mono-N-or di-N,N-(C,-C,)alkylamino, carbamoyl, mono-N- or di-N,N-(C,-C,)alkylcarbamoyl, cyano, 0 thiol, vitro, (C,-C,)alkylthio, (C,-C,)alkylsulfinyl; (C,-C,)alkylsulfonyl or mono-N- or di-N,N-(C,-C,)alkylaminosulfonyl or optionally substituted with one to nine fluorines.
Especially preferred NHE-1 inhibitors indude [1-(8-bromoquinolin-5-I -5-cydopropyl-1 H-pyrazofe-4-carbon y ) yt]guanidine; [1-(6-chloroquinotin-5-yl).
5-cydopropyl-1 H pyrazole-4-carbonyl]guanidine; [1-(indazol-7 ylr5-cyclopropyt-1H pyrazole-4-carbonyljguanidine; [1-(benzimidazol-5-y1~5-cydopropyt-1H pyrazole-4-carbonyf]guanidine; [1-(1-isoquinolyl~5-cydopropyl-1 H-pyrazoie-4-carbonyljguanidine; [5-~ydopropyl-1-(4-quinolinyl~
1 H-pyrazole-4-carbonyf]guanidine; [5-cydopropyl-1-(quinolin-S-yl)-1 H-pyrazole-4-carbonyf]guanidine; [5-cydopropyl-1-(quinolin-8-yl)-1 H-pyrazole~-carbonyl]guanidine; [1-(indazol-6-y1~5-ethyl-1 H pyrazole~-carbonyl]guanidine; [1-(indazol-5-yt}-5-ethyl-1H py~azole-4-carbonyl]guanidine; [1-(benzimidazol-5-yl)-5~thy1-7H pyrazote-4-carbonyQguanidine; [1-{1-methylbenzimidazol-6-y1~5-ethyl-1H-pyrazole~-carbony~guanidine; 1-(5-quinolinylr5-n-propyt-1H pyrazole-4-carbony(jguanidine; [1-(5-quinolinyl}-5-isopropyl-11+pyrazole~-carbonyl]guanidine; [b-ethyl-1-(6-quinolinyl)-1H-pyrazole-4-carbony(]guanidine; [1-{2-methylbenzimidazol-5-y1~5-ethyl-1H-Pyrazole~.
carbonyQguanidine; [1-(1,4-benzodioxan-6-yl~5~thyl-1H-pyrazole-4-carbony!]guanidine; [1-(benzotriazol-5-yl)-5-ethyl-1H-pyazole-4-carbonyQguanidine; [1-(3-chloroindazol-5-yl~5~thyl-1 H-pyrazole-4-ca(bonyl]guanidine; [1-(5-quinolinyl~5-butyl-1H-pyrazole-4-carbonyt]guanidine; [5-propyl-1-(6-quinolinyl~l H pyrazole-4-carbonyl]guanidine; [S-isopropyl-1-(6-quinoliny(~1 H pyrazole-4--11 &
carbonyl]guanidine: j1-(2-chloro-4-methylsulfonylphenylr5-cydopropy!-1H-' pyrazole-4-carbonyiJguanidine; [1-(2-chlorophenylj-5-cydopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-trifluoromethyl-~-fluorophenyl)-5-cydopropyl-1 H-pyrazote-4-carbonyQguanidine; j1-(2-brornophenyl)-5-cydopropyt-1H
pyrazole-4-carbonyl]guanidine; [1-(2-fluorophenyl)-5-cydopropyl-1H pyrazole-4-carbonyljguanidine; [1-(2-chioro-5-methoxyphenyl)-5-cydopropy!-1I+ .
pyrazole-4-carbonyljguanidine; [1-(2-chloro-4-methylaminosutfonylphenyl)-5-cyclopropyl-1H pyrazole-4-carbonylJguanidine; [1-(2,5~i~lorophenyl~5-cydopropyl-1 H-pyrazole-4-carbonyf]guanidine; [1-(2,3-dichlorophenyl}-5-cydopropyl-1H pyrazole-4-carbonyfjguanidine; [1-(2-chloro-5-aminocarbonylphenyl)-5-cydopropyl-1 H-pyrazole-4-carbonyljguanidine; [1-(2-chloro-5-aminosulfonytphenyl)-5-cydopropyl-i H-pyrazole-4-carbonylJguanidine; [1-(2-fluoro-6-trifluoromethylphenyl~5-cydopropyl-1H
pyrazole-4-carbonyiJguanidine; [1-(2-chloro-5-methylsulfonylphenyl~5-cydopropyl-1H pyrazole-4-carbonyljguanidine; [1-(2-chtoro-5-dimethylaminosulfonylphenyl~5-cydopropyl-1 H-pyr'azole-4-carbony(jguanidine; [1-(2-trifluoromethyf~-c~ilorophenyl~5-cyclopropyl-11-~
pyrazole-4-carbonytJguanidine; [1-(2-chlorophenyl~5-methyl-1H-pyrazole-4-carbonyl]guanidine; [5-methyl-1-(2-trifluoromethylphenyl)'1H-pyrazole-4-carbonytjguanidine; [5-ethyl-1-phenyl-1 H-pyrazole~-carbonyl]guanidine; [5-cydopropyl-1-(2-trifluoromethylphenyl)-1 H-pyrazole-4-carbonyljguanidine; [5-cydopropyl-1-phenyl-1 H-pyrazole-4-carbonyQguanidine; [5-cydopropyl-1-(2,6-dichiorophenyl~1 H-pyfazole-4-carbonyljguanidine or or a pharmaceutically acceptable salt thereof.
The preferred and especially preferred NHE-1 inhibitors disdosed in the above two paragraphs can be prepared according to methods set forth in International Patent Application No. PCTIlB99/002t76 or as set forth below, where the vartables in the following schemes and description refer only to the NHE-1 compounds.
WO 00/59510 PCT/IB00~00296 O O I ~ ' O O ~ \
R' N(H). / . R' I N~H> /
I_a NwOH t_b 1-c R~ R' COzH
N~H)w NI ~N ~ I O , , ~ \
~N~ ~Ni Rs Rs R' I NCH) /
I f I~ N~OH I-d SCHEME ll O R' is R\NH + N/'~ OR f ~ \\ N R' z~ N
I!- f 1a II-b O OR
It-c O
Rs HZN
-'120 SCHEME Iil Rs Rs N H) ~N~H) CICOC02R
R~
R~ ~ N
O v III-b R O ~ O NHZ
Rs N Rs N
OR ~ ~ N~NH
z N-N N-N
Ili-C 111-d SCHEME N
R~
S /N,~H) CICOC02R
~ N
Rs' _NH
a IV-a RS~NH
z iV-b Rs~N~N,--R'~ Rs j wN.~R, N' N
OR N
O O ~~NHx tV-c IV-d H.,N
WO 00/59510 pGTIIB001i100296 -t21 SCHEME V
O O
R''~~~OR
V-a O O
O O ~ .
R' ~ OR
R' ~ ~OR
R' NMe=
R' OEt V-c V-b RzNHNH2 R2NHNH2 V-d V-d R' COzR
NON R, R~
V~
' R' COZRH
NI . ~ R, N n (z Rs R
V_f . V-9 .122 SCHEME VI
Br R2 R' N~H~ ~ ,f" . RwN ~ R~
R ~ N C,OZEt RO "'~' N._ OEt Vha Vi-b , O
VI-c R~
RswN ~ R, N-N , O ~~NHz VI-d HzN
SCHEME VII
O OH
~,N Ra R NHNHZ ~- R3 \ N ROti N
Vii-a ~ ~ HCI
R N OH R ~OR
VII-c ~~O
Vil-b R' WO OOI59510 pCT/IB00/00296 SCHEME VIII , , , O O OLi R~NHNH2 VIII-d Rz LiN(SiMe~)2 Ri ' V(I
(COZR)z OR +
R' R' / Vlll-e Vllt-a O
Vtll-b OR R N
iN ~N NHZ
N~ I \O N~ I \O
R2 R' Rz R' ", VI11-d V111-f OR
N -.-' R'wNi ~ O R'N/ \ NH
s ~O
R= R' VIII-e RZ R~
VIII-g According to Scheme I, the Formula I-a compound, wherein R' is as described above for the compound of formula NHE, is dissolved or suspended in an aqueous alkali metal hydroxide solution (e.g. 1 N sodium hydroxide) along with sodium nitrite and the mixture is added to an aqueous aadic solution (e.g. 10% v/v sulfuric acrd) at a pH of about 0 at a temperature of about 0°C to about 5°C for about 30 min to about 1 hour. The resulting mixture is filtered to yield the Formula i-b oxime.
AitematNeiy, the Formula 1-a compound is dissolved in 1:1 acetic aadlpropionic acrd and soC~d sodium nitrite is added at about 0°C. The reaction mbct<rre is stirred at about 0°C for about 2 hours, then poured into ice water and the Fomwla !-b oxime is obtained by filtration.
The Fortnuia I-b compound is reacted with a Formula t-c cornpour~, vifierein R5 is as described above for the compound of formula NHE in a erotic solvent such as ethanol at a temperature of about 50°C to about 110°C .for about 10 min to about 1 hour to form the Formula I-d hydrazone. , , The Formula I-d hydrazone is cydized and hydrolyzed to the Formula I-a triazole in an alcoholic solvent such as 2-ethoxyethanol under basic conditions (e.g., potassium hydroxide) at a temperature of about 100 °C to about 175°C for about 1I2 hour to about 2 hours followed by addification to yield the Formula I-a triazole aad.
The Formula I-a aad is coupled with guanidine in the presence of a suitable coupling agent. A suitable coupling agent is one which transforms a carboxylic acid into a reactive speaes which fortes an amide linkage on readion with an amine.
The coupling agent may be a reagent which effects this condensation in a one pot process when mixed together with the carboxylic aad and guanidine.
Exemptary coupling reagents are 1-(3~imethylaminopropyl~3-ethylcarbodiimide hydrochloride-hydroxybenzotriazole (EDCIHBT), dicydohexylcarbodiimidelhydroxybenzotriazole(HBT), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), and diethylphosphoryfcyanide. The coupling is perfom~ed in an inert solvent, preferably an aprobc solvent at a temperature of about -20°C to about 50°C for about 1 to about 48 hours, in the presence of excess guanidine as base. Exemplary solvents include acetonitrile, dida~oromethane, dimethylfom~amide and chloroform or mixtures thereof.
The coupling agent may also be that agent which converts the carboxylic acid to an activated intermediate which is isolated and/or fom~ed in a first step and allowed to react with guanidine in a second step. Examples of such coupling agents and activated intermediates are thionyl chloride or oxalyl chloride to form the aad chloride, cyanuric fluoride to form an aad fluoride or an alkyl chlorofomiate such as isobutyl or isopropenyl chloroformate or propanephosphonic anhydride (propanephosphonic add anhydride, PPA) (with a tertiary amine base) to form a mixed anhydride of the carboxylic aad, or carbonyldiimidazote to form an acylimidazole. ff the coupling agent is oxaiyl chloride, it is advantageous to employ a small amount of dimethylforrrrarrode as cosolvent with another solvent (such as dichforomethane) to catalyze the formation of the acid chloride. This activated aad derivative may be coupled by mixing with excess guanidine in an appropriate solvent together with an appropriate base.
Appropriate solvent/base combinations are for example, dichloromethane, dimethylformamide or acetori~trile or mixtures thereof in the presence of excess WO OOI59510 PCTIIB~O/00296 guanidine as base. Other appropriate solvent/base combinations inGude water or a (C,-Cs~lcohot or a mixture thereof together with a cosplvent such as dichloromethane, tetrahydrofuran or dioxane and a base such as sodium, potassium or lithium hydroxide in sufficient quantity to consume the acid liberated in the reaction.
Use of these coupling agents and appropriate selection of solvents and temperatures are known to those skilled in the art or can be readily determined from the literature.
These and other exemplary conditions useful for coupling carboxylic aads are described in Houben-Weyl, Vol XV, part II, E. Wunsch, Ed., G. Theime Verlag,1974, Stuttgart: M. Bodansky, Prinapfes of Peptide Synthesis, Springer Verlag, 8eriin 1984;
and The Peptides, Analysis, Synthesis and Biology led: E. Gross and J.
Meienhofer), vols 1-5 (Academic Press, NY 1979-1983).
According to Scheme II, the Formula II-a primary amine wherein R5 is as described above for the compound of formula ~NHE is reacted with a Formula II-b a-diazo-p-keto-ester wherein R' is as described above for the compound of formula NHE, and R is lower alkyl, in the presence of titanium tetrachioride analogously to the method described in Eguchi S. ef al. Synthesis 7993, 793 to form the Formula II-c triazole carboxylic acrd ester. The Formula II-c ester is converted directly to the acylguanidine 11-d by reaction with guanidine in an,alcoholic solvent at a temperature of about 60 to about 110°C, preferably refluxing methanol, for a period of 8 to 20 hours. .
According to Scheme III, the Formula III-a compound wherein R' and Rs are as described above for the compound of formula NHE is treated with t-awesson's reagent (i.e., 2,4-bis(4-methoxyphenyl~l,3-dithia-2,4-diphosphetane-2,4-disulfide) in an aprotic solvent suds as dimethoxyethane at a temperature of about 20°C to about 120°C for about one to eight hours. The resulting thioamide is treated with an alkyla6ng agent such as methyl iodide in a polar, inert sohrent such as acetone, conveniently at ambient temperature for about eight hours to about forty-eight hours.
The resulting compound is reacted with anhydrous hydrazine in an alcohof~c solvent at a temperature of about 0°C to about 25°C for about one to eight hours to provide the Formula III-b compound (analogously as described in Doyle and Kurzer, Synthesis 1974, 583).
The Formula III-b compound is treated with a monoalkyloxalyl chloride in an aprotic solvent at a temperature of about 25°C to about 50°C for about one to eight -12s-hours to provide the Formula III-c carboxylic ester compound wherein R is lower alkyl.
The Formula III-c ester is directly coupled with guanidine in an alcoholic solvent at a temperature of about 60°C to about 110 °C, preferably refluxing methanol, for a period of eight to twenty hours, to prepare the Formula ~ , ttl-d triazole carbonyl guanidines.
According to Scheme N the Formula IV-a compound wherein R5 is as described above for the compound of formula NHE is treated with methyl iodide in an inert solvent, conveniently at ambient temperature for about four to twenty-four hours.
The resulflng compound is reacted with anhydrous R'-hydrazine (wherein R' is as described above for the compound of formula NHE) in an alcohofrc solvent at a temperature of about 0°C to about 25°C for about one to eight hours to provide the Formula N-b amidrazone compound (analogously as described in Doylg and ICurzer, Synthesis 1974, 583).
The Formula N-b compound is treated with a monoafkyloxalyl chloride in an aprotic solvent at a temperature of about 25°C to about 50°C for about one to eight hours to provide the Fortnuia IV-c carboxylic ester compound wherein R is lower alkyl.
The Fomzufa N-c ester is directly coupled with guanidine in an alcoholic solvent at a temperature of about 60°C to about 110°C, preferably refluxing methanol, for a period of eight to twenty hours to prepare the Formula N-d triazole carbonyl guanidines.
Aaoording to Scheme V the Formula V-a compound wherein R' is as described above for the compound of fonnuta NHE is combined with excess (CH,O)ZC(R')N(CH3)= (N,N-dimethy! amide dimethyl acetal) wherein R' is as described above for the compound of formula NHE, optionally in the presence of an aad catalyst such as p-toluenesulfonic aad at a temperature of about 90°C to about 110°C for about one to about two hours to prepare the Formula V-c compound above.
The Formula V-c compound is cyclized with a Fomurla V-d compound, wherein R2 is as described above for the compound of formula NHE, in an inert solvent such as ethanol at a temperature of about 20°C to about
30°C for about 5 minutes to about one hour followed by heating to a temperature of about 70°C to about 110°C for~about two hours to about four hours to fore the Fomurla V f pyramle.
Aitemabvely, according to Scheme V the Formula V-a found, wherein R' is as described above for the compound of formula NHE, is combined with a triethylorthoester (i.e., R'C(OEt), wherein R' is as described above for the compound ,, of formula NHE) and acetic anhydride at a temperature of about 120°C, to about 150 °C for about two to about five hours to prepare the Formula V-b compound.
The Formula V-b compound is cyctized with a Fomluta V-d compound, wherein R2 is as described above for the compound of formula NHE, to form the Formula V-c pyrazole.
The Formula V-c pyrazole is hydrolyzed with a base such as sodium hydroxide or lithium hydroxide in a solvent such as water andlor methanol andlor THF
conveniently at ambient temperature or at elevated temperature (e.g., reflux) for about one hour to about ftve hours to prepare the Fomtuta V-f acrd.
The Formula V-f acrd is coupled with guanidine in the presence of a suitable coupling agent as described for the above coupling of the Fomnula I-a acid and guanidine. In one embodiment, the Formula V-f acrd is activated with thionyl chtoiide at a temperature of about 60°C to about 90°C for about fifteen minutes to about two hours. The resulting activated acid chloride is combined with guanidine hydrochloride and an inorganic base (e.g., sodium hydroxide) in anhydrous tetratrydrof<rran and optionally methanol andlor water. The solution is heated, con~nientiy at reflux, for about one hour to about eight hours to prepare the Fomnula V-g compound.
Alternatively according to Scheme V the Fonnuta V-a compound can be directly converted to the Formula V-g compound by several methods. For example.
the Formula V-a compound can be heated in the presence of excess guanidine, in a polar protic solvent for example, methanol or isopropanol at a suitable temperature conveniently, at reflux for about one to about seventy two hours. This transfomsation may also be performed by repeatedly removing the solvent; for example removing ethanol or toluene about four times, from a mixhrre of the Formula Y-a compound and excess guanidine at a pressure of about one to about 100 mmHg and at a temperature of about 25°C to about 95°C. This reaction may also be performed in the absence of solvent by heating the rrindure of the Fortnuta V-a compound and excess guanidine at a temperature of about 100°C to about 180°C, optionaily at about a pressure of about 1 to about 100 mmHg for about five minutes to about eight hours.
According to Scheme VI, the Formula Vha compound, wherein R' is as described above for the compound of formula NHE, is reacted with the Formula VI-b compound, wherein R' and R2 are as described above for the compound of formula.
WO OOI59510 pGT/IB00/00296 NHE, in an aprotic solvent at a temperature of about 0°C to about 25°C for about two hours to about twenty-four hours in the presence of ah~appropriate amine base, such as triethylamine, to form the Formula VI-c compound.
The resulting Formula VI-c compound is hydrolyzed and coupled with guanidine using one of the methods described in earlier Schemes, such as the method employing carbonyldiimidazole, to form the Formula VI-d compound.
According to Scheme VII, the Formula VII-a hydrazine, wherein R2 is as described above for the compound of formula NHE, is reacted with the appropriate Formula VII-b compound to form the Formula VII-c pyrazote ester wherein R is lower alkyl according to the method of Bajnati, A. and Hubert Habart, M. Bu!!. Soc.
Chim.
France 1988, 540. 'The resulting pyrazole ester is converted to the Formula V11-d aryl guanidine using the hydrolysis and coupling methods described above.
According to Scheme Vlll, the Formula VIII-a compound wherein Rz and' R' are as described above for the compound of formula NHE is transfom~ed to the Formula Vllt-b Lithium salt where R is lower alkyl according to the method described in J. HeL Chem. ?989, 26,1389. the Formula VIII-b lithium salt is combined with the Formula VIII-c hydrazine, wherein R' is as described above for the compound of formula NHE, in an inert solvent such as ethanol, in the presence of a miners( acrd, at a temperatun: of about 20°C to about 30°C for about fare minutes to about one hour followed by heating to a temperature of about 70°C to about 110°C for two hours to about four hours to form both the Formula VIII-d and VIII-e pyrazotes. The Fom~ula Vlll-d and Vlll-e pyrazoles are converted to the Formula Vltl-f and VIII acyl guanidines respectively using the hydrolysis and coupling methods descrtbed above.
Some of the methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in Fom~ula I precursors). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods.
The need for such protection is readily determined by one skilled in the art The use of such protectioNdeprotection methods is also within the skill in the art For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley ~ Sons, New York, 1991.
The compounds of formula I of the present invention, when used in combination with NHE-1 inhibitors, inhibit the sodiumlproton (Na'!H') exchange transport system and hence are useful as a therapeutic or prophylactic agent for , diseases caused or aggravated by the acceleration of,the sodiumlproton (Na'!ti') exchange transport system, for example, cardiovascular diseases [e.g., arteriosclerosis, hypertension, atfiythmia (e.g. ischemic arrhythmia, ant~ythmia due to myocardial infarction, myocardial stunning, myocardial dysfunction, arrhythmia after PTCA or after thrombalysis, etc.), angina pectoris, cardiac hypertrophy,.
myocardial infarction, heart failure (e.g. congestive heart failure, acute heart failure, cardiac hypertrophy, etc.), restenosis after PTCA, PTCI, shock (e.g. hemorrhagic shock, endotoxin shock, etc.)], renal diseases (e.g. diabetes mellitus, diabetic nephropathy, isdlemic acute renal failure, etc.) organ disorders assodated with ischemia or tschemic reperfusion [e.g. heart muscle tschemic reperfusion assodated disorders, acute renal failure, or disorders induced by surgical treatment such as coronary artery bypass grafting (CABG) surgeries, vasarlar surgeries, organ transplantation, non-cardiac surgeries or perartaneous transluminat coronary angioplasty (PTCA)j, cerebrovascutar diseases (e.g. isdzemic stroke, hemorfiagtc stroke, etc.), cerebra ischemic disorders (e.g..disorders associated with cerebral infarction, disorders caused after cerebral apoplexy as sequelae, or cerebral edema.
Preferably, the compounds of fomwia t pf this invention can be used in combination with NHE-1 inhibitors as agents for myocardial protection before, during, or after coronary artery bypass grafting (CABG) surgeries; vascular surgeries, pen~rtaneous transluminat coronary angioplasty (PTCA), organ transplantation, or non-cardiac surgeries.
Preferably, the compounds of formula ! of this invention can be used in combination with NHE-1 inhibitors as agents for myocardial protection in patients presenting with ongoing cardiac (carte coronary syndromes, e.g. rrryocardial infarction or unstable angina) or cerebral ischemic events (e.g. stroke).
Preferably, the compounds of fomwta 1 of this invention can be used in combination with NHE-1 inhibitors as agents for chronic rtryocardial protection in patients with diagnosed coronary heart disease (e.g. previous myocardial infarction or unstable angina) or patients who are at high risk for myocardial infarction (age greater than 65 and two or more risk factors for coronary heart disease).
tn addition, a combination of the compounds of fomwla I of this.invention with NHE-1 inhibitors has a strong inhibitory effect on the proliferation of cells, for exar~le wo oo~s9s~o rcr~BOOiooz~
the proliferation of fibrobtast celis'and the proliferation of the smpQth muscle cells of the blood vessels. For this reason, the combination of the compounds of formula I of this invention with NHE-1 inhibitors of this invention is a valuable therapeutic agent for use in diseases in which cell proliferation fepresents a primary or secondary cause and may, therefore, be used as antiatherosderotic agents, and as agents against diabetic late complications, cancerous diseases, fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, glomerular nephrosderosis, organ hypertrophies or hyperplasias, in particular hyperptasia or hypertrophy of the prostate, pulmonary fibrosis, diabetic complications or recurrent strichrre after PTCA;
or diseases caused by endothelial cell injury.
The utility of the combination of compounds of the present invention with NHE-1 inhibitors as medical agents in the treatment of diseases, such as are detailed herein in mammals (e.g. humans) for example, myocardial protection during surgery or mycardiai protedyon in patients presenting with ongoing cardiac or cerebral isdzemic events or chronic cardioprotection in patients with diagnosed coronary heart disease, or at risk for coronary heart disease, cardiac dysfunction or myocardial stunning is demonstrated by the activity of said combination in conventional predinical cardioprotection assays [see the in vivo assay in Klein, H. et al., Circulation 92:912-917 (1995); the isolated heart assay in Schotz, W. et al., Cardiovascular Research 29:260-268 (1995); the antiacrhythmic assay in Yasutake M: et al., Am. J.
Physiol., 36:H2430-H2440 (1994); the NMR assay in Kolke et at., J. Thorac. Cardiovasc.
Sung.
112 ?65-775 (1996)] and the additional in vitro and in vivo assays described below.
Such assays also provide a means whereby the activities of the compounds of fomwla 1 of this invention can be compared with the activi(ies of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
Measurement of Human NHE-1 Inhibitory Activity Methodologies for measurement of human NHE-1 adtvity and inhibitor potency are based on those published by Watson et at., Am. J. Physiol., 24:6229-6238,1991 ), where NHE-mediated recovery of intracellular pH is measured following intracellular aad~cation. Thus, tabroblasts stably expressing human NHE-1 (Counillon; L et at.,,Mol. Pham~acol., 44:1041-1045 (1993) are plated onto collagen coated 96 well plates (50,QOOiwell) and grown to cont3uence in growth media (DMEM
WO 00/59510 PCTlIB00f00296 high glucose, 10°~ fetal bovine serum. 50 uiml penicillin and streptomyan)' ~ Confluent plates are incubated for 30 minutes at 37°C with the pH sensitive fluorescent probe BCECF (5 ~M; Molecular Probes, Eugene, OR). BCECF loaded cells are incubated for 30 minutes of 37°C in aad loading media (70 mM choline chloride, 50 mM NHCI,; 5 mM KCI, 1 mM MgCI?,1.8 mM CaCl2, 5 mM glucose,10 mM HEPES, pN 7.5), and then placed in a Fluorescent imaging Plate Reader (Mofecuiar Devices, CA):;, BCECF
,, fluorescence is monitored using exatation and emission wavelengths of 485 nM
and 525 nM, respectively. Intracellular aadihcatfon is initiated via rapid replacement of acid loading media with recovery media (120 mM NaCI, 5 mM KCI,1 mM MgCl2, 1.8 mM CaCl2, 5 mM glucose,10 mM HEPES, pH 7.5) ~ test combination, and NHE-mediated recovery of intracellular pH is monitored as the subsequent time-dependent increase BCECF fluorescence. The potency of the combinations of the compounds of formula I of this invention with NHE-1 inhibitors is calculated as the concentration that reduces recovery of intracellular pH by 50% (ICS). Under these conditions reference NHE inhibitors amiforide and HOE-642 had IC~ values for human NHE-1 of 50 ~AII
and 0.5 pM, respectively.
As background infom~ation, it is noted that brief periods of myocardial ischemia fo(iowed by coronary artery reperfusion protects the heart from subsequent severe myocardial ischemia (Muny et al., Circulation 74:1124-1136,1986).
The therapeutic effects of the combination of the compounds of formula 1 of this invention with NHE-1 inhibitors in preventing heart tissue damage resulting from an ischemic insult can be demonstrated in vitro along lines presented in Liu et al.
(Cardiovasc. Res., 28:1057-7061, 1994), as described specifically herein.
Cardioprotection, as indicated by a reduction in infarcted myocardium, can be induced pharrnacologicaNy using adenosine receptor agonists in isolated, retrogradely perfused rabbit hearts as an in vitro model of ~rdial ischemic preconditioning (Uu et al., Cardiovasc. Res., 28:1057-1061,1994). The in vitro test described below demonstrates thata test compound or, in this case a test combination (i.e., a combination of a compound of formula I with an NHE-1 antagonist) can also pham~acoiogically induce carciioprotection, i.e., reduced myocardial ir>tarct size, when administered to a rabbit isolated heart. The effects of the test combination are compared to ischemic preconditioning-and the A1/A3 adenosine agonise, APNEA
(N°-[2-(4-aminophenyl)ethytJadenosine), that has been shown to pharmaootogicatfy WO 00/59510 pCTIIB00I00296 induce cardioprotection in the rabbit isolated heart (Liu~et aL, Cardiovasc.
Res., 28:1057-1061, 1994). The exact methodology is described below.
The protocol used for these experiments closely follows that described by Liu et al., Cardiovasc. Res., 28:1057-1061,1994. Male New Zealand White rabbits (3-kg) are anesthetized with sodium pentobai~bitel (30 mglkg, i.v.). After deep anesthesia is achieved (determined by the absence of an ocular blink reflex) the animal is intubated and ventilated with 100°~ OZ using a positive pressure ventilator. A left thoracotomy is performed, the heart exposed, and a snare (2-0 silk) is placed loosely around a prominent branch of the left coronary artery, approximately 213 of the distance towards the apex of the heart The heart is removed from the diest and rapidly (<30 sec) mounted on a Langendorff apparatus. The heart is retrogradety perfused in a non-rearculating manner with a modified Krebs solution (NaCI
118.5 mM, KCI 4.7 mM, Mg SO, 1.2 mM, KHzPO, t.2 mM, NaHC03 24.8 mM, CaCh 2.5 mM, and glucose 10 mM), at a constant pressure of 80 mmHg and a temperature of 37°C. Perfusate pH is maintained at 7.4-7.5 by bubbling with 95% 015%
CO~. Heart temperature is tightly controlled by using heated reservoirs for the physiological solution and water jacketing around both the perfusion tubing and the isolated heart.
Heart rate and left ventricular pressures an: determined via a latex balloon which is inserted in the left ventride and connected by stainless steel tubing to a pressure transducer. The intraventricular balloon is inflated to provide a systolic pressure of 80-100 mmHg, and a diastolic pressure _< 10 mmHg. Total coronary flow is also continuously monitored using an in-line flow probe and normalized for heart weight The heart is allowed to equilibrate for 30 minutes, over which time the heart must show stable left ventricular pnasures within the parameters outlined above. If the heart rate falls below 180 bpm at any time prior to the 30 minutes period of regional ischemia, the heart is paced at about 200 bpm for the remainder of the experiment. tschemic preconditioning is induced by total cessation of cardiac perfusion (global ischemia) for 5 minutes, followed by reperfusi~ for 10 minutes. The regional ischemia is provided by tightening the snare around the coronary artery branch. Following the 30 minutes regional ischemia, the snare is released and the heart reperfused for an additional 120 minutes.
Pharmacological cardioprotection is induced by infusing the test combination, i.e., a corrrbinafron of a compound of formula I with an NHE-1 inhibitor, at WO 00/59510 PCTIIB00~00296 predetermined concentrations, starting 30 minutes poor to the 30 minutes regional ischemia, and continuing until the end of the 120 minutes reperfuston period.
Hearts which receive the test combination do not undergo the period of ischemic preconditioning. The reference compound, APNF~ (500 nM) is perfused through hearts (which do not receive the test compound) for a 5 minutes period which ends 10 minutes before the 30 minutes regional ischemia. , At the end of the 120 minutes reperfusion period, the coronary artery snare is tightened, and a 0.5% suspension of fluorescent zinc cadmium sulfate par6Ges (1-10 NM) Duke Scientific Corp.(Palo Atto, CA) is perfused through the hearty this stains alt of the myocardium, except that area-at-risk for infarct development (area-at-risk). The heart is removed from the Langendorff apparatus, blotted dry, wrapped in aluminum foil and stored overnight at -20°C. The next day, the heart is sliced into ,~ mm transverse sections from the apex to the top of the ventrides_ The slices are stained v~i~th 1 % triphenyt tetrazotium chloride (TTC) in phosphate-buffered saline for 20 minutes at 37°C. Since TTC reacts with living flssue (containing NAD-dependent dehydrogenases), this stain differentiates between fnring (red stained) tissue, and dead tissue (unstained infarcted tissue). The infarcted area (no stain) and the area-at-risk (no fluorescent partides) are catculated for each slice of left ventride using a precalibrated image analyzer. To normalize the ischemic injury for differences in the area-at-risk between hearts, the data is expressed as the ratio of infarct area vs. area-at-risk (%IAlAAR). All data are expressed as mean t SE and compared statistiraliy using a Mann-Whitney non-parametric test with a Bonfemoni cornection for multiple comparisons. Significance is considered as p < 0.05.
The results from the above in vitro test demonstrate that a combination of a compound of this invention with an NHE-1 inhibitor induce signficartt cardioprotection relative to the control group.
The therapeutic effects of a combination of a compound of formula t of this invention with an NHE-1 inhibitor in preventing heart tissue damage otherwise resulting from an ischemic insult can also be demonstrated in vivo along Unes presented in tau et at. (Circulation, Voi. &4:350-356,1991 ) as described speaficalty herein. The in vivo assay tests the cardioprotedion of the test combination, i.e., a compound of formula ! together with an NHE-1 inhibitor, relative to the control group which receives saline vehide. Cardioprotection, as indicated by a reducfion in pGTIIB00/00296 infarcted myocardium, can be induced pharmacologically using intravenously administered adenosine receptor agonists in intact; anesthetized rabbits studied as an in situ model of myocardial ischemic preconditioning (Liu et af., Circulation 84:350-356, 1991 ). The in vivo assay tests whether the instant combination of a compound of formula I with an NHE-1 inhibitor can phaiinaGOlogicaliy induce cardioprotection, i.e., reduced myocardial infarct size, when parenterally administered to intact, anesthetized rabbits. The effects of the combination of a compound of formula I of this invention with an NHE-11 inhibitor can be compared to ischemic preconditioning using the A1 adenosine agonist, N6-1-(phenyl-2R-isopropyl) adenosine (PIA) that has been shown to phamiacologicaAy induce cardioprotection in intact anesthetized rabbits studied in situ (Liu et al., Circulation 84:350-356, 1991 ). The methodology is described below.
Surcrerv: New Zealand White male rabbits (3-4 kg) are anesthetized with sodium .
pentobarbital (30 mg/kg, i.v.). A tracheotomy is performed via a ventral midline cervical incision and the rabbits are ventilated with 100% oxygen using a positive p pressure ventilator. Catheters are placed in the left jugular vein for dntg administration and in the left carotid artery for blood pressure measurements.
The hearts are then exposed through a left thoracotomy and a snare (00 silk) placed around a prorinent branch of the left coronary artery. lschemia is induced by pulling the snare tight and damping it in place. Releasing the snare allows the affected area to repertuse. Myocardial ischemia is evidenced by regional cyanosis;
reperfusion is evidenced by readive hyperemia.
Protocol: Once arterial pressure and heart rate have been stable for at least minutes the test is started. Ischemic preconditioning is induced by occluding the coronary artery for 5 rtvnutes followed by a 10 minutes reperfusion.
Pharmacological preconditioning is induced by infusing the test combination, i.e., a combination of a compound of formula I of this invention with an NHE-1 inhibitor, over, for example, 5 minutes and allowing 10 minutes before further intervention or by infusing the adenosine agonist, PiA (0.25 mg/kg). Following ischemic preconditioning, pham~acologicat preconditioning or no conditioning (unconditioned, vehicle control) the artery is occluded for 30 minutes and then reperfused for two hours to induce myocardial infarction. The test combination and PIA are dissolved in saline or other suitable vehicle and delivered at 1 to 5 mglkg, respectively.
wo oo~s9sio rcrnsooiooz~
Stainin (Liu et al., Circulation 84:350-356, 7 991 ): At the end of the 2 hour ~ , , reperfusion period, the hearts are quiddy removed, hung on a Langendorff apparatus, , and flushed for 1 minute with normal saline heated to body temperature (38°C). The silk suture used as the snare is then tied tighny to reocdude the artery and a 0.5%
suspension of fluorescent zinc cadmium sulphate particles (1-10 um) Duke Sdentific Corp. (Palo Alto, CA) is infused with the perfusate to stain all of the myocardium except the area at risk (nonfiuorescent ventricle). The hearts are then quiddy frozen and stored overnight at -20°c. On the following day, the hearts are cut into 2 mm slices and stained with 7 % triphenyl tetrazolium chloride (1'TC). Since TTY
reacts with living tissue, this stain differentiates between living (red stained) tissue, and dead tissue (unstained infarcted tissue). The infarded area (no stain) and the area at risk (no fluorescent particles) are calculated for each slice of left ventricle using a pre-calibrated image analyzer. To normalize the ischemic injury for differences in the area at risk between hearts, the data is expressed as the ratio of infarct area vs.
area at risk (%IA/AAR). All data are expressed as MeantSEM and compared statistically using single factor ANOVA or Mann Whitney non parametric test. Signficance is considered as p<0.05.
The combination of a compound of formula I of this invention with an NHE-1 inhibitor can be tested for their utility in redudng or preventing ischemic injury in non-cardiac tissues, for example, the brain, or the liver, utilizing procedures reported in the scientific literature. The combination of a compound of formula I of this invention with an NHE-1 inhibitor in such tests can be administered by the preferred route and vehicle of administration and at the preferred bme of administration either prior to the ischemic episode, during the ischemic episode, following the isdiemic episode (reperfusion period) or during any of the below-mentioned experimental stages.
The benefit of the combination of NHE-1 inhibitors and compounds of fortnuta 1 of this invention to reduce ischemic brain damage can be demonstrated, for example, in mammals using the method of Park, et al (Ann. Neurol.1988;24:543-551 ).
According to the procedure of Park, et al., adult male Sprague Dawley rats are anesthetized initially with 2% halothane, and thereafter by mechanical venWabon with a nitrous oxide-oxygen mixture (70%:30%) containing 0.5-1% halothane. A
tracheostotny is then perfom~ed. The stroke volume of the ventilator is adjusted to maintain arterial carbon dioxide tension at approximately 35 mm Hg and adequate arterial oxygenation (PaOz>90 mm Hg). Body temperature can, be monitofed by a rectal thermometer, and the animals can be maintained normothermic, if necessary, by external heating. The animals next undergo subtemporal cxanieto expose the main trunk of the left middle cerebral artery (MCA) under an operating microscope, and the exposed artery is occluded with microbipolar coagulation to generate large ischemic lesions in the cerebral cortex and basal ganglia.
After three hours of MCA occlusion, the rats are deeply anesthetized with 2% halothane and a thoracotomy is pertormed to infuse heparinized saline into the left ventricle.
The effluent is collected via an indsion of the right atrium. The saline washout is followed by approximately 200 m! of a 40% formaldehyde, glaclal acetic add and absolute methanol solution (FAM;1:1:8, v/vlv), then the animals are decapitated and the head is stored in fixative for 24 hours. The brain is then removed, dissected, embedded in paraffin wax, and sectioned (approximately 100 sections 0.2mm per brain). The sections are then stained with hematoxylin~osin or with a combination of cresyl violet and Luxol fast blue, and examined by light microscopy to identify and quantitate the ischemic damage using a precalibrated image analyzer. The isdzemic volumes and areas are expressed in absolute units (mm' and mmz) and as a peroentage of the total region examined. The effect of the compositions and methods of this invention to reduce ischemic brain damage induced by MCA occlusion is noted based on a reduction in the area or volume of relative or absolute ischemic damage in the brain sections from the rats in the treatment group compared to brain sections from rats in a ptaoebo-treated control group.
Other methods which could alternatively be utilized to demonstrate the benefit of the invention to reduce ischemic brain damage include those described by Nakayama, et al, in Neurology 1988, 38:1667-1673;_ Memezawa, et al. in Stroke 1992, 23:552-559; Folbergrova, et al. in Pros. Natl. Acad. Sd 1995, 925057-5059; and Goth, et al. in Brain Res.1990, 522:290-307.
The benefit of the compositions and methods of this invention to reduce ischemic liver damage can be demonstrated, for example, in mammals using the method of Yokoyama, et al. (Am. J. Physiol.1990~58:G564-G570). According tp the procedure of Yokoyama, et al., fasted adult male Sprague Dawley rats are anesthetized with sodium pentobarbital (40 mglkg i.p.), then the animals are trad~eotomized and mechanically ventilated with room air. The fryer is extirpated and placed in an environmental chamber maintained at constant temperature (37 ~°C), then perfused through the portal vein at a constant pressure pf 15 cm H=0 with a mod~ed, hemoglobin-free Krebs-Henseleit buffer (n mM:118 NaCI, 4.7 KCI, 27 NaHCO', 2.5 CaClz, 1.2 MgSO" 12 KH=PO,, 0.05 EDTA, and 11, mM,glucose, plus 300 U
heparin).
The pH of the perfusate is maintained at 7.4 by gassing the buffer with 95% 02 - 5%
COZ. Each liver is perfused at a flow rate of 20 mUminutes in a single-pass, manner for a 30 minutes washout and equilibration period (preischemic period), followed by a 2 hour period of global ischemia, and then a 2 hour period of reperfusion under conditions identical to the preisdtemic period. Aliquots (20 ml) of the perfusate are collected during the preischemic period, immediately after the occlusive isd~emic period, and every 30 minutes of the 2 hour reperfusion period. The perfusate samples are assayed for the appearance of hepatocellular enzymes, for example, aspartate amino-transferase (AS't~, alanine amino-transferase (ALTS, and lactate dehydrogenase (LDH), which are taken to quantitatively reflect the degree of ischemic liver tissue damage during the procedure. AST, ALT, and LDH activities in the perfusate can be determined by several methods, for example, by the reflectometry method using an automatic Kodak Ektachem 500 analyzer reported by Nakano, et al.
(Hepatology 1995;22:539-545). The effect of the compositions and methods of this invention in reducing ischemic liver damage induced by occlusion is noted based on a reduction in the release of hepatooelluiar enzymes immediately following the ocdus'rve period andlor during the postischemio-reperfusion period in the perfused livers from the rats in the treatment group compared to perfused fivers from rats in a placebo-treated control group.
Other methods and parameters which could alternatively be utifrzed to demonstrate the benefit of the compositions and methods of this invention in redudng isd~emic liver damage include those described by Nakano, et at. (Hepatology 1995;22:539-545).
Any glycogen phosphorylase inhibitor may be used as the second compound of this invention, The term glycogen phosphorylase inhibitor refers to any substance or agent or any combination of substances andlor agents which reduces, retards, or eliminates the enzymatic action of glycogen phosphorytase. The currently known enzymatic action of glycogen phosphorylase is the degradation of glycogen by catalysis of the reversible reaction of a glycogen macrortrolearle and incxganic phosphate to glucose-i-phosphate and a glycogen macromolecule which is one glucosyl residue shorter than the original glycogen macromolecule (forward direction of gfycogenolysis). Such actions are readily determined by those. skilled in the art according to standard assays (e.g., as described hereinafter). A variety of these compounds are inducted in the following published PCT patent applications: PCT
application publication WO 96139384 and W096I39385. However, other glycogen phosphoryiase inhibitors will be known to those skilled in the art Compounds of formula l, prodrugs thereof, mutual prodrugs of the compounds of formula I with aldose reductase inhibitors, pharmaceutically acceptable salts of any of the above and pharmaceutical compositions comprising a compound of formula 1, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug and either (a) an aldose reductase inhibitor, a prodrug thereof or a pham~aceutically acceptable salt of said aldose reductase inhibitor or said prodrug, (b) a NHE-1 inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said NHE-1 inhibitor or said prodrug, or a glycogen phosphorytase inhibitor, a prodrug thereof or a pham~aoeutically acceptable salt of said glycogen phosphorylase inh~itor or said prodnrg are hereinafter referred to, collectively, as "the active compounds and oomopositions of this invention."
The active compounds and compositions of this invention may be administered to a subject in need of treatment by a variety of conventional routes of administration; inducting orally, parenterally and topically. In general, compounds of the formula I and their pharmaceutically acceptable salts will be administered orally or parenterally at dosages between about 0.001 and about 100 mglkg body weight of the subject to be treated per day, preferably from about 0.01 to 10 mglkg, in single or divided doses. Mutual prodrugs of compounds of the formula Land aldose reductase intu'bitors will generally be administered orally or parenterally at dosages between about O.OOi and about 100 mglkg body weight of the subject to be treated per day, preferably from about 0.01 to about 10 mglkg, in single or divided doses.
Compositions containing both a compound of the fom~ula I and an aldose reductase inhibitor will generally be administered orally or parenterally at dosages between about 0.001 and about 100 mg of each active component (i.e., the cor~ound of fomwia I and the aldose reductase inhibitor) per kg body weight of the subject to be treated per day, preferably from about 0.01 to about 10 mglkg. Compositions containing both a compound of formula I and a NHE-1 inhibitor will generally be administered orally or parenterally at dosages between about 0:001 and 100 mg of said compound of formula I per kg body weight of the subject to be treated per day and about 0.001 to 100 mglkg/day of the NHE-1 inhibitor. An especially preferred dosage contains between about 0.01 anti 10 mglkglday of said compound of formula I
and between about 0.01 and 50 mglkglday of said NHE-1 inhibitor. Compositions containing both a compound of fortiiula I and a gicogen phosphorylase inhibitor will generally be administered orally or parenterally at dosages between about 0.001 and 100 mg of said compound of formula I per kg body weight of the subject to be treated per day and 0:005 to 50 mg/kglday of said glycogen phosphorytase inhibitor, preferably 0.01 and 10 mglkglday of said compound of formula and 0.01 to 25 mglkg/day of said glycogen phosphorylase inhibitor and most preferably 0:01 and 10 mglkg/day of said compound of formula and 0.1 to 15 mglkglday of said glycogen phosphorylase inhibitor. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
The active compounds and compositions of this invention may be administered alone or in combination with pharme~utically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical carriers indude inert solid diluents or fillers, sterile aqueous solutions and various organic solvents_ The pharmaceutical compositions formed by combining the active compounds of formula I
of this invention and the phamnaceutically acceptable carriers are then readily administered in a variety of dosage fom~s such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pham~aceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, exapients and the like.
Thus, for purposes of oral administration, tablets containing various exapients such as sodium citrate, cafaum carbonate and calaum phosphate may be employed along with various disintegrants such as starch, alginic aad and certain complex silicates, together with binding agents such as potyvinylpyrrolidone, sucrose, gelatin and acaaa. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as 511ers in soft and hard filled gelatin capsules.
WO 00159510 pCTIIB00100296 Prefer-ed materials for this indude lactose or milk sugar and high molearlar weight polyethylene gtycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring ri~atter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
For parenteral administration; solutions of the active compounds and compositions of this invention in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be t 0 suitably buffered if necessary and the liquid diiuent first~rendenrd isotonic with sufficient saline or glucose. These partiarlar aqueous solutions are espeaally suitable for intravenous, intramuscxriar, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media employed arse all readily available by standard techniques known to those skilled in the art Administration of the compounds of formula 1 of this inventi~ can be via any method which delivers a compound of this invention preferentially to the desired tissue (e.g., nerve, kidney, retina andlor cardiac tissues). These methods indude oral routes, parenteral, intraduodenal routes; etc. Generally, the compounds of the present invention are administered in single (e.g., once daily) or multiple doses or via ant infusion.
The compositions of this invention comprising a compound of fomu~la I in combination with an NHE-1 inhibitor are useful, for example, in reduang or minimizing damage effected directly to any tissue that may be susceptible to ischemialreperfusion injury (e.g., heart, brain, lung, kidney, Liver, gut, skeletal muscle, retina) as the result of an ischemic event (e.g., myocardial infarction). The composition is therefore usefully employed prophytadically to prevent, i.e.
(P~Pe~IY ~ ProPhY~~~IIY) m blunt or stem, tissue darrrage (eg., rtyoc~rdial tissue) in patients who are~at risk for ischemia (e.g., myocardial ischert~ia).
Generally, a compound of formula I of this invention is adrronistened orally, or parenterany (e.g., intravenous, intramuscutar, subcutaneous or intramedullary).
Topical administration may also be indicated, for example, where the patient is suffering from gastrointestinal disorders or whenever the medication is.best applied to the surface of a tissue or organ as determined by the attending physician.
pCTIIB00/00296 The amount and timing of compounds administered wilt, of course,'be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgement of the prescribing physidan. Thus, because of patient to patient variability, the dosages given below are a guideline and the physician may titrate doses of the drug to achieve the treatment that the physidan considers appropriate for the patient In considering the degree of treatment desired, the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases.
Thus, for example, in one mode of administration the compounds of formula I
of this invention may be administered just prior to surgery (e.g., within twenty-four hours before surgery for example cardiac surgery) during or subsequent to surgery (e.g., within twenty-four hours after surgery) where there is risk of myocardial ischemia. The compounds of formula I of this invention may also'be administered in a chronic daily mode.
The compounds of the present invention are generally administered in the form of a pham~aceutical composition comprising at least one of the compounds of formula I of this invention together with a pham~aceutically acceptable vehide or diluent. Thus, the compounds of formula I of this invention can be administered individually or together in any conventional oral, parenteral, rectal flr transdem~al dosage forma For purposes of transdem~al (e.g.,topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1 % to 5%
concentration), otherwise similar to the above parenteral solutions, are prepared.
Methods of preparing various phamiaceubcal compositions with a certain amount of active ingredient are known, or will be apparent in light of this disdosure, to those skilled in this art For examples of methods of preparing pharmaceutical compositions, see Reminaton's Pharmaceutical Sciences, Madc Publishing Company, Easton, Pa:, '19th Edition (1995).
Pham~aoeutical compositions according to the invention may contain for example 0.0001%-95% of the compounds) of this invention. In any event, the composition or-formulation to be administered wiA contain a quantity of a compounds) according to the invention in an amount effective to treat the diseaselcondition of the subject being treated.
WO 00!59510 PGT/IB00/00296 The two different compounds of this combination of this invention can be co-administered simultaneously or sequentially in any order, or as a single pharmaceutical composition comprising a compound of Formuta I and an aldose reductase inhibitor as described above or a giyoQgen phosphorylase inhibitor as described above or a cardiovascular agent ~"
Since the present invention has an aspect that relates to the treatment of the diseaselconditions described herein with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharrnaceuticai compositions in kit form. The kit comprises two separate pham~aceutical compositions: a compound of formula I a prodnrg thereof or a satt of such compound or prodnrg and a second compound as described above The k'rt comprises means for containing the separate compositions such as a container, a divided bottle 'or a divided foil packet. TypicaNy the kit comprises dir~ec~tions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage fom~.s (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescxibing physican.
An example of such a kit is a so-called blister pads. Blister packs are well known in the packaging industry and are being widely used for the packaging of phamiaoeutical unit dosage fortes (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. the recesses have the size ancJ shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet Preferably the strength of the sheet is such that the tablets or capsules can be removed from tide blister pads by manually applying pressure on the recesses whereby an opening is fom~ed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specfied should be ingested.
Another example of such a memory aid is a calendar printed on the card, e.g., as follows ~Fin;t Wesk, Monday, Tuesday, ...etc.... Second Week, Monday, Tuesday,.. "
etc. Other variations of memory aids will be readily apparent. A "daily dose"~
can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of Formula I compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.
tn another speafic embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use~is provided.
Preferably, the dispenser is equipped with a memory-aid, so as to further facititate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed.
Another example of such a memory-aid is a battery-powered miao-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the fast daily dose has been taken andlor reminds one when the next dose is to be taken.
The compounds of formula I of this invention generally will be administered in a convenient formulation. The following formulation examples are illustrative only and are not intended to limit the scope of the present invention.
In the formulations which follow, "active ingredient" means a compounds) of this invention.
Formulation 1: Gelatin Capsules Hard gelatin capsules are prepared using the following:
Ingredient Quantity (mglcapsule) Alive ingredient 0.25-100 Starch. NF p.65p Starch fiowable powder 0.50 Silicone fluid 350 centistokes o-5 A tablet formulation is prepared using the ingredients below:
' WO 00/59510 pCT/IB00/00296 Formutation 2: Tablets . , Ingredient ' Quantity (mg/tablet) ' Active ingredient 0.25-100 Cellulose, microcrystalline , . , ' ' - 200-650 Silicon dioxide, fumed 10-650 Stearate acid 5-15 The components are blended and compressed to form tablets.
Alternatively, tablets each containing 0.25-100 mg of active ingredients are made up as follows:
Formulation 3: Tablets Ingredient Quantity (mg/tablet) Active ingredient 0.25-100 Starch 45 Cellulose, micxocrystalline 35 Polyvinylpyrrolidone (as 10% solution in water) 4 Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc 1 The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
The granules so produced are dried at 50° - 60°C and passed through a No. 18 mesh U.S:
sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
Suspensions each containing 0.25-100 mg of active ingredient per 5 ml dose are made as follows:
Formulation 4: Suspensions Ingredient Quantity (mgl5 ml) Active ingredient 0.25-100 mg Sodium carboxymethyl cellulose . 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 mL
Flavor q.v.
Color q.v.
Purified Water to 5 mL , The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Suffiaent water is then added to produce the required volume.
An aerosol solution is prepared containing the following ingredients:
Formulation 5: Aerosol Ingredient Quantity (% by weight) Active ingredient X0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane) 74.00 The active ingredient is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to 30°C, and transfer-ed to a filling device. The required amount is then fed to a stainless steel container and diluted with the remaining propellant. The valve units are then fitted to the container.
Suppositories are prepared as follows:
Formulation 6: Suppositories Ingredient Quantity (mglsuppository) Active ingredient 25p Saturated fatty aad glycerides 2,000 The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty aad glycerides previously melted using the minimal _1~
necessary heat. The mixture is then poured into a suppo$i~ry mold of nominal 2.g capacity and allowed to cool.
An intravenous fomwlation is prepared as follows:
Formulation 7: Intravenous Solution Ingredient . Quantity. .
Alive ingredient. 25 mg-10,000 mg Isotonic saline 1,000 mL
The solution of the above ingredients is intravenouslyr administered to a patient.
The active ingredient above may also be a combination of agents.
GENERAL EXPERIMENTAL PROCEDURES
Melting points were determined on a Thomas-Hoover Capillary Melting Point tus*, and are uncorrected. 'H NMR spectra were obtained, on a Bndcer AM-250*
(Broker Co., Billeriaa, Massachusetts), a Broker AM.300; a Varian XL 300 (Vari~tl Co., Palo Alto, Cafifomia), or a Varian Unily 400 at about 23 °C at 250, 300, or 400-MHz for proton. Chemical shifts are reported it parts per million (5) relative to residual chlorofornn (726 ppm), dimethylsulfoxide (249 ppm), or methanol (3.30 ppm) as an internal refen:noe. The peak shapes and descriptors for the peak shapes are der>abed as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, mufflplet; c, oompie~ br, broad;
app, apparent Law-resolution mass spectra were obtained under thertnospray (TS) conditions;on a Fsons-(now Micromass) Trio 1000 Mass Spec~romete~ (Miaornass -Inc., Beverly, Massachusetts); under chemical-ionization (CI) conditions on a Hewlett Padcard 5989A Particle Beam Mass Spectrometer (Hewlett Padcard Co., Palo Al~o, . California), or under atmospheric pressure chemical ion~tion (APCI) on a F~sons .
(now Miaomass) Platform II Spectrometeei optical rotations were obtained on a-Perkin-Elmer 241 MC Polarimete~ (Perkin-Elmer, Norvvalk, Connec~iart),using a standard path length of 1 clan at about 23 °C at the indicated concentration in the ~iaated soiveM.
Liquid column chromatography was performed using foroed flow (flash cluo<natography) of the indicated solvent on either Baker SH~a lief (40 Nm, J:
-T.
Baker, Phillipsburg, New Jersey) or Silica Gel 60~(EM Sclenoes, Gi>abstawa, New Jersey) in glass columns or using low nitrogen or air pressure in Flash 40~ or Flash *Trade-stark 12"" (Biotage; Charlottesville, Virginia) cartridges. Radial chromatography was perfomled using a Chromatrori (Harrison Research, Paio Alto. California). The temvs "concentrated" and "evaporated" refer to removal of solvent using a rotary evaporator ' at water aspirator pressure or at similar pressures generated by a Bi~chi B-Vacobox (Brinkmann Instrumertts, Inc., Westbury, New York) or a Bilchi B~177 -Vacobox with a bath temperature equal to or less than 50 °C. Reactions requiring the use of hydrogen gas at pressures greater than 1 atmosphere were run using a Parr hydrogen apparatus (Parr Instrument Co., Moline, Illinois). Unless otherwise specified, reagents were obtained from commercial sources. The abbreviations "d", "h", and "min" stand for "day(s)", "hour(s)", and "minute(s)", respectively.
~ 1 LRl-1-f4-f4-Quinoxalin-2 vl-~iperazin-1-vll-ovrimidin-2-vil-ethanol.
Me~~~~
Step A: L,RI-1-t4-l4-Quinoxalin-2-vl-oiperazin-1 vll-nyrimidin-2ar11-ethyl acetate. To a solution of (R}-1-(4-chioro-pyrimidin-2-yl}-ethyl acetate (prepared axording to the method of Preparation Five, 7.3 g, 362 mmol) in isopropanol (240 mL) was added triethylamine (10.1 mL, 72.4 mmol) followed by 2-(1-piper~azinyl~uinoxaline (10.1 g, 47.1 mmol; J. Med Chem.~ 1981, 24, 93). This mixture was stirred at room temperature overnight then concentrated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (5x): The combined organic extracts rare dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2% methanoUchloroform) to give 12.4 g t9i %) of the tills oompamd of Example 1, Step A as a yellow foam. 'H NMR (CDC~,, 250 MHz) b 8.61 (s,1 H), 8.27 (d,1 H), 7.91 (dd,1 H), 7.72 (dd, 1 H). 7.61 (td,1 H), 7.44 ~(td,1 H), 6.43 (d,1 H), 5.70 (q,1 H), 3.96-3.84 (c, 8H), 2.18 (s, 3H),1.G1 (d, 3H); MS
(CIINH~
379 (MH').
Step B: fR)-i-f4-(4-Quinoxafin-2-vl-nioerazin-1 vl)wrimidin-~ vll-ethanol. To a solution of(Rr1-[4-(4-quinoxalin-2-yl-piperatin-1-yl~pyrimidin-2-ylj-ethyl aoebte (prepared according to the method of Example 1, Step A, 14.1 g, 372 mirrol) in a *Trade-mark 3:1:1 mixture of tetrahydrofuranlwater/methanol (375 mL) was added lithiuri~
hydroxide hydrate (4.7 g, 112 mmol). This mixture wa$,stirred at room temperature for 1 h 45 min, concentrated, and extracted with chloroform (6x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2x; 2% methanoUchloroform) to give 11.3 g (90%) of the title compound as a pale yellow solid after tritration with hexanes. mp:
106.5-108 °C;'H NMR (CDCI,, 250 MHz) b 8.62 (s, 1H), 8.26 (d, 1 H), 7.92 (dd, 1 H), 7.72 (dd, 1 H), 7.61 (td, 1 H), 7.44 (td, 1 H), 6.45 (d, 1 H), 4.75 (m, 1 H), 3.95-3.85 (c, 8H), 1.54 (d, 3H); MS (CI/NH3) 337 (MH'); [a]o +15:3 (c 2.3, MeOH).
Example 2 (Rl-1-f4-t4-Oxazolof5.4-clpvridin-2-yl-oiperazin-1-yl~-ovrimidin-2-vll-ethanol.
N
Me~
Step A: (R~1-f4-(4-Oxazolof5.4-clpvridin-2-vl-oioerazin-1-vl~ovrimidin-2-vfl-ethyl but)rrate. To a sotu6on of 2-(1-piperazinyl~xazoto[5,4-c]pyridine (775 mg, 3.8 mmol;
J. Org. Chem. 1995, 60, 5721 ) in isopropanol (38 mL) was added (Ry-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 868 mg, 3.8 mmol) followed by triethylamine (1.6 mL, 11.4 mmol). This mixture was sfin-ed at reflux overnight, cooled to room temperature, and evaporated.
The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3x). , The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2x; 3%
methanoUchloroform then 6~8% methanoUethyl acetate, where used herein, the arrow symbol, ~, indicates a gradient) to give 1.2 g (T9%) of the title compound of Example 2, Step A as a pale yellow oil which solidfied upon standing. 'H NMR
(CDCI,, 250 MHz) b 8.57 (s,1 H), 8.39 (d, 1 H), 8.28 (d,1 H), 7.30 (d, 1 H);
6.44 (d, 1 H), 5.70 (q, 1 H), 3.85 (s, SH), 2.42 (t, 2H), 1.78 -1.61 (c, 2H), 1.60 (d, 3H), 0.98 (t, 3H);
MS (APCI) 397 (MH').
Step B: IRS-1-f4-(4-Oxazolof5 4-cjovridin-2-vl-Diperazin-1 yll-ovrimidin 2 vfl~thanol.
To a solution of (Rj'1-[4-(4-oxazolo[5,4-c]pyridin-2-yl-piperazin-1-yl}-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Example 2, Step A, 1.2'g, 3.0 mmol) in methanol (30 mL) was added potassium carbonate (823 rng, 6.0 mmol).
This mixture was stirred at room temperature for 5 h, diluted with saturated aqueous ammonium chloride, concentrated, and extracted with chloroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (6% methanoUchloroform) to give 915 mg,,(94%,) of the title compound as a white solid after tritra6on with hexanes. mp: 181-183 °C; 'H NMR
(CDC13, 300 MHz) b 8.54 (d, 1 H), 8.35 (d, 1 H), 8.25 (d, 1 H), 7.27 (dd, 1 H), 6.44 (d, 1 H), 4.71 (q, 1 H), 4.25 (br s, 1 H), 3.86-3.83 (c, 8H), 1.50 (d, 3H); MS
(APCI) 327 (MH'); (a]D +15.3 (c 0.5, MeOH).
Example 3 1 R-l4-f 1'-f2-f 1 R-Hydroxy-ethyll-avrimidin~-vl1-f4 4'lbipiaeridin~rl-1-vl~-ovrimidir~ 2 v11-ethanol.
N~N N~N
\ N~ ~ ~N
Me~~~~ Me OH OH
A mixture of (R)-1-(4-chloro-pyrimidin-2-ylrethanoi (prepared according to the method of Preparation Ten, 100 mg, 0.63 mmol), 4,4'-bipiperidine dihydrochloride (76 mg, 0.32 mmol), and triethylamine (0.44 mL, 32 mmol) in isopropanol (3 mL) was refluxed overnight and cooled to room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (4x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (Biotage Flash 40S"', 5%
methanoUchlorofortn) to give 110 mg (85%) of the title compound as a white solid.
mp: 144-153 °C,'H NMR (CDCI,, 400 MHz) S 8.14 (d, 2H), 6.36 (d, 2H), 4.67 (q, 2H), 4.53.4.28 (c: 4H), 2.84 (t, 4H), 1.82 (d, 4H), 1.49 (d, 6H), 1.43-1.40 (c, 2H),1.30-1.18 (c, 4H); MS (APCI) 413 (MH'); [a]p +22,6 (c 1.0, MeOH).
Examples 4 to 8 Examples 4 to 8 were prepared from the appropriate starting materials in a manner analogous to the method of Example 3.
Example 4 1 R-l4-f4-f2-( 1 R-Hvdroxv-ethvll-ovrimidin-4-v(1-2R.5S-dimethvl-oiperazin-1-vi~-wrimidin-2-v1)-ethanol.
Me. , N~N N~N
\ N ~---/ ~N
Me~~~~ Me Me OH OH
mp: 153-155 °C,'H NMR (CDCI,, 400 MHz) 8 8.23 (d, 2H), 6.40 (d, 2H), 4.71 (m, 2H), 4.28 (dd, 2H), 3.51-3.45 (c, 4H),1.51 (d, 6H), 1.23 (d, 6H); MS (APCI) 359 (MH'); [ac)p +18.6 (c 1.2, CHCI3).
OH HO
Me .... Me -N N-N ~ / N-linker- N ~ / N
Example N-tinker-N mp (°C) MS (MHO
5 N,N'~thylenediamine 141-143 333 6 [1,4)diazepane 136-138 345 7 4,4'-ethylenebipiperidine 8 methyl-piperidin~-ylmethyl-amine 373 Example 9 IRl-1-f4-(4-Oxazolof5.4-blpyridin-2-yl-~iperazin-1-vll-wrimidin-2-ytl-ethanol.
N
N~n~~ I
\ N ~ O N
Me"..
OH
Step A: 2-l1-Pioerazinvl)oxazolof5 4-bloyridine. A mixture of 2-(thiomethyl~xazolo[5,4-b)pyridine (92 g, 55.5 mmol; J. Org. Chem. 1995, 60, 5721 ) pGTIIB00/00296 and piperazine (23.9 g, 277 mmol), with a small amount of ethyl acetate wHich was ; , used for washing the compound down the sides of the flask, was heated at 90 °C for , , 1.5 h. The reaction mixture was cooled to room temperature, diluted with -20%
saturated aqueous sodium bicarbonate solution, and eXtracted with chiorofortn (4x).
The combined organic extracts were washed with saturated aqueous sodium bicarbonate {1 x), dried over sodium,sutfate, filtered, evaporated, and purified by flash column chromatography (3-~5% methanoUchloroform + 1% ammonium hydroxide) to give 9.1 g (81 °1°) of the title compound of Example 9, Step A
as an off white solid. 'H
NMR (CDCI,, 300 MHz) S 7.92 (dd, 1 H), 7.55 (dd, 1 H), 7.10 (dd, 1 H), 3.74-3.70 (c, 4H), 3.02-2.97 (c, 4H); MS (APCI) 205 (MH').
Step B: (R~1-f4-l4-OxazoloT5.4-blavridin-2-vl-oioerazin-1-vl)-ovrimidin-2-vll-ethyl bu te. To a solution of (R~1-(4-chloro-pyrimidin-2-yl~ethyl butyrate (pfepar~ed according to the method of Preparation Seven, 6.8 g, 29.9 mmol) and triethylamine (12.5 mL, 89.6 mmol) in isopropanol (100 mL) was added 2-(1-piperazinyl)oxazolo[5,4-b]pyridine (prepared according to the method of Example 9, Step A, 6.1 g, 29.9 mmol). This mixture was stirred at reflux overnight, cooled to room temperature, and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform {3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5->2% methanoUchloroform) to give 11.1 g (94%) of the title compound of Example 9, Step B as a yellow oil which solidfied upon standing. 'H
NMR~(CDCI,, 250 MHz) b 8.28 (d, 1 H), 7.97 (dd, 1 H), 7.60 (dd, 1 H), 7.25 (dd, 1 H), 6.44 (d, 1 H), 5.70 (q,1 H), 3.85 (app s, 8H), 2.42 (t; 2H), 1.78 -1.61 (c, 2H),1.60 (d, 3H), 0.98 (t, 3H); MS (APCI) 397 (MH').
Step C: (R)-1-I4-f4-Oxazolof5.4-blpvridin-2-vl-pioerazin-1-vl~ovcimidin-2-vll-ethanol.
To a solution of (Ry-1-[4-(4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2 ylj-ethyl butyrate (prepared according to the method of Example 9, Step B, 11.0 g, 27.6 mmol) in dioxane (11.5 mL) was added concentrated hydrochloric aad (23 mL, 276 mmol). This mixture was stirred at room temperature overnight, neutralized with 6 N
aqueous sodium_hydroxide, and extracted with chloroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purfied by flash column chromatography (3.5% methanoUchloroform) to give 8.4 g (93%) of the title compound as a white solid. mp: 153-156 °C; 'H NMR (CDCIj, 300 MHz) S 825 (d, 1 H), 7.95 (dd, 1 H), 7.58 (dd, 1 H), 7.15 (dd, 1 H), 6.45 (d, 1 H), 4.72 (q, 1 H), 4.25 (br s, 1H), 3.85-3.82 (c; 8H), 7.51 (d, 3H); MS (CIINH,) 327 (MH'); [~ajp +16.1 (c t.0, MeOH) Examoies 10 tol5 Examples 10 to 15 were prepared from the appropriate starting materials in a manner analogous to the method of Example 9.
R~
_ _ ~ N~ , ~N
Example X-Ar' R' nip (C) MS (MH') 10 oxazolo[4,5-c]pytidin-2-yl(R~CH(CH,)OH 178-180 327 11 oxazofo[5,4-c]pyridin-2-yl-C(CH,)ZOH 181-184 341 12 oxazolo[5,4-c]pyridin-2yl(t)-CH(CH3~H 153-758 327-13 oxazolo[5,4-cjpyridin-2-yl{S)-CH(CH,)OH 175-179 327 14 quinoxalin-2-yl (t)-CH(CH,~H 102-105 337 (5-iodorbenzoxazol-2-yl(R)-CH(CH,)OH 452 Example 16 1 R-f4-(3S-Methvl~-oxazolof5.4-blnvridin-2-vi-oinerazin-1 vl1-ovrimidin-2-vll-ethanol.
/~'~ N
N //- ~ --~~
\ N ~ O N
Me~~~~ Me OH
15 Step A: (Sl-2-f4-Benzv!-2-methyl-~ioerazin-1 vll~xazofo~5 4-blQVridine. A
modure of 2-(thiomethyl)oxazolo[5,4-b]pyridine (44 g, 264 mmol; J. Olg. Chem.1995, 60.
5721 ) and (Sy-1-benzyl-3-methyl-piperazine (25 8,132 mmol; J. Org. Chem.1995, 60, 4177) was sflmed at 130 °C for 3 d, cooled to room temperature, and purfied by flash column chromatography (1783% ethyl acetatelhexanes) to give 30 g (74%) of the tatte compound of Example 16, Step A as a dark yellow oil. 'H NMR (COCK, 400 MHz) 8 7.89 (d, 1 H), 7.53 (d, 1 H), 7.34-7.25 (c, 5H), 7.10 (dd, 1 H), 4.45 (m, 1 H), 4.11 (d, WO 00!59510 pCT/IB00/00296 1 H), 3.59 (d, 1 H), 3.52-3.45 (c, 2H), 2.90 (d, 1 H), 2.73 (d, 1 H), 2.32 (dd, 1 H), 2.21 (td, .,, 1 H), 1.41 (d, 3H); MS (APCI) 309 (MH').
Step B: fS)-2-f2-Methyl-oioerazin-1-vl)-oxazolo15.4-blp ny_dine. To a solution of (S)-2-(4-benzyl-2-methyl-piperazin-1-yl}-oxazolo[5,4-b]pyridine (prepared according to the method of Example 16, Step A, 30 g, 97 mmol) in methanol (970 mL) was added hydrogen chloride (5.85 M in methanol, 20 mL, 116 mmol), ammonium folmate (122 g, 1.95 mol), and 10 % palladium on carbon (60 g, 200 wt%). This mixture was stirred at reflux for 50 min, cooled, and filtered through Celite. The filtrate was concentrated, diluted with saturated aqueous sodium bicarbonate, and extracted with chlproform (1x) followed by 10% isopropanoUchloroform (4x). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give 16 g (76%) of the title compound of Example 16, Step B as a green oil. 'H NMR (CDCl,, 400 (MHz) 8 7.89 (m, 1 H), 7.53 (m, 1 H), 7.09 (m, 1 H), 4.42 (m, 1 H), 4.11 (d, 1 H), 3.35 (td, 1 H), 3.09=
3.03 (c, 2H), 2.85 (d, 1 H), 2.82 (td,1 H), 1.38 (d, 3H); MS (APCI) 219 (MH').
Step C: 1 R~4-l3S-Methvl-4-oxazolof5.4-blpvridin-2-vl-oioerazin-1-yl3-ovrimidin-2-v(1-ethvlbutvrate. A mixture of (S}-2-(2-methyl-piperazin-1-yl}-oxazolo[5,4-b]pyridine (prepared according to the method of Example 16, Step B, 10 g, 45.9 mmol), (R~1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 9.5 g, 41.7 mmol), and triethylamine (17.3 mL, 125 mmol) in isopropanol (230 mL) was heated at reflux for 30 h, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, and extracted with chloroform (4x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5% methanoUchlorofortn) to give 16 g (93%) of the title compound of Example 16, Step C as a yellow oil. 'H NMR (CDCI,, 400 MHz) S
8.23 (d, 1 H), 7.93 (dd, 1 H), 7.57 (d, 1 H), 7.13 (dd, 1 H), 6.39 (d, 1 H), 5.67 (q, 1 H), 4.61 (m, 1 H), 4.42 (m, 1 H), 4.28 (m, 1 H), 4.18 (dt, 1 H), 3.51 (td, 1 H), 3.41 (dd, 1 H), 3.17 (td, 1 H), 2.39 (t, 2H), 1.72-1.59 (c, 2H), 1.57 (d, 3H), 1.30 (d, 3H), 0.95 (t, 3H); MS
(APCI) 411 (MH').
Step D: 1 R~4-(3S-Methvl-4-oxazolof5.4-blavridin-2-vl-oioerazin-1 vl~nvrimidin-2 ~~
ethanol. A mixture of 1 R-[4-(3S-methyl-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-ylr pyrimidin-2-y(]-ethyl butyrate (prepared according to the method of Example 16, Step C,16 g, 39.0 mmol) and potassium carbonate (10.8 g, 78.1 mmol) in methanol (195 mL) was stirred at room temperature for 4 h, diluted with saturated aqueous sodium pCTnB00/00296 bicarbonate, and extracted with chforofonn (1x) followed by 10%
isopropanol/chloroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purfied by flash column chromatography (1->2.5%
methanoUchioroform) to give a white foam that was reaystallized from ether/chloroform to give 8.9 g (67%) of the tide compound as a white solid.
mp:147-149 °C; 'H NMR (CDCI,, 400 MHz) S 824 (d,1 H), 7.94 (dd,1 H), 7.58 (d,1 H); 7.14 (dd, 1 H), 6.42 (d, 1 H), 4.72 (m, 1 H), 4.64 (m, 1 H), 4.42 (m, 1 H), 4.32 (m, 1 H), 4.25 (d, 1 H), 4.21 (dt, 1 H), 3.54 (td,1 H), 3.46 (dd, 1 H), 3.24 (td,1 H), i .51 (d, 3H),1.33 (d, 3H); MS (APCI) 411 (MH'); [a]o +70.4 (c 1.1, MeOH).
Examples 17 to 25 Examples 17 to 25 were prepared from the appropriate starting materials in a manner analogous to the method of Example 16.
Examcle 17 i R-f4-(3S-Methvl-4-auinoxalin-2-vl-nioerazin-1 vl~-nvrimidin-2-vlt-ethanol.
Me~
'H NMR (CDC13, 400 MHz) b 8.56 (d, 1 H), 8.23 (d, 1 H), 7.89 (d, 1 H), 7.69 (d,1 H), 7.59 (t, 1 H), 7.41 (t, 1 H), 6.42 (d, 1 H), 4.78 (m, 1 H), 4.73 (m, 1 H), 4.43 (m,1 H), 4.38-4.23 (c, 2H), 3.64-3.52 (c, 2H), 3.38 (m, 1H),1.52 (d, 3H), 1.30 (d, 3H); MS (APCI) (MH'); [a]o +57.0 (c 1.2, CHCI3).
Example 18 1R-(4-f 4.6-Dimethvl-ovrimidin-2-vl~3S-methyl-vioerazin-1-vll-rnrrimidin-2-vt~-ethanol.
Me N-N~N N
N ~--~ \N
Me~~~~ Me Me OH
pCTIIB00100296 'H NMR (CDCI,, 400 MHz) b 8.18 (d, 1 H), 6.37 (d, 1 Hj, 6.30 (s, 1 H), 5.04 (m, 1 H), ~ ' 4.70 (q, 1 H), 4.60 (dt, 1 H), 4.37 (br s, 1 H), 4.36.12 (c, 2H), 3.40 (dd, 1 H), 3.34 (td, 1 H), 3.16 (td, 1 H), 2.28 (s, 6H), 1.51 (d, 3H), 1.16 (d, 3H); MS (APCI) 329 (MH'); (a]o +78.8 (c 1.6, MeOH).
Example 19 1 R-t4-f4-(2-Hvdroxymethvl-6-methyl-oyrimidin-d-vl~-3S-methyl-piperazin-'1-vf1-p~rrimidin-2 yf~-ethanol.
Me Me~~~~ , 'H NMR (CDCI,, 400 MHz) b 8.23 (d, 1 H), 6.38 (d, 1 H), 6.23 (s, 1 H), 4.71 (q, 1 H), 4.58 (s, 3H), 4.36-4.18 (c, 4H), 3.86 (br s, 1 H), 3.57 (dd, 1 H), 3.46 (td, 1 H);
3.32 (td, 1 H), 2.38 (s, 3H), 1.51 (d, 3H), 1.22 (d, 3H); MS (APCI) 345 (MH'); (a]~ +72.6 (c 1.1, MeOH).
Examaie 20 1 R-f4-(3S-Methyl-4-oxazolof4.5-blflvridin-2-yl-pit~erazin-1-~rl~pvrimidin-2-yf1-ethanol.
N N
N~N N---C
N ~ O /
Me~w Me OH
mp: 158-161 °C; 'H NMR (CDCI,, 400 MHz) b 8.22-8.15 (c, 2H), 7.40 (dd,1 H), 6.86 (dd, 1 H), 6.40 (d, 1 Hj, 4.65 (m, 1 H), 4.61 (m, 1 H), 4.44-4.20 (c, 3H), 4.18 (dt, 1 H), 3.50 (td, 1 H), 3.41 (dd, 1 H), 3.19 (td, 1 H), 1.45 (d, 3H), 1.26 (d, 3H); MS
(APCt) 341 (MH'); [aJo +582 (c 1.1, MeOH).
Example 21 1 R-f4-(3S-Methyl-4-oxazolo!'4 5-clpvridin-2 girl-c~ioerazin-1 yl)-nyimidin-2-v(a~thanol.
N ~N
N~/ --N N-~r~
N O I
Me ~". , , Me , OH
rcrnsooroo~
'H NMR (CDCI,, 400 MHz) b 8.68 (d,1 H), 8.32 (d,1 H), 8.24 (d, 1 H), 7.25 (dd,1 H), 6.42 (d, 1 H), 4.71 (m,1 H), 4.60 (m,1 H), 4.42 (m,1 H), 4.32-4.23 (c, 2H), 4.17 (dt,1 H), 3.56 (td, 1 H), 3.47 (dd, 1 H), 3.24 (td, 1,H),1.51 (d, 3H), 1.32 (d, 3H); MS
(APCI) 341 (MH'); [a]o +57.9 (c 1.6, MeOH).
Example 22 1 R-t4-(3S-Methyl~-oxazolof5.4-ciamidin-2-vl-oioerazin-1 vll-ovrimidin-2=vIl-ethanol.
N
N .rl ~ -~r I
N ~ O. /
Me~~~~ Me OH
'H NMR (CDC13, 40D MHz) b 8.56 (s,1 H), 8.37 (d, 1 H), 8.25 (d, 1 H), 7.29 (d, 1 H), 6.43 (d,1 H), 4.72 (m, 1 H), 4.65 (m,1 H), 4.45 (m,1 H); 4.29 (m,1 H), 4.26-420 (c, 2H), 3.58 (td, 1 H), 3.48 (dd, 1 H), 3.26 (td, 1 H), 1.51 (d, 3H), 1.34 (d, 3H); MS
(APCI) 341 (MH');
[a)p +61.1 (c 1.0, MeOH).
HO
Me ~~~~Me N-Ar'-X-N N~ . N
Example X~4~' C' Jo (°C) MS (MH"y 23 quinoxaiin-2-yl R 351 24 _ - (2-[C(CH~)zOH]}- py~imidin~-yi S 359 benzoxazol-2-yi S 340 -i 57-(=xam~le 26 1 R-l4-f4-f2-(1 R-Hvdroxv-ethyl)-pvrimidin-4-vIl-2R.6S-dimethvl-piperazin-1-vlf-pyrimidin-2-vl~ethanol.
Me~
OH OH
Method 1: To a~solution of 1R-[4-(2R,6S-dimethyl-piperazin-1-y!)-pyrimidin-2-yQ-ethyl butyrate (prepared according to the method of Preparation Four, 72.8 g, 238 mmol) and triethylamine (50 mL, 357 mmol) in isopropanol (793 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl~thyl butyrate (prepared according to the method of Preparation Seven, 54.3 g, 238 mmol). This mixture was stirred at reflux for 12 h and concentrated. The residue was dissolved in a 3:1:1 mixture of tetrahydrofuraNmethanoUwater (1200 mL) and lithium hydroxide hydrate (60 g, 1.43 mot) was added. This mixture was stirred at room temperature for 2.5 h, concentrated somewhat, diluted with saturated aqueous sodium bicarbonate, and extracted with 10% isopropanoUchloroform (6x). The combined organic extracts were dried over sodium sulfate; filtered, and evaporated. The residue was diluted with 1:1 ethyl acetatelmethanol (1100 mL) and stirred at room temperature for 1 h. The precipitate was collected by filtration and the filtrate was concentrated to about 850 mL.
After 1 h, more preapitate had formed and this material was collected by filtration. The filtrate was concentrated somewhat and ethyl acetate was added. After 1 h more precipitate had again formed and this material was collected by filtration. This was repeated one more time to give in total 65.9 g (77%) of the title compound as a white solid. mp:
163-164.5 °C; 'H NMR (CDCI,, 400 MHz) S 824 (d, 1 H), 823 (d, 1 H);
6.46 (d, 1 H), 6.36 (d, 1 H), 4.74-4.70 (c, 2H), 4.704.50 (c, 2H), 4.50-4.30 (c, 2H), 4.30 (d, 1 H), 427 (d, 1 H), 3.31 (dt, 2H), 1.51 (d, 6H), 1.26 (d, 6H); MS (APCI) 359 (MH'); [a]o +42.3 (c 1.0, MeOH).
Method 2, Step A: 1 R-(4-f4-f2-(1 R-Buivrvloxv~thvl~pvrimidin-4-vtl-2R 6S-dimethvl-piperazin-1-vl~-ovrimidin-2-vll-ethyl butyrate. To a solution of (R~2-(1-btrtyryloxy-ethylr3H-pyrimidin-4-one (828 g, 3.9 rr~ol) in dichloromethane (50 L) was added triethylamine (576 mL, 4.1 mol) and the resulting solution was copied to 5 °C. A
solution of trifluoromethanesulfonic anhydride (729 mL, 4.3 mol) in dichloromethane (6 L) was added slowly such that the internal temperature was maintained at <10 °C.
After the addition was complete, the reaction was judged complete by TLC and quenched by the addition of water (5.3 L). The organic layer was separated, washed with water (20 L) and saturated aqueous sodium bicarbonate (20 L), and'dried over sodium sulfate. This solution was then slowly added to a solution of 1 R-[4-(2R,fiS-dimethyl-piperazin-1-yl)-pyrimidin-2-ylj-ethyl butyrate dibenzoyl-L-tartrate salt (prepared according to the method of Preparation Fifteen, 2.49 kg, 3.75 mdl) and triethylamine (1.6 L, 11.6 mol) in dimethylacetamide (18 L) such that the internal temperature was maintained at <10 °C. The resulting solution was allowed to stir for 12 h at 10 °C and then diluted with ethyl acetate (40 L) and water (27 L).' The aqueous layer was removed and the organic layer was washed twice with water (40 L) and once with brine (20 L), and dried over sodium sulfate. The resulting solution was partially concentrated (8 L) and then hexanes (23 L) was added. The resulting suspension was allowed to granulate for 12 h and then filtered over cotton.
The solids were dried under vacuum (40 °C) to provide 1178 gm (63%) of the title compound of Example 26, Method 2, Step A as a white solid. The'H NMR and MS data for this compound are in agreement with that of Example 266.
Method 2, Step B: 1 R~4-t4-f2-l1 R-Hvdroxy-ethyl~pyrimidin~-v(1-2R.6S-dimethvl-piperazin-1-vll-pvrimidin-2-v()-ethanol. To a solution of 1 R-(4-(4-[2-(1 R-butyryloxy-ethylrpyrimidin-4-ylj-2R,6S-dimethyl-piperazin-1-yI)-pyrimidin-2-yl~ethyl butyrate (prepared according to the method of Example 26, Method 2, Step A, 1140 g, 2.28 mol) in isopropanol (11.4 L) was added 40% aqueous potassium hydroxide (800 mL) at room temperature. The resulting solution was allowed to stir for 16 h and then diluted with water (5 L) and dichloromethane (4 L). The organic layer was separated and the aqueous layer was extracted with dichloromethane (4 L). The combined organic layers were washed twice with 1 M aqueous sodium hydroxide (10 L) and twice with water {5 L), partially concentrated {5 L), diluted with ethyl acetate (4 L), and again partially concentrated (6 L). Hexanes (10 L) was added and the resulting slurry was allowed to stir at reflux for 12 h, cooled to room temperature, and filtered. The resulting solid was dried under vacuum to provide 758 g (93%) of the title compound pC'f/IB00/00296 as a white solid. The mp, 'H NMR, MS, and optical rotation data for this compound are in agreement with that of Example 26. Method 1.
Examples 27 to 62 Examples 27 to 62 were prepared from the appropriate, starting materials in a manner analogous to the method of Example 26.
Example 27 1 R-f4-f4-(4.6-Dimethyl-avrimidin-2-yll-2R.6S-dimethvl-oioerazin-1-yIl-pvrimidin-2 yll-ethanol.
Me Me N- ., N~N --~~
\ N N
Me~~w Me Me OH
mp: 150.5-152 °C;'H NMR (CD,OD, 300 MHz) S 8.14 (d, 1H), 6.62 (d, 1H), 6.46 (d, 1 H), 6.40 (s, 1 H), 4.83 (d, 2 H), 4.72-4.52 (c, 3H), 3.30 (dd, 2H), 2.28 (s, 6H), 1.46 (d, 3H), 1.23 (d, 6H); MS (APCi} 343 (MH'); [a]p +12.0 (c 1.3, MeOH).
Example 28 1 R-f4-12R.6S-Dimethv!-4-oxazolof5.4-clayridin-2-yl-pioerazin-1-vl)-ovrimidin-2-vl~
ethanol.
Me N
N~N N--<~
N ~ O ~N
Me~~~~ Me OH
'H NMR (CD,OD, 300 MHz) S 8.53 (d, 1 H), 8.28 (d, 1 H), 8.20 (d, 1 H), 7.34 (dd,1 H), fi.68 (d, 1 H), 4.90-4.72 (c, 2H), 4.69 (q, 1 H), 4.32 (d, 2H), 3.56 (dd, 2H), 1.47 (d, 3H), 1.33 (d, 6H); MS (APCf) 343 (MH'); [aj~ +8.1 (c 1.3, MeOH).
Example 29 i R-f4-f4-(4-Hvdroxymethyl-6-methyl-ovrimidin-2-yl~-2R.6S-dimethyl-oinerazin-1-vft-gyrimidin-2=vtl-ethanol.
pCT/IB00/00296 Me Me , N~N N~~
N~ ~ , . ~N
Me".. Me' OH OH
mp: 139-141 °C;'H NMR (CD,OD, 300 MHz) b 8.24 (d, 1H), 6.51 (d, 1H), 6.38 (s 1 H), 4.90 (m, 1 H), 4.84 (d, 2H), 4.77-4.53 (c, 2H), 4.55 (s, 2H), 3.24 (dd, 2H), 2.37 (s, 3H), 1.61 (d, 3H), 1.32 (d, 6H); MS (APCt) 359 (MH'); [a]p +14.8 (c 1.0, MeOH).
Example 30 1 R-(4-14-(2.6-Dimethyl-ovrimidin-4-yl1-2R.6S-dimethyl-oiperazin-1-yl1-oyrimidin-2-vll-ethanol.
Me~
'H NMR (CDCI,, 300 MHz) b 8.22 (d, 1 H), 6.36 {d,1 H), 626 (s, 1 H), 4.71 (m, 1 H), 4.65-4.50 (c, 2H), 4.42-4.28 (c, 3H), 3.24 (dd, 2H), 2.49 (s, 3H), 2.35 (s, 3H), 1.52 (d, 3H), 1.26 (d, 6H); MS (APCI) 343 (MH'); [a]o +11.4 (c 0.8, MeOH).
Example 31 1 R-f4-(2R.6S-Dimethvl~-oxazolof4.5-blovridin-2-vl-oinerazin-1 vl~-pvdmidin-2-vIl-ethanol.
Me N
N~N N
~ N ~ O /
Me~~~~ Me ~ OH
mp: 231-233 °C;_'H NMR (CDCI3, 400 MHz) 8 8.26-8.23 (c, 2H), 7.47 (d, 1 H), 6.94 (dd, 1 H), 6.39 (d, 1 H), 4.75-4.53 (c, 2H), 4.72 (q, 1 H), 4.35 {d, 1 H), 4.28 (m, 1 H), 3.44 (dd, 2H), 1.51 (d, 3H), 1.34 (d, 6H); MS (APCI) 355 (MH'); [a]p +8.0 (c 0.8, MeOH).
Exam~ie 32 , 1 R-(4-f4-(2-Hvd~oxvmethvl-6-methyl-ovrimidin-4-yl~2R.6S-dimethyi-ainerazin-1-vil-p~rrimidin-2-vii-ethanol.
-N ~ ~~N N~~ / N , N/ ~ ~N
Me""' Me OH OH
'H NMR (CD30D, 300 MHz) b 8.16 (d, 1 H), 6.66 (s, 1 H), 6:63 (d, 1 H), 4.85-4.63 (c, 2H), 4.67 (q, 1 H), 4.58 (d, 2H), 4.50 (s, 2H), 3.26 (dd, 2H), 2.35 (s, 3H), 1.46 (d, 3H), 1.24 (d, 6H); MS (APCI) 359 (MH'); [a]D +11.8 (c 0.9. MeOH).
Example 33 1 R-f4-(2R.6S-Dimethvl-4-oxazolof5.4-blpyridin-2-vl-pi~erazin-1-vl)-pvrimidin-2-vtl-ethanol.
Me~
OH
Me N
N~N N--<~
\ N ~ O N
Me mp: 204-207 °C; 'H NMR (CDCI,, 400 MHz) b 8.25 (d, 1 H), 7.95 (dd, 1 H), 7.59 (dd, 1 H), 7.15 (dd, 1 H), 6.39 (d, 1 H), 4.80-4.57 (c, 2H), 4.73 (q, 1 H), 4.30 (d, 2H), 3.42 (dd, 2H), 1.51 (d, 3H), 1.35 (d, 6H); MS (APCI) 355 (MH'); [a]o +7.5 (c 0.7, MeOH).
Example 34 2-(4-~4-f2-(1 R-Hvdroxv-ethvll-ovrimidin-4-vf1-3R.5S-dimethvl-piperazin-1-vfl-cvrimidin-2-vi~roaan-2-ol.
~N
~N /
Me Me~~
OH OH Me pC"f/IB00/00296 mp: 138-140 °C;'H NMR (CDCI,, 400 MHz) S 8.23 (d, 2H). 6.45 (d; 1H), 6.36 (d,1H), "
4.86 (s, 1 H), 4.70 (m, 1 H), 4.67-4.33 (c, 4H), 4.30 (d, 1 H), 3.31 (dd, 2H), 1.53 (s, 6H), 1.51 (d, 3H), 1.25 (d, 6H); MS (APCI) 373 (MH'); [a]~ +15.5 (c 1.2, MeOH).
Example 35 , 1 R-I4-f4-f4-Hvdroxvmethvl-6-methyl-oyrimidin-2-yl~2S-methv!-ni~erazin-1-v(1-pvrimidin-2-vll-ethanol.
Me .~ N-N~N N~~
\ N ~ ~N
Me~~~~ Me OH OH
' H NMR (CDCI,, 400 MHz) b 8.18 (d,1 H), 6.36. (d,1 H), 6.32 (s,1 H), 4.69 (q,1 H), .
4.60-4.53 (c, 3H), 4.52 (s, 2H), 4.38-4.18 (c, 2H), 3.63 (m,1 H), 3.40-3.29 (c, 2H), 324 (m, 1H), 2.32 (s, 3H), 1.49 (d, 3H), 1.20 (d, 3H); MS (APCI) 345 (MH'); [a]o +66.5 (c 1.0, MeOH).
Example 36 1 R-f4-f4-f4-Hvdroxvmethyl-6-methv!-ovrimidin-2-yl)-2R-methyl-nit~erazin-1 y~-pvrimidin-2-vl~-ethanol.
Me~~~
'H NMR (CDCI,, 400 MHz) b 8.21 (d, 1 H), 6.37 (d, 1 H), 6.33 (s, 1 H), 4.72 (m,1 H), 4.fi7-4.54 (c, 3H), 4.54 (s, 2H), 4.34 (d, 1 H), 4.20 (d, 1 H), 3.58 (b~ s,1 H), 3.42-3.32 (c, 2H), 3.26 (td, 1 H), 2.34 (s, 3H), 1.51 (d, 3H),121 (d, 3H); MS (APCI) 345 (MH'); [a]o -35.0 (c 1.1, MeOH).
pGT/IB00ro0296 Example 37 , , 1 R-~4-f4-l2-Hydrox~methvfrpvrimidin-4-vl~3S-methyl-oiaerazin-1 v(1-avrimidin-2-vl~-ethanol.
N -I ~ .\.~ N
N ~ N , Me",. Me OH OH
mp: 178-181 °C;'H NMR (CDCI$, 400 MHz) & 8.23 (d, 2H), 6.38 (d, 2H), 4.60 (q,1H), 4.60 (s, 2H), 4.56 (m, 1 H), 4.28-4.15 (c, 4H), 3.72 (br s, 1 H), 3.58 (dd, 1 H),~ 3.48 (m, 1 H), 3.33 (td,1 H), 1.51 (d, 3H),1.23 (d, 3H); MS. (APCI) 331 (MH'); [a]Q
+88.9 (c 1.1, MeOH). ,, Example 38 1 R-l4-~4-f2-l1 R-Hvdroxv-ethvll-ovrimidin-4 v1l-2S-methyl-oioerazin-1-yl)..pyrimidin-2-I thanol.
N I ~ ~N
I
N ~ N
Me~,~. Me~ ~ Me OH OH
mp:158-160 °C; 'H NMR (CDC1,, 400 MHz) 8 8.24 (d, 2H), 6.39 (d,1 H), 6.38 (d, 1 H), 4.71 (m, 2H), 4.55 (br s, 1 H), 4.32-4.16 (c, 5H), 3.60 (dd, 1 H), 3.48 (td, 1 H), 3.38 (td, 1 H), 1.52 (d, 6H), 1.24 (d, 3H); MS (APCi) 345 (MH'); [a]p +82.5 (c 1.0, MeOH).
Exam~ie 39 1 R-(4-~4-f2-(1 R-Hvdroxy~thyl~ovrimidin.-4-vt1-2R-methyl-niDerazin-1-vl~-ovrimidin-2-thanol.
Me~~.
WO 00159510 PCTIIB00l00296 -1~
mp: 155-157 °C;'H NMR (CDCI3, 400 MHz) 8 8.24 (d, 2H), 6.39 (d, 1H), 6.38 (d, 1H), 4.73 (m, 2H), 4.58 (br s, 1 H), 4.32-4.16 (c, 5H), 3.59 (dd, 1 H), 3.50 (m, 1 H), 3:38 (m, 1 H), 1.52 (d, 6H), 1.25 (d, 3H); MS (APCI) 345 (MH'); [a]~ -30.4 (c 0.9, MeOH).
Example 40 1 R-(4-t'3-f2-(1 R-Hydroxy~thyl)-oyrimidin-4-yll-3.9-diaza-bicyclof3.3.1)non-9-yt)-pyrimidin-2-vi)-ethanol.
N ~ N N~N
N N
Me Me~
OH OH
mp: 151-158 °C; 'H NMR (CDC13, 400 MHz) 8 8.24 (d, 2H), 6.42 (d, 1 H), 6.41 (d, 1 H), 4.72 (m, 2H), 4.48.18 (c, 2H), 4.29 (dd, 2H), 3.28 (d, 2H), 2.03 (m, 1 H),11.98-1.82. (c, 4 H), 1.58 (m, 1 H), 1.51 (d, 3H), 1.50 (d, 3H); MS (APCI) 371 (MH'); [a]o +27.6 (c 0.9, MeOH).
Examote 41 1 R-l4-f4-f2-l1 S-Hvdroxv-ethvl~pvrimidin-4-v(1-2R.6S~Jimethvt-pioerazin-1-yt~
pyrimidin-2-yl)-ethanol.
Me N~N N~N
N~ ~ \N
Me~~~~~ Me ~~~ Me OH OH
mp: 222-223.5 °C; 'H NMR (CDCI,, 400 MHz) 8 8.24 (d, 1 H), 8.23 (d, 1 H), 6.46 (d, 1 H), 6.36 (d, 1 H), 4.75-4.51 (c, 4H), 4.50-4.30 (c, 4H), 3.31 (dt, 2H), 1.51 (d, 6H), 1.26 (d, 6H); MS (APCI) 359 (MH'); [a]o -3.4 (c 0.5, CHCI3).
Example 42 "
1 S-(4-~4-f2-l1 R-Hvdroxv-ethvll-oyrimidin-d-vfl-2R fiS-dimethvl-piperazin-1-vll-hyrimidin-2-vll-ethanol.
N~ ~ ~N
N ~ ~N
Me Me Me OH OH
mp: 224-226 °C; 'H NMR (CDCI,, 400 MHz) b 8.24 (d, 1 H), 8.23 (d, 1 H), 6.46 (d, 1 H), 6.36 (d, 1 H), 4.76-4.51 (c, 4H), 4.50-4.23 (c, 4H), 3.33 (dt, 2H), 1.51 (d, 6H), 1.25 (d, 6H); MS (APCI) 359 (MH'); [aJo +64.2 (c 0.5, CHCl,).
Example 43 1 S-(4-(4-f2-(1 S-Hydroxy-ethyl)-oyrimidin-4-vfl-2R 6S~imethyl-piaerazin-1 vl~-pvrimidin-2-vl)-ethanol.
Me N /rN N~N
\ N/ ~ ~ ~N
Me Me w~~ Me OH OH
mp: 164-165.5 °C; 'H NMR (CDC13, 400 MHz) b 8.24 (d, 1 H), 8.23 (d, 1 H), 6.46 (d, 1 H), 6.36 (d, 1 H), 4.75-4.51 (c, 4H), 4.50-4.23 (c, 4H), 3.47-3.28 (c, 2H), 1.51 (d, 6H), 1.25 (d, 6H); MS (APCI) 359 (MH'); [a]p -43.8 (c 1.0, MeOH).
Example 4.4 1RS-l4-t4-f2-IIRS-Hvdroxv-ethvl~cvrimidin-4-y(1-2R'6S'~imethv! nioerazin 1 vlf-nyrimidin-2-vll-ethanol.
Me N~N N-~(\ N
~ N~ Y \N
Me Me Me OH OH
mp: 180-186 °C;'H NMR (CDCI9, 400 MHz) s 8.24 (d, 1 H), 8.23 (d, 1 H}, 6.46 (d, 1 H), 6.36 (d, 1H), 4.75-4.51 (c, 4H), 4.50-423 (c, 4H), 3.47,-,3.28 (c, 2H), 1.51 (d, 6H), 1.25 (d, 6H); MS (APCI) 359 (MH').
Example 45..
1-(4-~4-f2-(1 R-Hvdroxv-ethyl~pvrimidin-4-y(1-2R.6S-dimethvl-piaerazin-1-vll-ovrimidin-211-ethanone.
Me N~N N~N
\ N~ ~ ~N
Me Me Me O OH
mp: 123-i27 °C;'H NMR (CDCI,, 400 MHz) 8.8.41 (d, 1H), 8.24 (d, 1H), 6.56 (d, 1H), 6.47 (d, 1 H), 4.75-4.53 (c, 3H), 4.52-4.28 (c, 2H), 4.26 (m, 1 H), 3.36-3.29 (c, 2H), 2.68 (s, 3H), 1.51 (d, 3H), 128 (d, 6H); MS (APCt) 357 (MH'); [ajo+19.4 (c 1.0, MeOH).
Example 46 1-l4-~4-f2-l1 R-Hvdroxv-ethyl)-ovrimidin-4-vfl-3R 5S-dimethvl-oioerazin-1-vl~-ayrimidin-2-vl~ethanone.
Me N~N N~N
\ N~ ~ ~N
Me~~~~ Me Me OH O
mp: 150-164 °C; 'H NMR (CDCI,, 400 MHz) 8 8.40 (d, 1 H), 8.24 (d,1 H), 6.66 (d, 1 H), 6.37 (d, 1H), 4.74-4.52 (c, 3H), 4.51-4.31 (c, 2H), 4.29 (m, 1H), 3.36 (dd, 2H), 2.69 (s, 3H), 1.51 (d, 3H), 1.27 (d, 6H); MS (APCI) 357 (MH'); [ajo+21.8 (c 1.1, MeOH).
pC'f/IB00/00296 Example 47 "
1 R-l4-~4-f2-f1 R-Hvdroxv-ethyl)-pvdmidin-4-vll-2R.6R~dimethvl-piaerazin-1-vll-pyrimidin-2-vi)-ethanol.
Me N ~ N N~N
\ N ~ N
Me~.,.. Me Me OH OH
mp: 168-171 °C; 'H NMR (CDCI,, 400 MHz) 8 8.27 (d, 1 H), 823 (d, 1 H), 6:33 (d, 1 H), 6.30 (d, 1 H), 4.78-4.69 (c, 2H), 4.68-4.28 (c, 5H), 3.83-3.69 (c, 2H), 3.54 (m, 1 H), 1.53 (d, 3H), 1.52 (d, 3H), 1.43-1.22 (c, 6H); MS (APCI) 359 (MH'); [acJD+92.2 (c 0.5, MeOH).
Example 48 1 R-(4-~4-f2-l1 R-Hvdroxv-ethyl)-oyrimidin-4-yll-2S.6S-dimethyl-pioeraZin-1-vf~-vvrimidin-2-vl)-ethanol.
Me N ~ N N '~N
N ~ N
Me~~w Me Me OH OH
mp: 168-178 °C;'H NMR (CDC1,, 400 MHz) 8 8.26 (d, 1H), 8.23 (d, 1H), 6.32 (d, 1H), 6.29 (d, 1 H), 4.78-4.68 {c, 2H), 4.65.27 (c, 5H), 3.82-3.71 (c, 2H), 3.55 (m, 1 H), 1.52 (d, 3H), 1.51 {d, 3H); 7 .43-1.20 {c, 6H); MS (APCI) 359 (MH'); [aJo- 32.4 (c 0.7, MeOH).
' WO 00!59510 PGTIIB00100Z96 ~~~~Me Ar'--X
Example X-Ar' R R' mp (C) MS (MH'~
49 benzoxazol-2-yl (R)-Me (S}-Me 354 50 ~ benzothiazol-2-yl(R}-Me (S}-Me ~ 370 51 oxazofa[4,5-c]pyridin-2-yl(R)-Me (SrMe 355 52 quinoxafin-2-yl (R?-Me H 351 53 quinoxaiin-2-yl (S~Me H ~ 351 54 quinoxalin-2-yl (RrMe (S~Me 365 55 (4.6-dimethyl)- H H 132-133 315 pyrimidin-2-yl 56 (4,6-dimethyl)- (S}-Me H 329 pyrimidin=2-yl 57 (2,6-dimethyl~ H H 125.5-127314 pyrimidin-4-yl 58 (2-hydroxymethyl~ (S~Me H 146-148 331 pyrimidin-4-yl 59 (2-hydroxymethyl}- (R~Me (S~Me 168-171 345 pyrimidin-4-yl 60 (2-hydroxymethyl~- (S)-Me H 345 methyl)-pyrimidin-4-yl HO
~~~~Me N_ Ar'-X-N~N ~ / N
~5 Example X A~' mp (°C) MS (MHO
61 ~ ~ (4-hydroxymethyl-6-methy)- 357 Ipyrimidin-2-yl 62 (R ~[2-(1-hydroxy-ethyl)]- 357 pyrimidin-4-yl Fxamole 63 1-f4-f4-!2-Acety-avrimidin-4-vl)-2R'.6S'-dimethyl-oiaerazin-1-vll-nvrimidin-2-vl1-ethanone. , , , .
Me N ~ N N~N
\ N ~ N
Me Me Me ' O O ,.
A mixture of 1 S-(4-{4-[2-(1 R-hydrooy-ethyl)-pyrimidin-4-yfJ-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol (prepared according to the method of Example 42, 1.05 g, 2.93 mmol) and manganese(t~ oxide (5.15 g; 59.3 mmol) in dichloroethane (28 mL) was heated at reflux for 7 h, and filtered through Celite (hot). The filtrate was concentrated and purified by flash column chromatography (Flash 40M~, 5%
methanoUchlorofonn) to give 0.67 g (64%) of the title compound as a white solid. mp:
>235 °C (dec); 'H NMR (CDCI,, 400 MHz) 8 8.42 (d, 1 H), 8.41 (d, 1 H), 6.68 (d, 1 H), 6.57 (d, 1 H), 4.81.36 (c, 4H), 3.39 (dd, 2H), 2.69, (s, 3H), 2.68 (s, 3H),1.29 (d, 6H);
MS (APC1) 355 (MH').
Examflle 64 1 R-(4-f4-(4-Hydroxymethyf-6-methyl=pyrimidin-2-y1)-3R.5S-dimethyl-pinerazin-1 y1 pyrimidin-2-vl~-ethanol.
Me N \ ,~N N-N/
Me~~~~ Me OH
Step A: 1 R-f4-!4-ltart-Butoxvcarbonvlamino-tert-butoxvcarbonvlimino-methyl)-dimethvl-oiperazin-1 v(1-o3nimidin-2-yl~-ethyl butyrrate. To a mixture of 1 R-[4-(3R,5S-dimethyl-pipera~in-1-yl~pyrimidin-2-yQ-ethyl butyrate (prepared according to the method of~Preparation Three, 10 g, 32.7 mmol), N,N'-bis(tert butoxyc~rbonyt~hiourea (8.6 g, 32.7 mmol; Synth: Commun. 1993, 23, 1443), and triethytamine (9.0 mL, 65.4 pCT/IB00100296 mmol) in dimethylfonnamide (1 i 0 mL) at 0 °C was added mercury(II) chloride (9.8 g, 36.0 mmol). This mixture was stirred overnight with wat~ming to room temperature, diluted with ethyl acetate, and washed with water (3x) and brine (1x). The organic phase was dried over sodium sulfate, filtered, and evaporated to give 17.9 g (100%) of the title compound of Example 64, Step A as a yellow foam. 'H NMR (CDCI3, MHz) S 9.61 (s,1 H), 8.19 (d,1 H), 6.37 (d,1 H), 5.66 (q,1 H), 4.51-4.14 (c,, 4H), 3.36-3.23 (c, 2H), 2.37 (t, 2H), 1.75-1.60 (c, 2H), 1.55 (d, 3H),1.49 (s, 9H), 1.46 (s, 9H), 1.28 (d, 3H), 1.26 (d, 3H), 0.94 (t, 3H); MS (APCI) 549 (MH').
Step B: 1 R-14-l4-Carbamimidovl-3R.5S-dimethvl-piaerazin-1-vl~-ovrimidin.2-vi1-ethyl butyrate trifluoroacetic acid salt. A mixture of fR-{4-(4-(tent-butoxycarbonylamino~ert-butoxycarbonylimino-methyl}-3R,5S-dimethyl-piperazin-1-yI]-pyrimidin-2-YI}-ethyl butyrate (prepared according to the method of Example 64, Step A,17.9~ g, 32.7 mmol) in a 3:1 rt>ixture of dichloromethaneltriflUoroacetic add (300 mL) was stirred at room temperature overnight and concentrated to provide ~36 g of the tifle compound of Example 64, Step B as an oil that was used as is. 'H NMR (CD,OD, 400 MHz) 8 8.24 (d, 1 H), 7.25 (d, 1 H), 5.69 (q, 1 H), 4.19-4.10 (c, 4H), 3.79-3.42 (c, 2H), 2.45 (t, 2H), 1.67-1.45 (c, 2H), 1.63 (d, 3H),1.32-1.25 (c, 6H), 0.95 (t, 3H); MS
(APCI) 349 (MH').
Step C: 1 R-f4-f4-f4-Methoxvmethvl-6-methyl-ovrimidin-2-vl1-3R 5S~imethvl-pioerazin-1-vl1-pvrimidin-2y11-ethanol. A solution of 1 M sodium isopropoxide in isopropanol was prepared by adding sodium metal (3.8 g, 160 mmol) to isopropanol (160 mL) and heating at reflux until all the metal was consumed. 1 R-[4-(4-Carbamimidoyl-3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yij-ethyl butyrate t~ifluoroa~tic add salt (prepared according to the method of Example 64, Step B, 32.7 mmol theory) was added to the refluxing sodium isopropoxidefisopropanof solution followed, after 1 h, by 1-methoxy-pentane-2,4-dione (212 8,163 mmol;
J.
Am. Chem. Soc 1944, 22, 2092). After 12 h, another aliquot of sodium fsopropoxide (1 M in isopropanol, 65 mL, 65 mmol) was added. After refluxing overnight, the reaction mixture was cooled to room temperature and diluted with water (100 mL).
lithium hydroxide hydrate (6.9 g, 163 mmol) was added and this mixture was stirred for 3 h, concentrated, and extracted with 10% isopropanoUchloroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purfied by flash column chromatography (1-X2.5% methanoUchlorofonn) to give 10.5 g (87%, 2 steps) of the title compound of Example 64: Step C as a yellow solid. 'H
NMR {CDCI,, 400 MHz) 8 8.18 (d, 1H), 6.54 (s, 1H), 6.43 (d, 1H), 5_00.94 (c, 2H), 4.69 (m, 1 H), 4.37-4.34 (c, 2H), 4.33 (s, 2H), 3.45 (s, 3H), 3.29-3.23 (c, 2H), 2.33 (s, 3H), 1.51 (d, 3H),1.20 (s, 6H); MS (APCI) 373 (MH').
Step D: 1 R-f4-t4-(4..Hvdroxvmethvl-6-methyl-bvrimidin-2y11-3R.SS-dimethvl-piperazin-1-vll-oyrimidin-2-vll-ethanol. To a solution of 1R-{4-[4-(4-methoxymethyi-6-methyl-pyrimidin-2-yl~3R,5S-dimethyl-piperazin-1 ylj-pyrimidin-2 yt)~thanol (prepared according to the method of Example 64, Step C, 8.0 g, 21.5 mmol) in dichloromethane (150 mL) at 0 °C was added boron tribromide (1 M in i 0 dichloromethane, 64.3 mL, 64.3 mmol). This mixture was stirred overnight with warming to room temperature and quenched by careful addition of saturated aqueous sodium bicart~onate. The layers were separated and the aqueous phase was extracted with 10% isopropanoUchloroform (3x). The combined organic extracts were washed with brine (ix), dried over sodium sulfate, filtered, and evaporated.
The resulting solid was refluxed in ethyl acetate and filtered (hot). This procedure was repeated and the combined filtrates were concentrated to a minimal volume.
After standing at room temperature overnight, a tan solid was collected by filtration. The resulting filtrate was again allowed to stand at room temperature overnight to yield an additional crop of the desired product to give all together 6.0 g (78%) of the frtie compound as a tan solid. mp: 149-151 °C;'H NMR (CDCI,, 400 MHz) b 8.19 (d, 1H), 6.45 (d, 1 H), 6.32 (s, 1 H), 5.02-4.96 (c, 2H), 4.71 (q, 1 H), 4.53 (s, 2H), 4.50r4.23 (c, 2H), 3.31-3.25 (c, 2H), 2.33 (s, 3H), 1.51 (d, 3H), 1.23 (s, 6H); MS (APCI) 359 (MH');
[ocj~+18.9 (c 1.1, MeOH).
Examples 65 to 74 Examples 65 to 74 were prepared from the appropriate starting materials in a manner analogous to the method of Example 64.
~~DD~Z96 , -172-Exarrroie 65 lR?-1-~4-f4-(4-Hvdroxvmethvl-6-methyl-pvrimidin-2-vl)-cioerazin-1-vI1-pvrimidin-2-vl~-ethanol.
Me N-N
Me~~~
OH
mp: 139-140 °C; 'H NMR (CDCi,, 300 MHz) 8 8:21 (d, 1 H), 6.41 (d, 7 H), 6.37 (s, 1 H), 4.71 (m, 1 H), 4.54 (s, 2H), 4.32 (d, 1 H), 4.02-3.93 (c, 4H), 3.7&3.68 (c, 4H), 3.65 (b~
s, t H), 2.34 (s, 3H), 1.19 (d, 3H); MS (TS) 331 (MH'); [aj~ +21.6 (c 2.0, M,eOH).
Example 66 1R-(4-f4-14.6-Dimethvl-pvrimidin-2-vil-3R.5S-dimethvl-ninerazin-1-vll-avtimidin-2 v!1 ethanol.
Me~~~
mp: 141.5-142.5 °C; 'H NMR (CDCI,, 400 MHz) b 8.17 (d, 1 H), 6.43 (d, 1 H), 6.28 (s, 1 H), 5.03.97 (c, 2H), 4.70 (q,1 H), 4,44.18 (c, 2H), 3.32-3.20 (c, 2H), 2.27 (s, 6H), 1.50 (d, 3H), 1.20 (d, 6H); MS (APCI) 343 (MH'); jaJ~ +19.2 (c 1.1, MeOH).
18 Example 67 1 R-14-t4-l4-Methoxvmethvl-6-methyl-amimidin-2-vl~3R.5S-dimethyl-nioerazin-1 vt1-ovn'~idin-2-v11-ethanol.
Me~~~
OH
'H NMR (CDCl3, 400 MHz) b 8.18.(d, 1H), 6.55 (s, 1H), 6:43 (d, 1,H), 5.02-4.9~
(c, 2H), 4.69 (m, 1 H), 4.43-4:20 (c, 2H), 4.36 (d,1 H), 4.33 (s, 2H). 3.46 (s, 3H), 3.30-3.21 (c, 2H), 2.34 (s, 3H), 1.51 (d; 3H), 1.20 (d, 6H); MS (APCI) 373 (MH'); (a]o +16.0 (c 0.9, MeOH). , ~~ , Example 68 1 R-~4-f4-l4-Hvdroxvmethvl-6-methyl-avrimidin-2-yl)-3R-meth~rl-oinerazin-1 vll-.
p~rrimidin-2-vl~-ethanol.
Me~~~
' H NMR (CDCl3, 400 MHz) S 8. ~ 7 (d,1 H), 6.36 (d, 1 H), 6.32 (s, 1 H), 4.98 (m, 1 H), 4.69 (q, 1 H), 4.58 (dt, 1 H), 4.51 (s, 2H), 4.37-4.11 (c, 3H), 3.62 (br s, 1 H), 3.48-3.36 (c, 2H), 3.18 (td, 1 H), 2.31 (s, 3H), 1.49 (d, 3H),1.17 (s, 3H); MS (APC!) 359 (MH');
[a]o -40.6 (c 1.0, MeOH).
Examole~9 1R-f4-f4-(4-Hvdroxvmethyl-6-meth~midin-2-v(1-3S-methyl-oioerazin-1 Dyrimidin-2,rll-ethanol.
Me""
'H NMR (CDC13, 400 MHz) 8 8.17 (d,1 H), 6.36 (d,1 H), 6.33 (s,1 H), 4.99 (m,1 H), 4.69 (q, 1 H), 4.58 (m,1 H), 4.52 (s, 2H), 4.40-4.i 1 (c, 3H), 3.60 (br s, 1 H), 3.45-3.34 (c, 2H), 3.19 (td;1 H), 2.32 (s, 3H),1.49 (d, 3H),1.16 (s, 3H); MS (APCI) 359 (MH');
[a]Q +68.1 (c 0.7; MeOH).
R'2 ~ ..,. Me R' i N~N~N~ ~
R" R6 Example R" R'~ R' R mp (C) MS (MH') 70 H OH 3R-Me SS-Me 331 71 Me OH 3R-Me 5S-Me 231-232 ~ 345 72 Ph OH 3R-Me 5S-Me 407 73 Me ethoxymethyl3R-Me 5S-Me 387 74 Me ethoxymethyl2R-Me 6S-Me 106-108 ~ 387 Example 75 fR)-5-f2-(1-Hvdroxv~thvll-ovrimidin~-vtl-1-methyl-2-giuinoxafin-2-vl-1 2 4 5 6 hexah~rdro-nvrazolof4.3-clovddin-3-one.
N
N
Me~~~
OH
Step A: 3-Oxo-2-ouinoxalin-2 vl-1.2.3.4.6,7fiexat~,ydro-pvrazolof4 3-c]pmidine-carboxylic aad tert-b ester. To a solution of 4-oxo-piperidine-1,3-dicartioxylic acid 1-tert-butyl ester 3-ethyl ester (500 mg,1.84 mmol; Tebahedron 1994, 50, 515) in toluene (i0 mL) was added quinoxalin-2-ylfiydrazine (295 mg, 1.85 mmol;
Hefenxycles 9985, 23, 2603). This mixture was stirred at refiux overnight, cooled to room temperature, concentrated, and purified by flash column chromatography (25-X75% ethyl acetatelhexanes) to give 600 mg (89°~) of the title compound of Example 75, Step A as a tight orange solid. 'H NMR (CDCI,, 250 MHz, 5:1 mixture of tautomers) b 11:94 (br s, 0.83H), 10.16 (s, 0.17H), 9.57 (s, 0.83H), 8.13 (dd, 1 H), 7.91-7.69 (c, 3H), 4.45 (s, 1.66H), 4.33 (s, 0.34H), 3.79-3.72 (c, 2H), 282-2.72 (c, 2H), 1.52 (s, 9H); MS (APCI) 368 (MH').
WO 00159510 P~~0~2~
Step B: 1-Methyl-3-oxo-2-auinoxalin-2~t-1.2.3.4.6.7-hexahvdro-nyrazolof4.3- , , clovridine-5-carboxylic acid tert-b~yt I ester. To a solution of 3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (prepared according to the method of Example 75; Step.A, 250 mg, 0.68 mmol) in dimethylfom~amide (2 mL) at 0 °C with stirring under nitrogen was added sodium hydride (60% dispersion in mineral oil, 41 mg,1.02 mmol). After 10 min, ipdomethane (51 NL, 0.82 mmol) was added. This mixture was allowed to stir at 0 °C
for 2 h, quenched by addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (4x). The combined organic extracts were dried over sodium sulfate, t0 filtered, evaporated, and purified by flash column chromatography (40%
ethyl acetatelhexanes) to give 164 mg (63%) of the title compound of Example 75, Step B
as a yellow foam. 'H NMR (CDCI,, 250 MHz) 8 9.71 (s, 1 H), 8.15 (dd, 1 H),.8.02 (m, 1 H), 7.80-7.70 (c, 2H), 4.29 (s, 2H), 4.74 (t, 2H), 3.79 (s, 3H), 2.72-2.67 (c, 2H),1.50 (s, 9H); MS (APCI) 382 (MH').
Step C: 1-Methvt-2-auinoxalin-2 yl-1.2.4.5.6.7-hexahvdro-ovrazolot4 3-clovridin-3-one hydrochloride. To a solution of 1-methyl-3-oxo-2-quinoxalin-2-yh1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic aad tart butyl ester (prepared according to the method of Example 75, Step B, 27, 9 mg, 0.73 mmol) in methanol (6 mL) was added hydrogen chloride (5.85 M in methanol, 1.25 mL, 7.3 mmol). This mixture was heated at 60 °C for 30 min, cooled to room temperature, and concentrated to give 249 mg (>100%) of the title compound of Example 75, Step C as a dark red solid. 'H NMR (CD,OD, 250 MHz) S 9.45 (s, 1 H), 8.13 (dd, 1 H), 8.05 (m, 1 H), T.9i-7.83 (c, 2H), 4.05 (s, 2H), 3.64 (t, 2H), 3.56 (s, 3H), 3.12 (t, 2H); MS (APCI) 282 (MH').
Step O: (Rl-1-f4-l1-Methyl-3-oxo-2-auinoxalin-2-vl-1.2.3.4.6.7-hexa~dro-oyrazolof4.3-clovridin-5-vl~ovrimidin-2-v(I~thvl butyrate. To a stirred solution of 1-methyl-2-quinoxalin-2-yl-1,2,4,5,6,7fiexahydro-pyrazolo[4,3-cjpyridin-3-one hydrochloride (prepared according to the method of Example 75, Step C,175 mg, 0.55 nunol) and (R~1-(4-chloro-pyrimidin-2-ylj-ethyl butyrate (prepared aooording to the method of Preparation Seven,126 mg, 0.55 mmol) in isopropanol (6 mL) was added triethylamine (230 NL, 1.66 mmol). This mixture was heated to reflux overnight, cooled to room temperature, and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3x). The dined -17&
organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5% methanoUchloroform) to give 248 mg (95%) of the title compound of Example 75, Step D as a yellow oil.'H NMR (CDCI3, 250 MHz) b 9.70 (s, 1 H), 8.29 (d,1 H), 8.15 (dd, 1 H), 8.03 (m, '! H), 7.82-7.70 (c, 2H), 6.48 (d, 1 H) 5.72 (q, 1 H), 4.36 (s, 2H), 4.35-4.15 (c, 2H), 3.42 (s, 3H), 2.77-2.82 (c, 2H), 2.43 (t, 2H), 1.79-1.60 (c, 2H),1.61 (d, 3H)', 0.99 (t, 3H); MS (APCI) 474 (MH'). ' Step E: (R1-5-l2-l1-Hydroxv-ethyl)-dvrimidin-4-v11-1-meth~~l-2-auinoxalin-2-vl-1.2.4.5.6.7-hexahydro-ovrazolpJ4.3-clgyridin-3-one. To a solution of (R)-1-[4-(1-methyl-3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl}-pyrimidin-2-y~-ethyl butyrate (prepan:d according to the method of Example 75, Step D, 248 mg, 0.52 mmot) in a 52 mixture of methanoUtetrahydrofucan (7 mL) was added potassium carbonate (218 mg,1.57 mmol). This mixture was stirred at 'room temperature overnight and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5-.~3% methanol/chloroform) to give 150 mg (71%) of the title compound as a white solid. mp: 217-219 °C (dec);'H NMR
(CDCI,, 250 MHz) b 9.66 (s,1 H), 825 (d,1 H), 8.12 (dd,1 H), 7.99 (m,1 H), 7.68-7.78 (c, 2H), 6.47 (d, 1H), 4.72 (q, 12H), 4.32 (s, 2H), 4.19-4.14 (c, 3H), 3.4.1 (s, 3H), 2.80 (t, 2H), 1.51 (d, 3H); MS (APCt) 404 (MH'); [a]o +13.4 (c 1.5, CHCI3).
Examoies 76 and 77 Examples 76 and 77 were prepared from the approprtate starting n-iaterials in a manner analogous to the method of Example 75.
HO
R ~N~B ....Me N-A
~N
Example A R" B mp (C) MS (MH') 76 ~ N-Me benzothiazol-2-ylCO 176-778 4pg 77 . CO quinoxalin-2-ylN-Me 201-204 (dec)404 -177_ ~xamole 78 ' LRl-6-Chloro-1'-12-l1-hvdroxy-ettwl)-flvrimidin-4-v(1-sairofchroman-2.4'-pioeridinl-4-one.
Me~
Step A: 6-Chloro-soiro[chroman-2.4'-pperidin)~-one hvdrochforide. To a solution of 1'-benzyl-6-chloro-spiro[chroman-2,4'-piperidinJ-4-one (300 mg, 0.88 mmol, Chem.
Pharm. Bull. 1981, 29, 3494) in acetone (5 mL) at 0 °C was added 1-chtoroethyl chloroformate (0.29 mL, 2.64 mmol). This mixture was warmed to room temperature, stirred overnight, and concentrated. The residue was purified by flash column chromatography {10-X20% ethyl acetatelhexanes) to give the intermediate carbamate which was refluxed in methanol (3 mL) for 1 h. Evaporation of the reaction mbchne provided 149 mg (59%) of the tifle compound of Example 78, Step A as a colorless solid. 'H NMR (CD,OD, 250 MHz) S 7.77 (d,1 H), 7.58 (dd,1 H), 7.15 (d,1 H), 3.33 (buried, 4H), 2.90 (s, 2H), 2.46-2.20 (c, 2H), 2.04-1.81 (c, 2H); MS (APCI) 252, 254 (MH').
Step B:1Rl-1'-(2-l1-Butvrvloxv-ethvl~ovrtmidin-4-v11-6-chloro-sDirolchroman-2 4'-oioeridinl~-one. To a solution of 6-chforo-spiro[chroman-2,4'-piperidin]-4-one hydrochloride (prepared according to the method of Example 78, Step A, 175 mg, .
0.61 mmol) in isopropanol (5 mL) was added {R~1-(4-chloro-pyrimidin-2-ytrethyl butyrate (prepared according to the method of Preparation Seven, 160 mg, 0.70 mmol) followed by triethylamine (029 mL, 2.1 mmot). This mixture was stirred at reflex for 1.5 h, concentrated, and purified by flash column chromatography (1 methanoUchlorofonn) to give 270 mg (100%) of the title compound of Example 78, Step 8 as a yeElow oil. 'H NMR (CDCI,, 400 MHz) S 8.19 (d, 1 H), 7.83 (d, 1 H), T.44 (dd,1 H), 6.97 (d, ~ H), 6.37 (d,1 H), 5.64 (q,1 H), 4.18 (app s, 2H), 3.34 (t, 2H), 272 (s, 2H), 2.37 (t, 2H), 2.10 (d, 2H),1.71-1.60 (c, 4H),1.55 (d, 3H), 0.94 (t, 3H); MS
(APCI) 444, 446 (MH').
. PCT/IBOOI00296 Step C: LR~-6-Chioro-1'-f2-(1-hvdroxv-ethv(~vvrimidin-4-v!1-svirofchroman-2.4'-', pper?dinl-4-one. A mixture of (R)-1'-[2-(1-butyryloxy-ethyl)-pyrimidin-4-yi}-6-chloro-spiro[chroman-2,4'-piperidin]-4-one (prepared according to the method of F~cample 78, Step B, 270 mg, 0.61 mmol) and lithium hydroxide hydrate (80 mg, 1.83 mmol) in a 3:1:1 mixture of tetrahydrofuraNmetharioUwater (5 mL) was stirred at room temperature for 1.5 h. The organic solvents were evaporated and the residue was extracted with chloroform (4x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (ethyl acetate) to give 41 mg (18%) of the title compound as a reddish foam.
'H NMR
(CDCt,, 300 MHz) 8 8.19 (d, 1 H), 7.82 (d, 1 H), 7.44 (dd, 1 H), 6.96 (d, t H), 6.40 (d, 1 H), 4.65 (q, 1 H), 4.20 (app s, 2H), 3.42-3.32 (c,,2H), 2.73 (s, 2H), 2.14 (d; 2H),1.67 (td, 2H), 1.48 (d, 3H); MS (APCI) 374, 376 (MH'); [a]p +12.6 (c 0.5, MeQH).
Exam~~les 79 to 85 Examples 79 to 85 were prepared from the appropriate starting materials in a manner analogous to the method of Example 78.
HO
~~~~Me s N._ Rs~
IN
Example R'~ R" D mp (C) MS (MH') 79 6-Ph H CH2 402 80 6-Ph H CHOH 418 81 6-Ph H CO 416 82 6-0Me H CO 156.5-157.5 370 83 7-Br H CO 418,420 84 5-CI 6-Ct CO 408,410 85 6-OMe 7-OMe CO 400 Examn~, 86 ~Rl-1-f4-l2-Methyl-4-phenyl-5.8-dihvdro-6H-ovridof3.4-dlovrimidin-7-yl)-oyrimidin-2-I -eth ol.
N
Me~~~~~
Step A: 7-Benzvl-2-methyl-5.6.7.8-tetrahvdro-3H-ovridof3.4-dloyrimidin-4-one.
A
solution of sodium ethoxide in ethanol was prepared by addition of sodium metal (5.7 g, 247 mmol) to absolute ethanol (141 mL). After the sodium metal had all dissolved, ethyl 1-benzy!-3-oxo-4-piperidine carboxytate hydrochloride (21 g, 70.5 mmol) was added followed by acetamidine hydrochloride (13.3 g, 141 mmol). This mixture was stirred at reflex for 1 h, cooled to room temperature, and concentrated. The residue was dissolved in a minimum amount of water and the pH was adjusted to about 7 with glaaal acetic aad. The resulting yellow preapitate was filtered, washed with water (3x), air-dried for 2 h, then vacuum-dried overnight to provide 17.1 g (95%) of the tifle compound of F~cample 86, Step A as a yellow solid. 'H NMR (CDCI,, 250 MHz) 8 7.35-7.25 (c, SH), 3.70 (s, 2H), 3.42 (s, 2H), 2.73-2.64 (c, 2H), 2.64-2.60 (c, 2H), 2.41 (s, 3H); MS (APCI) 256 (MH').
Step B: 7-Benzvl~-chloro-2-methyl-5.8-dihvdro-6H-pvrfdof3.4-dlovrimidine. 7-Benzyl-2-methyl-5,6,7.8-tetrahydro-3H-pyrido[3,4-djpyrimidin-4-one (prepared according to the method of Example 86, Step A,17.1 g, 67.0 mmol) was suspended in phosphorus oxychloride (66 mL, 335 mmol). This mixture was stirred at reflex for 1 h, pooled to room temperature, evaporated, then chased with toluene. The residue was carefully diluted with ice/wateNchloroform and the layers were separated. The aqueous phase was extracted with chloroform (3x) and the combined organic extracts were washed with saturated aqueous sodium bicarbonate (1x) and water (1x), dried over sodium sulfate, filtered, and evaporated to give the title compound of Example 86, Step B as a brown oil that was used without purfication in the next step.:
'H NMR
pGT/IB00/00296 (CDCI,, 250 MHz) S 7.36-7.23 (c, 5H), 3.73 (s, 2H), 3.63 (s, 2H), 2.63 (app s, 4H), 2.36 (s, 3H); MS (APCI) 274, 276 (MH').
Step C: 7-Benzvl-2-methyl-4-phenyl-5.8-dihydro-6H-oyrid~3.4-dlovrimidine. To a suspension of 1,4-diphenylphosphinobutane (1.43, g, 3.35 mmol) in toluene (50 mL) was added bis(benzonitrile)palladium(II) chloride (1.28 g, 3.35 mmol). This mixture was stirred for 25 min at room temperature, then was added to a suspension of benzyl-4-chioro-2-methyl-5,8-dihydro-6H-pyrido[3,4-djpyrimidine (prepared according to the method of Example 86, Step B, 67.0 mmol, assumed) and phenylboronic acid (10.6 g, 87.1 mmol) in a mixture of absolute ethanol (40 mL), toluene (175, mL), and 2 N aqueous sodium carbonate (33.5 mL). This mixture was stirred at reflux for 6.5 h, cooled to room temperature and stirred for --2.5 d, then filtered through a.
pad of Celite. The filtrate was concentrated and the residue was diluted with water and extracted with chloroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (4550% ethyl acetate/hexanes) to give 16.5 g (78%, two steps) of the title compound of Example 86, Step C as a yellow oil. 'H NMR (CDCI,, 250 MHz) 8 7.57-7.54 (c, 2H), 7.48-7.24 (c, 8H), 3.71 (app s, 4H), 2.85 (t, 2H), 2.71-2.67 (c, 2H), 2.69 (s, 3H); MS (APCI) 316 (MH').
Step D: 2-Methyl-4-ohenvl-5.8-dihvdnr6H-oyridof3.4-dlovrimidine. 7-Benzyl-2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-djpyrimidine hydrochloride was fom~ed in situ by addition of hydrogen chloride (1.9 M in methanol, 31.1 mL, 51.1 mmol) to a solution of 7-benzyl-2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine (prepared according to the method of Example 86, Step C, 16.5 g, 522 mmol) in methanol (75 mL). After sorting 10 min at room temperature; a preapitate fom~ed, and another aliquot of methanol (100 mL) was added to obtain a homogeneous solution. To this mixture was added a siuny of 10% palladium on carbon (3.3 g, wl%) in methanol followed by ammonium fomiate (16.5 g, 261 mmol). This mixture was stirred at retlux for 5 h, cooled to room temperature, and filtered through Celite.
The filtrate was evaporated, diluted with saturated aqueous sodium bicarbonate, and extracted with chloroform (3x). The combined organic extracts wen: dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (3%
methanoUchloroform + 1 % ammonium hydroxide) to give 6.7 g (57%) o~ the Frtle compound of Example 86, Step D as an off~nrhite solid and 2.4 g (19%) of 7-fomryl-2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine as a yellow gum.
Treatment of the 7-formyl byproduct with methanalic hydrogen chloride at room temperature overnight followed by aqueous workup and column chromatography provided an additional 1.4 g (12%) of the title compound of Example 86, Step D. 'H NMR
(CDCt,, 250 Mtiz) b 7.55-7.40 (c, 5H), 4.09 (s, 2H), 3.05 (t, 2H); 2.75 (t, 2H), 2.79 (s, 3H); MS
(APCt) 226 (MH').
Step E: fR)-1-1'4-(2-Methyl-4-phenyl-5.8-dihvdro-6H-avrido(3.4-dlpvrimidin-7 vl~
eyrimidin-2-yll-ethyl butt irate. To a solution of 2-methyl-4-phenyl-5,8~iihydn~..6H-pyrido[3,4-djpyrimidine (prepared according to the method of Example 86, Step D, 6.8 g, 30.0 mmol) in isopropanol (125 mL) was added (R~1-(4-chioro-pyrimidin-2-yl~thyl butyrate (prepared according to the method of Preparation Seven. 6.8 g, 30 mmoi) followed by triethylamine (12.5 mL, 89.9 mmol). This mixture was stirred at reflux for 8 h, cooled to room temperature overnight, and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3x).
The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2% methanoUethyl acetate) to give 11.0 g (88%) of the title compound of Example 86, Step E, as a yellow oil. 'N
NMR
(CDCI,, 250 MHz) 8 8.28 (d, 1 H), 7.62-7.40 (c, 5H), 6.45 (d,1 H), 5.69 (q,1 H), 4.78 (s, 2H), 3.93 (app s, 2H), 2.95 (t, 2H), 2.77 (s, 3H), 2.40 (t, 2H),1.?7-1.63 (c, 2H), 1.60 (d, 3H), 0.98 (t, 3H); MS (APCI) 418 (MH').
Step !_: ~Rl-1~t4-!2-Methyl-4-r~henvl 5 8-dihvdro-6H-oyridoL3 4-d~ovrimidin-7 yll~
py~imidin-2-vtl-ethanol. To a solution of (R~1-[4-(2-methyl-phenyl-5,8-dihydro-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yt]-ethyl butyrate (prepared according to the method of Example 86, Step E. 11.0 g, 26.4 mmol) in dioxane (13 mL) was added concentrated hydrochloric aad (22 mL, 264 mmol). This rriodure was stirred at room temperature overnight, cooled to 0 °C, neutralized via slow addition of 6 N aqueous sodium hydroxide, and extracted with ethyl acetate (4x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2-~5% methanoUethyl acetate) to give an oil which after filtration with hexanes provided 8.0 g (88%) of the title compound as a white solid.
mp:114-116 °C;~'H NMR (CD,OD, 250 MHz) 8 8.26 (d,1H), 7.62 7.47 (c, 5H), 6.52 (d,1H), 4.79 (s, 2H), 4.66 (q, 1 H), 424 (br s, 9 H), 3.90-3.80 (c, 2H), 295 (t, 2H), 270 (s, 3H),1.49 (d, 3H); MS (APCI) 348 (MH'), [ajp +15.6 (c 1.0, MeOH).
E~camnles 87 to_ 100 ' Examples 87 to 100 were prepared from the appropriate starting' materials in a manner analogous to the method of Example 86.
Me Example R~' R~' mp (C) MS (MH'~
87 H Ph 72 74 88 Ph H ~ 334 89 Ph Et ' 362 90 Ph NH2 225-228 (dec) 349 91 Ph Ph 73-?5 410 92 Ph 4-pyridy! 411 93 (4-OMe)Ph Me 62-64 378 94 (4-t7Ph Me 55-58 366 95 (4-Ct)Ph H 368, 370 96 OMe Me 302 97 OPh Me 156-158 364 98 SPh Me 103-105 380 99 N-indolinyfMe 128-131 38g 100 NMez Et 329 Example 101 ~4-f2-(1 R-Hvdroxv~thvl~ovrimidin-4-y~f -2R 6S-dimethvl oioerazin-1~r(~-(2-ohenvl-7 8-dihydro-SH-ovridot4.3-dipvrimidin~-vl~methanone.
wo oors9sio -~ s3-M
Step A: 4-0xo-oioeridine-1-carboxvlic.aad tert-butyl ester. A mixture of 4-piperidone monohydrate hydrochloride (9.22 g; 60 mmoi) and di-tert-butyl Bicarbonate, (10.9 g, 50 mmol) in a 1:1 mixture of dichloromethane/saturated aqueous sodium bicarbonate (100 mL) was stirred at room temperature for 15.5 h. The layers were separated and the aqueous layer was extracted with chloroform (3x). The combined organic extracts were washed with 1 N aqueous phosphoric acid (3x), dried over sodium sulfate, filtered, and evaporated to give 10.0 g (100%) of the title compound of Example 101, Step A as a white solid. 'H NMR (CDCl3, 400 MHz) 8 3.70 (t, 4H), 2:42 (t, 4H),1.47 (s, 9H).
Step B: 3-Dimethvlaminomethvlene~4-oxo-oioeridine-1-carboxylic add tert-by~l ester. To a solution of 4-oxo-piperidine-1-carboxylic acid tart-butyl ester (prepared acxording to the method of Example 101, Step A, 4.0 g, 20.0 mmo!) in dimethyfformamide (40 mL) was added tart-butoxybis(dimethylamino)methane (4.35 mL, 22 mmol). This rriucture was stirred at reflex for 15 h, cooled to room temperature, diluted with water, and extracted with ethyl acetate (Sx). The combined organic extracts were washed with water (3x) and brine (1 x), drted over sodium sulfate, filtered, and evaporated to give 3.64 g (72%) of the title compound of Example 101, Step B as a brown oil that was suffiaentfy pure to carry on to the next step.
'H NMR
(CDCI,, 400 MHz) S 7.47 (s,1 H), 4.53 (s, 2H), 3.58 (t, 2H), 3.09 (s, 6H), 2.43 (t, 2H), 1.46 (s, 9H); MS (APCI) 255 (MH').
Step C: 2-Phenyl-7 8~iihvdro-SH-ovrido(4 3-dlpvrimidine-6-carboxylic acid tart-buhrl ester. A rriucture of 3~imethylaminomethylene-4~xo-piperidine-1-carboxylic aad tert-butyl ester (preRared according to the method of Example 101, Step B, 509 mg, 2.0 mmol), benzamidine hydrochloride hydrate (470 mg, 3.0 mmol), and sodium ethoxide (1 M in ethanol, 6.0 mL, 6.0 mmol) in,absolute ethanol (4 mL) was heated to reflex for about 3 d, cooled to room temperature, and concentrated. The residue was diluted ' WO OOI59510 PCTIIBOOI0029G
with saturated aqueous sodium bicarbonate and extracted with chloroform (3x).
The combined organic extracts were dried over sodium suffate, filtered, evaporated, and purified by flash column chromatography (Biotage Flash 40S"', 1015% ethyl acetatelhexanes) to give 304 mg (49%) of the title compound of Example 101, Step C
as a yellow oil. 'H NMR {CDCI3, 400 MHzj S $.52 (s, 1 H), 8.40-8.38 (c, 2H), 7.50-7.44 (c, 3H), 4.62 (s, 2H), 3.78 (t, 2H) 3.02 (t, 2H),1.50 (s, 9H); MS (APCt) 312 (MH').
Step D: 2-Phenv(-7.8-dihvdro-SH-ovridof4.3-d~pvrimidine hydrochloride. To a sotution of 2-phenyl-7,8-dihydro-SH-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester (prepared according to the method of Example 101, Step C, 304 mg, 0.98, mmol) in ethyl acetate (2 mL) was added hydrogen chloride (2.5 M in ethyl acetate, 3.9 mL, 9.76 mmol). This mixture was stirred at room temperature far 16 h and concentrated to give 256 mg (>100%) of the title compound of Example 101, Step D es a pale yellow solid. 'H NMR (CD,OD, 400 MHz) 8 8.75 (s, 1 H), 8.42-8.38 (c, 2H), 7.57-7.45 (c, 3H), 4.48 (s, 2H), 3.68 (t, 2H) 3.35-3.25 (buried, 2H); MS (APCI) 212 (MH').
Step E: 1 R-f4-(4-Chlorocarbonvt-3R.5S-dimethvl_piperazin-1 vt)-ovrimidin-2-vll-ethv!
butyrate. To a solution of 1 R-[4-(3R,5S-dimethyl-piperazin-1 yl)-pyrimidin-2-yI]~thyl butyrate (prepared according to the method of Preparation Three, 1.36 g, 4.44 mmol) in dichloromethane (22 mL) at 0°C under nitrogen was added pyridine (0.36 mL, 4.44 nunol) followed by triphosgene (883 mg, 2.97 mmol). This mixture was stirred with wamung to room temperature for 1.5 h and quenched with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous phase was extracted with chloroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.-~2°~
methanoUchloroform) to give 1.59 g (97%) of the title compound of Example 101, Step E as a brown oil. 'H NMR (CDCI,, 400 MHz) 8 8.23 (d,1 H), 6.39 (d,1 H), 5.66 (q, 1 H), 4.54-4.47 (c, 2H), 4.35 (m,1 H), 4.25 (m,1 H), 3.20 (dt, 2H), 2.38 (t, 2H),1.72-1.62 (c, 2H),1.5fi (d, 3H),1.31 (d, 3H),1.30 (d, 3H), 0.95 (t, 3H); MS (APCI) 369, 371 (MH').
Step I=: f4-f2-(1 R-Hvdroxv-ethvl~vrimidin~yl~-2R 6S~iimethvl oioer~rn 1 v11~2 phenyl-7.8-dihvdro-SH-ovridof4.3~ilovrimidin-6 vl~methanone. A mixture of 2-phenyl-7,8-dihydro-SH=pyrido[4,3-djpyrimidine hydrochloride (prepared according to the method of Example 101, Step D,160 mg, 0.65 mmol),1 R-[4-(4-chlorocarbonyl-3R,5S-dimethyl-p'~perazin-1-ylj-pyrimidin-2-yl~ethyl butyrate (prepared according to the method of Example 101, Step E, 200 mg, 0.54 mmol), and triethylamine (0.19 mL, - WO 00!59510 1.36 mmol) in tetrahydrofuran (5 mL) was stirred at reflux for 3 h; cooled to room temperature overnight, and concentrated. The residue'was diluted with a 4:1 mixture of methanoUwater (5 mL) and lithium hydroxide hydrate (114 mg, 2.71 mmol) was added. This mixture was stirred for 2.5 h, .concentrated; and partitioned between saturated aqueous sodium bicarbonate and chtorofortn. The layers were separated and the aqueous phase was extracted with 20% isopropanoUchioroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2-.>5% methanollchloroform) to give mg (71%) the title compound as a white foam.'H NMR (CDCI9, 400 MHz) 88.56 (s, 1 H), 8.41-8.39 (c, 2H), 8.20 (d,1 H), 7.50-7.46 (c, 3H), 6.38 (d, 1 H), 4.71 (s, 2H), 4.69 (m, 1 H), 4.28 (d, 1 H), 3.89 (t, 2H) 3.83 (d, 2H), 3.60-3.56 (c, 2H), 3.46-3.39 (c, 2H), 3.09 (t, 2H), 1.50 (d, 3H), 1.18 (d, 6H); MS (APCI) 212 (MH'); [cz]p +6.i (c"1.8, CHCh).
Exam~fes 102 to 110 Examples 102 to 110 were prepared from the appropriate starting materials in a manner analogous to the method of Example 101.
NO
R,e .,... Mg O z $ N-~N " N ~ / N
zz R N
Rz,. R,a , Example R~ Rz' R" R'° mp (°C) MS (MH') i02 quinolin-2-yl H 3R-Me 5S-Me 772-174:5 407 103 quinolin-3-yl H 2R-Me 6S-Me . 4p7 104 quinolin-4-yl H 3R-Me 5S-Me 407 105 quinolin-6-yl H 3R-Me 5S-Me 4p7 106 pyridin-3-yl- pyridin-3-2R-Me 6S-Me . ' 462 methyl y!-methyl Example NR='R~ R" R" mp (C) MS (MHO
107 2-amino-7,8-dihydro-SH-2R-Me 6S-Me 225=228 413 pyrido[4,3-dJpyrimidin-6-yl 108 2-(1-hydroxy-1-methyl-2R-Me 6S-Me 4~
ethyl}-7.8~ihydro-5H-pyiid~[4,3-dJpyrimidin-6-yl 109 5,7-dihydro- 2R-Me 6S-Me 458 dibenzo[c.e]azepin-6-yl 110 4-[2-{1 R-hydroxy-ethyl)-3R-Me 5S-Me 499 pyrimidin-4-ylJ-3R,5S-dimethyl-piperazin-1-yl Example 111 (E?-1 R-f4-f4-l2-Phenvl-ethenesulfonvl~-oit~erazin-1-vfl-nyrirnidin-2-vl~-ethanol.
HO
....Me N-~ si, ~ N
II ~ ~ /
WO 00/59510 rcr~BOOiooi~
Step A: (E)-1 R-f4-t4-f2-Phenyl-ethenesulfonvl)-oiperazin-1-vtlwrimidin-2-vlf-ethyl acetate. To a solution of (R~1-[4-piperazin-1-ytrpyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Two, 0.25 g, 1.0 mmol) and triethylamine (0.10 g, 1.0 mmol) in tetrahydrofuran~ (5 mL) was added (~
styrenesulfonyl chloride (0.21 g, 1.0 mmol)~at ambient temperature and stirred for 1 h.
The mixture was diluted with water and extracted twice with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and the filtrate was concentrated to an oil, which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound of Example 111, Step A as an oil, 0.15 g (34%). 'H NMR
(CDCI,, 300 MHz) 81.48' (d, 3H), 2.15 (s, 3H), 323 (m, 4H), 3.84 (m, 4H), 5.67 (q,1H), 6.40 (d,1 H), 6.65 (d,1 H), 7.39-7.52 (m, 6H), 821 (d,1 H); MS (TS) 417 (MH'). ;
Step B: (El-1R-f4-f4-(2-Phenv!-ethenesulfonyl~oiaerazin-1-vll-ovtimidin-2-vll-ethanol, To a solution (E)-1 R-{4-[4-(2-phenyl-ethenesuifonyl~piperazin-1-yl]-pyrimidin-2 yI}=
ethyl acetate (prepared according the method of Example 111, Step A, 0.14 g, 0.33 mmol) in methanol (1 mL) was added at ambient temperature 6 N aqueous potassium hydroxide (0.25 mL). After stirring for 3 h, the solution was diluted with ethyl acetate and washed twice with water. The organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound as a white solid, 0.09 g (69%).'H NMR (CDCI', 300 MHz) 81.48 (d, 3H), 3.23 (m, 4H), 3:84 (m, 4H), 4.20 (br s,1 H), 4.71 (q, 1 H), 6.40 (d, 1 H), 6.65 (d, 1 N), 7.39-7.52 (m, 6H), 8.21 (d, 1 H); mp: 68-70 °C; MS (TS) 375 (MH'); [a]p +20.9 (c 1.0, MeOH).
Examples 112 and 113 Examples 112 and 11.3 were prepared from the appropriate starting materials in a manner analogous to the method of Example 111.
HO
R~° :.,.Me N-R"-N N, ~ / N
R
Example .R' R" R" mp (C) '. MS
(MH') 112 (RrMe (S~Me isopropylsulfonyl 7 52-154 343 113 (R~Me (S)-Me 1-methyl-1 H-imidazol-4-157-158 381 yl-sulfonyl Example 114 1 R-f4-f5-(4-Bromobenzenesulfonvl~2R.5S-diaza-bievclo[2.2.11heat-2-y(1-ovrimidin-2-vl~-ethanol.
HO
~~~~Me O N-CI ~ ~ SI-N N N
II ~ /
Step A: 1~4-(2R.5S-Diaza-biwclof2.2.11hept-2-yl~ovrimidin-2-y(1-ethyl butyrate. To a suspension of 2,5-diaza-bicyGo[2.2.1)heptane dihydrobromide (7.57 g, 88.0 mmot;
Synthesis 1990, 10, 925) in dichloromethane (90 mL) was added 1,8-diazabicyGo[5.4.0]undec-7-ene (13.7 g, 90 mmol) and stirred until homogeneous.
A
solution of (R~1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 10.2 g, 45 mmol) in dichioromethane (10 mL) was added and stirred at reflux for 14 h. The mixture was filtered and washed with saturated aqueous sodium bicarbonate. The organic tayer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a aude product which was purified b~ flash chromatography (9:1->5:1 dichloromethane:methanoll to give the title compound of Example 114, Step A as an oil, 6.75 g (51 %). 'H NMR (CDCI,, 300 MHz) b 0.92 (t, 3H), 1.54 (d, 3H), 1.68-1.78 (m, 5H), 2.68 (t, 2H), 3:38 (m, 1 H), 3.76 (m, 3H), 4.42 (m, 1 H), 5.35 (q, 1 H), 6.16 (d, 1 H), 8:12 (d, 1 H); MS (CI) 291 (MH').
Step B: 1 R-f4-f5-l4-Bromobenzenesulfonvl)-2R.5S-diaza-bicvclof2.2.11hent-2-y(1-Qvrimidin-2-vl)-eth~tyrate. To a solution of 1R~,4~2R,5S-diaza-bicydoj2.2.1]hept-2-yl~pyrimidin-2-ylj-ethyl butyrate (prepared according to the method of Example 114, Step A, 0.58 g, 2.0 mmol) and triethylamine (0.22 g, 2.2 mmol) in chloroform (10 mL) was added 4-bromobenzenesulfonyl chloride (0.56 g, 2.2 mmol) and stirred at ambient temperature for 16 h. The mixture was washed once with water, once with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound of Example 114, Step B as a dear oil, 0.92 g (90%). 'H NMR
(CDCl3, 300 MHz) S 0.92 (t, 3H), 1.54 (d, 3H), 7.68-1.78 (m, 5H), 2.68 (t, 2H), 325 (m, 1 H), 3.46 (m, 3H), 4.28 (m, 1 H), 5.25 (q, 1 H), 6.16 (d, 1 H), 7.58 -7.64 (m, 4H), 8.12 (d, 1 H); MS (CI) 510 (MH').
Step C: 1 R-(4-f5-l4-Bromobenzenesulfonvl)-2R.5S-diaza-bicvclof2.2.11hent-2-v(1-evrimidin-2-vl)-ethanol. To a solution of 1 R-{4-[5-(4-bromobenzenesulfonylr2R,5S-diaza-bicydo[2.2.1]hept-2-yl]-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 114, Step 8, 0.85 g,1.6 mmol) in a 2:1 mixture of tetrahydrofuran:methanol (10 mL) was added at ambient temperature 6 N aqueous potassium hydroxide (1 mL). After stirting for 6 h the solution was diluted with dichioromethane and washed twice with water. The organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to a viscous oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound as a white foam, 0.49 g (66%). 'H NMR (CDCI,, 300 MHz) 1.54 (d, 3H), 1.68 (m,,2H), 1.78 (m, 1H), 3.25 (m, 1H), 3.46 (m, 3H), 4.28 (m, 1H), 4.78 (q, 1 H), 6.16 (d, 1 H), 7.64 (m, 4H), 8.12 (d, 1 H); mp: 83-88 °C; MS (C!) 440 (MH'); [a]D -49.2 (c 1.0, MeOH).
Examples 115 to 120 Examples 115 to 120 were prepared from the appropriate starting materials in a manner analogous to the method of Example 114.
WO 00!59510 PCTIIB00/00296 HO
w~~Me N-R"-N' \ -N , ~ /N'_ Example R" mp (C) MS (MH') 115 4-chlorophenylsulfonyl 83-88 395, 397 116 2-~ienylsulfonyl 84-86 '~ 367 117 2-(5-chlorothienyl)-sulfonyl62-64 401, 403 118 4-carboxamidoylphenyl-sulfonyl148-151 404 H
119 4-(tart-butylphenyl~sulfonyl72-75 417 120 N,N-dimethylsutfamoyl 110-111 328 Example 121 {4-(4-(Pvrrolidine-1-sulfonvl)-piperazin-1-vll-ovrimidin-2-vl1-methanol.
HO
N-\NIIN~ ~~N
O
Step A: 2-Methoxvmethvl-4-t4-(QVrrofidine-1-suffonv()-oioerazin-1-vf!-ovrimidine. To a solution of 2-methoxymethyl-4-piperazin-1-yl-pyrimidine (prepared according to the method of Preparation One, 2.08 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in tetrahydrofuran (20 mL) was added N-pyrrolidinesulfonyl chloride {1.69 g, 10 mmol) at 0 °C and stirred for 3 h at ambient temperature. The mixture was diluted with ethyl acetate and washed twice with water. The organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to an oil which was purified by flash chromatography (95:5 dichloromethane:methanol) to give the title compound of Example 121, Step A as a dear oil, 3.24 g (93%). 'H NMR (CDCl3, MHz) 81.81-1.85 (m, 4H), 3.12-3.18 (m, 8H), 3.59 (s, 3H), 3.81 (m, 4H~ 4.43 (s, 2H), 6.71 (d, 1 H), 8.18 (d, 1 H); MS (TS) 342 (MH').
Step B: f4-f4-lPvrrolidine-1-sulfonvll-oiDerazin-1-vll-ovrimidin-2-~rt~-methanol. To a solution of 2-methoxymethyl~-[4-(pyrrolidine-1-sulfonyL~piperazin-1-yl]-pyrimidine I 1 , , (prepared according to the method of Example 121, Step A, 3.1 g, 9.4 mmol) in dichlorornethane (47 mL) was added boron tribromide (1 M in dichioromethane, mL, 18.7 mmol) at 0 °C then stirred at ambient temperature for 2 h. The mixture was washed twice with saturated aqueous sodium bicarbonate; and the organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give an oil which was crystallized from isopropyl ether to give the title compound as a white solid, 2.43 g (7790). 'H NMR (CDCI3, 300 MHz) b 1.82 (m, 4H), 3.15 (m, 8H), 3.81 (m, 4H), 4.35 (d, 2H), 4.83 (t,1H), 6.71 (d;1H), 8.18 (d, 1H); mp:128-131 °C;
MS (Cl) 328 (MH').
Examples g22 to 125 "
Examples 122 to 125 were prepared from the appropriate starting materials in a manner analogous to the method of Example 121.
R' N
R" ~ ~ ~\N
Example R' R" mp (C) MS (MHO
122 CHZOH 2,5-dimethyipymolidin-1-128-131 356 ytsulfonyl 123 CHZOH piperidin-1-ylsulfonyl141-142 342 124 (R)-CH(Me)OH aza-bicydo[3.21]octan-8-11 i-112 382 ylsulfonyl 125 (R~CH(Me)OH aza-bicydo(32.1]octan-3-113-114 396 one-8-yl-sulfonyl Examote 126 (E?-1-f4-f2-f 1 R-Hvdroxv-ethvl~-ovrimidin~.-vll-oinerazin-1-vl~-2-methyl-3-ohernrl-pro~enone.
~~~~ Me ., pCTIIB00/00296 Step A: ~E>-1 R-(4-~4-(2-Methvl-3-phenyl-acrvlovl~cioera~in-1-vll-avrimidin-2-vl~-ethyl acetate. To a solution of (R}-1-(4-piperazin-1-y!-pyrimidin-2-yl~ethyl acetate (prepared according to the method of Preparation Two, 0.54 g, 2.1 mmol) and a-methylcinnamic acid (0.34 g, 2.1 mmol) in diG~loromethane (10 mL) was added 1-hydroxybenzotriazole (0.50 g, 3.6 mmol) followed by 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (0.45 g, 2.4 mmot) at ambient temperature and stirred for 48 h. The mixture was washed once with water, once with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and the ftltrate was concentrated to an oil which was purified by flash chromatography (9:1 dichloromethane:methanot) to give the title compound of Example 126, Step A as a Gear viscous oil, 0.53 g (63%). 'H NMR (CDCI,, 300 MHz) S 1.51 (d. 3H), 2.14 (s, 3H), 2.18 (s, 3H), 3.75 (m, 8H), 5.fi8 (q,1 H), 6.41 (d,1 H), 6.59 (s,1 H), 725-7.43 (m, 5H), 8.23 (d, 1 H); MS (CI) 395 (MH'); ja]~ +38.6 (c 1.0, MeOH).
Step B: ~E?-1-f4-T2-(1R-Hydroxv-ethvl~-ovrimidin-4-vll-flioerazin-1-vl~-2-methyl-3-phenvl-aropenone. To a sotution of (E}-1 R-{4-[4-(2-methyl-3-phenyl-acryfoyl~
piperazin-1-yl}-pyrimidin-2-yl}-ethyl acetate (prepared according to the method of Example 126, Step A, 0.51 g, 1.3mmo1) in methanol (5 mL) was added at ambient temperature 6 N aqueous potassium hydroxide (1 mL). Afterstining for 1 h the solution was diluted with ethyl acetate and washed twice with water. The organic layer was separated, dried over magnesium sulfate, ftltered, and the ftltrate was concentrated to give the title compound as a white solid, 0.25 g (55%). 'H NMR
(CDC1,, 300 MHz) 51.51 (d, 3H), 2.14 (s, 3H), 3.75 (m, 8H), 4.22 (br s, 1 H), 4.71 (q, 1 H), 6.41 (d, 1 H), 6.59 (s, 1 H), 7.25-7.43 (m, 5H), 8.23 (d,1 H); mp: 119-121 °C; MS
(CI) 353 (MH'); [c~J~ +16.0 (c 1.0, MeOH).
Examples 127 to 129 Examples 127 to 129 were prepared from the appropriate starting materials in a manner analogous to the method of Example 126.
WO 00/59510 PC'TIIBOOf00296 ,."Me R' Example ~ A~' R° R' mp (°C) ~ ~ MS (MH') 127 thien-2-yl H H 104-106 345 128 thien-2-yl (R}-Me . (S~Me 69-73 373 Ho ~~~~Me An~ ~ N-Jr--N N N
O
Example A~ mp (°C) MS (MH') 129 . 4-(o-tolylcarbamoyly-phenyl 9&103 446 Example 130 (E~3-Benzofuran-2-vl-1-(4-f2-(1 R-hvdroxv-ethyl)-ovrimidin-4-vf1-2R,6S-dimethvi-piperazin-1-vl~-oropenone.
HO
1Ae w~~Me N-Me Step A: (E)-1 R-(4-f4-(3-Benzofuran-2-vl-acrvIovIJ-3R.5S-dimethvl-oioerazin-1-vll-p, r~rimidin-2-vf)-ethyl butyrate. To a solution of 1 R-(4-(3R,5S-dimethyl-piperazin-1-yl~
pyrimidin-2-yfJ-ethyl butyrate (prepared according to the method of Preparation Three, 0.79 g, 2.6 mmol) and triethylamine (0.26 g, 2.6 mmol) in dichloromethane (90 mL) was added (E)-3-benzofuran-2-yl-acryloyl chloride (0.54 g, 2.6 mmol) and stirred at ambient temperature for 16 h, then at reflux for 2.5 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product, which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound of Example 130, Step A as a viscous oil, 0.79 g (54%). 'H NMR (CDCI,, 300 MHz) i; 0.95 (t, 3H), 1.40 (d, 6H), 1.56 (d, 3H), 1.67 (q, 2H), 2.38 (t, 2H), 3.25 (d, 2H), 4.33 (m, 2H), 4.75 (m, 2H), 5.66 (q, 1 H), 5.95 (d, 1 H), 6.40 (d, 1 H), 7.14-7.37, (m, 5H), 8.06 (d, 1 H), 8.22 (d, 1 H); MS (Ci) 477 (MH'); [a]o +49.1 (c 1Ø MeOH).
Step B: (El-3-Benzofuran-2-vl-1-(4-f2-(1R-hvdroxy~thvl)-pvrimidin-4-vfl-2R 6S-dimethvl-piperazin-1-vl)-orooenone. To a solution of (E~-1 R-(4-[4-(3-benzofuran-2-yt-acryloyl)-3R,5S-dimethyl-piperazin-1-yt]-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 130, Step A, 0.51 g, 1.1 mmol) in methanol (5 mL) was added at ambient temperature 6 N aqueous potassium hydroxide (1 mL).
After stirring for 1 h the solution was diluted with ethyl acetate and washed twice with water. The organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound as a white soiid, 0.49 g (75%).
'H NMR (CDC13, 300 MHz) 8 1.40 (d, 6H), 1.56 (d, 3H); 325 (d, 2H), 4.33 (m, 2H), WO 00159510 PC'f/IB00/00296 4.75 (m, 2H), 4.68 (q, 1 H), 5.95 (d; 1 H), 6.40 (d, 1 H), 7.14-7.37, (m, 5H), 8.06 (d, 1 H), "
8.22 (d, t H); mp: 80-82 °C; MS (CI) 407 (MH'); [a]~ +17.7 (c t.0, MeOH).
Examflle 131 Cvclohexvl-f4-f2-(1 R-hvdroxv-ethyl)-pvrimidin~l-vtl-2R.6S-dimethvt-oioerazin-1-vl)-methanone.
HO
Me ~~~~Me N-N. N ~ /N
O
Me Step A: 1 R-f4-(4-Cvclohexaneca~onvf-3R.5S-dimethvl-aioerazin-1-vl~oyrimidin-2-vll-ethyl butyrate. To a solution of 1R-j4-(3R,5S-dimethyl-piperazin-1-yl)-pynmidin-2-yfJ-ethyl butyrate (prepared according to the method of Preparation Three, 306 mg, 1.0 mmol) and triethylamine (230 mg, 1.2 mmol) in dichloromethane (10 mL) was added at ambient temperature cydohexanecarbonyl chloride (161 mg,1.1 mmoi).
After 1 h the mixture was washed with water, and the dichloromethane layer was dried over magnesium sulfate and filtered. The filtrate was oonoentrated to give the tine compound of Example 131, Step A as an oil, 388 mg (94%). 'H NMR (CDCI,, 300 MHz) 8 0.94 (t, 3H), 1.2-1.4 (m, 6H), 1.54 (d, 3H), 1.5-1.83 (m, t2H), 2.44 (m, 3H), 3.2-3.3 (m, 2Hj, 4.4-4.6 (m, 4H), 5.52 (q, 1 H), 6.44 (d; 1 H), 8.22 (d, 1 H);
MS (CI) 417 (MH').
Step B: Cvdohexvl-(4-f2-f 1 R-hvdroxv-ethyll-ovrimidin-4-vt1-2R.6S-dimethvl-oioerazin-1-v(1-methanone. Ta a solution of 1 R-j4-(4-cydohexanecarbonyl-3R.5S-dimethyl-piperazn-1-yl)-pyrimidin-2-yt]-ethyl butyrate (prepared according to the method of Example 131, Step A, 375 mg, 9.0 mmol) in methanol (5 mL) was added 6 N
aqueous potassium hydroxide (0.5 mL) and stirred at ambient temperature for 4 h. The reaction mixture was concentrated, diluted with water, and extracted into dichloromethane. The extract was washed twice with water, dried over magnesium sulfate, and evaporated to an oil. The cxude product was crystallized from ethyl ether to give the title compound as a white soiid,106 mg (34%). 'H NMR (CDCI,, 300 MHz) 81.2-1.4 (m, 6H),1.55 (d, 3H),1.6-1.8 (m,10H), 2.46 (m,1 H), 3.2-3.3 (m, 2H), 4.6 (m, 4H), 4.78 (q, 1H), 6.43 (d, 1H), 8.22 (d, 1H); mp: 174-175 °C;
MS (CI) 347(MH'); [a]p +18:4 (c 1.0, MeOH).
Example 132 Furof3.2-clovridin-2-vl-f4-f2-( 1 R-hvdroxv-ethyl)-pyrimidin-4-yl]-2R.6S-dimethvt-eiperazin-1-vl)-methanone.
~~~~Me Me Step A: 7-Chloro-furoL.2-clpvridine-2-cart~oxvlic acid. To a solution of,n-butyllithium (2.5 M in hexanes, 17 mt_, g, 42.6 mmol) in anhydrous ethyl ether (90 mL) was added dropwise a solution of 4-chloro-furo[3,2-c]pyridine (5.81 g, 37.8 mmot; J.
Heterocycl.
Chem. 1975, 12, 705) in ethyl ether (85 mt-) at 78 °C under nitrogen atmosphere.
This mixture was stirred for 1.5 h at--65 °C, poured onto dry ice (100 cx) and warmed to ambient temperature and quenched into water. The separated organic layer was extracted once with water and the combined aqueous layers were aadified to pH
with concentrated hydrochloric aad to give the title compound of Example 132, Step A
as a white solid, 3.33 g (45%). 'H NMR (CDCI,, 300 MHz) 8 7.69 (s, 1H), 7.85 (d, 1H), 8.42 (d, 1 H); mp: 233-235 °C (dec); MS (CI) 153 (MH' - CO= ).
Step B: 7-Chloro-furo(3 2-clovridine-2-cart~oxvlic aad chloride. 7-Chloro-faro[3,2-c]pyridine-2-carboxylic aad (prepared according to the method of Example 132, Step A, 8.94 g, 45.2 mmol) was combined with thionyl chloride (30 ml-) and sodium carbonate (9.59 g, 90.5 mmol) and heated to reflux for 16 h under nitrogen atmosphere. The cooled mixture was diluted with dichloromethane and filtered.
The filtrate was evaporated to give the title compound of Example 132, Step B as an orange oil, 9.19 g (94%). The aad chloride was used directly without further purificafjon.
Step C:1 R-(4=f4-(4-Chloro-faro(3.2-clayridine-2-carbonyl)-3R 5S-dimethyl-o,perazin-1-vtl-ovrimidin-2-vl~thyl butyrate. To a soluflon of 1 R-[4-(3R,5S-dimethyl-piperatin-1-yl~pyrimidin-2-y~-ethyl butyrate (prepared according to the method of Preparation Three, 13.04 g, 42.5 mmot) and triethytamine (8.61 g, 85.1 mmol) in dichlorbmethane (90 mL) was added 7-chloro-furo[3,2-c]pyridine-2-carboxylic acid chloride (prepared according to the method of Example 132, Step B, 9.1 g; 84.0 mmol) and stirred at ambient temperature for 2 h. The mixture was washed-successively with saturated aqueous sodium bicarbonate and water, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound of Example 132. Step C as. a viscous oil,18.9 g (91 %). 'H NMR
(CDCI,, 300 MHZ) 8 0.95 (t, 3H),1.40 (d, 6H),1.56 (d, 3H),1.67 (m, 2H), 2.38 (t, 2H), 3.25 (d, 2H), 4.33 (m, 2H), 4.75 (m, 2H), 5.66 (q,1 H), 6.40 (d, 1 H), 7.33 (s. 1 H), 7.41 (d, 1 H), 8.23 (d, 1 H), 8.35 (d, 1 H); MS (CI) 487 (MH'); [ot]p +33.3 (c 1.0, MeOH).
Step D: 1 R-l4-f4-(Furof3.2-clovridine-2-carbonyl)-3R.5S-dimethvt-nioerazin-1-vl1-pvrimidin-2-vll-ethyl butyrate. To a solution of 1 R-{4-[4-(4-chloro-furo(3,2-c]pyridine-2-carbonyl)-3R,5S-dimethyl-piperazin-1-yfj-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 132, Step C, 18.6 g, 38.4 mmol) in ethanol (1f0 mL) was added sodium carbonate (4.07 g, 38.4 mmol) and 10% palladium on carbon (6.10 g, 33 wt%). This mixture was hydrogenated at 50 psi hydn~gen for 6 h using a Parr apparatus. The catalyst was filtered and the filtrate was evaporated to an oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to gi~re the title compound of Example 132, Step D as a yellow oil, 14.2 g (82°~). 'H NMR
(CDCI,, 300 MHz) S 0.95 (t, 3H),1.40 (d. 6H),1.56 (d, 3H),1.67 (q, 2H), 2.38 (t, 2H), 3.25 (d, 2H), 4.33 (m, 2H), 4.75 (m, 2H), 5.68 (q, 1 H), 6.40 (d, 1 H), 7.37 (s, 1 H), 7.48 (d, 1 H), 8.22 (d,1 H), 9.04 (s,1 H); MS (CI) 452 (MH'); [ac]o +36.7 (c 1.0, MeOH).
Step E: Furoj3.2-clpyridin-2-v!-f4~-(1R-hvdroxv~thvll-ovrtmidin-.4-v(1-2R.6S-øimethyl-oioerazin-1-vtl~-methanone. 1 R-{4-{4-(Furo[3,2-c]pyridine-2-ca~onyl)-3R,5S-dimethyl-piperazin-1-yIj-pyrimidin-2-yl}-ethyl butyrate (prepared aooording to the method of Example 132, Step D, 5.48 8,12.1 mmol) was combined with concentrated hydrochloric aad (15 mL) and stirred at ambient temperature for 6 h. The mixture was poured into cold 6 M aqueous sodium hydroxide and extracted twice with ethyl acetate. The organic extract was washed once with water, dried over sodium sulfate and evaporated to a foam which crystallized from isopropyl ether to give the tibe compound as a white solid, 3.33 g (72%). 'H NMR (CDCl,, 300 MHz) S 1.43 (d, 6H).
1.52 (d, 3H), 3.37 (m; 2H), 4.38 (m, 2H), 4.71 (q,1 H), 4.83 (m, 2H), 6.43 (d,1 H), 7.38 (s, 1 H), 7.47 (m, 1 H), 8.22 (m, 1 H), 8.54 (d, 1 H), 8.58 (d, 1 H), 9.04 (s, 1 H); inp: 142-,, 143 °C; MS (CI) 382 (MH'); [aJ~ +15.9 (c 1.0, MeOH). , , Example 133 f4-f2-f1R-Hvdroxv-ethyll-pvrimidin-4-yll-2R 6S-dimethyl-piDerazin-1-vl}-(4-ovrrolidin-1-yl-furof3.2-cipvridin-2-vl)-methanone.
~~~~Me Me A solution of 1 R-{4-[4-(4-chloro-furo[3,2-c]pyridine-2-carbonyl~3R,5S-dirrtethyf-piperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 132, Step C, 0.046 g, 0.11 mmol) in pyrrolidine (0.037 mL, 0.44 mmol) was heated to reflux for 14 h and evaporated to give the title compound as a tan solid, 0.04 g (80%). 'H NMR (CDCI,, 300 MHz) 81.43 (d, 6H), 1.53 (d, 3H), 2.08 (m, 4H), 3.43 (m; 2H), 3.77 (m, 4H), 4.43 (m, 2H), 4.71 (q, 1 H), 4.92 (m, 2H), 6.43 (d, 1 H), 6.70 (d, 1 H), 7.60 (s, 1 H), 8.08 (d, 1 H), 8.23 (d, 1 H); MS (CI) 451 (MH').
Examples 134 to 158 I ' Examples 140 and 142 to 158 were prepared from the appropriate starting materials in a manner analogous to the method of Example 131. Example 141 was prepared from the appropriate starting materials in a manner analogous to the method of Example 133.
HO
R,e. "" Me N-R"N N ~ / N
Example R" R' R" mp (C) MS (MH') 134 cyclopropylcarbonyl2R-Me 6S-Me 110-111 305 135 cyclobutylcarbonyl2R-Me 6S-Me 134-135 319 136 cyclopentylcarbonyl2R-Me 6S-Me 199-200 333 137 tert-butylcart~onyl2R-Me 6S-Me 168-169 321 WO 00/59510 PGTlIB00l00296 'Me O
z~
Ar R.- ', Exampl Ars R" R" mp (°C) MS (MH') a 138 benzofuran-2 yl 2R-Me 6S-Me 124-126 381 139 furo[3,2-cjpyridin-2-ylH H 55-65 354 140 faro[3,2-cjpyridin-2-yl3R-Me 5S-Me , 382 141 morphofin-4 y!-furoj3,2-2R-Me 6S-Me ~ 467 cjpyridin-2-yl 142 faro[2,3-c]pyridine-2-yl2R-Me 6S-Me 129-131 382 143 5-chtorobenzofuran-2 H H 387, 389 yl 144 5-chlorobenzofuran-2-yl3R-Me 5S-Me 114-116 415, 417 145 5.7-dichtorobenzofuran-2-yl2R-Me 6S-Me 136-137 450, 452 146 5,7-dichtorobenzofuran-2-yl3R-Me 5S-Me 152-153 450, 452 ~
147 5-nitrobenzofuran-2-yl2R-Me 6S-Me 153-154 426 148 5,7-dimethyibenzofuran-2-yl3R-Me 5S-Me 134-136 409 149 5-methoxybenzofuran-2-yl3R-Me 5S-Me 137-138 411 150 5-methoxybenzofuran-2-yl2R-Me 6S-Me 118-119 411 151 imidazo[1.2-a]pyridin-2H H 149-150 353 yl 152 imidazo[1.2-a]pytidin-23R-Me 5S-Me 171-173 381 yl 153 imidazo[1.2-a]py~idin-2-yl2R Me 6S-Me 147-149 381 154 6-chtoroimidazo[1,2- 2R-Me 6S-Me 76-84 416, 418 b]pytidazin-2-yl 155 6-methylimidazo[1,2- 3R-Me 5S-Me 164-165 395 ajpyridin-2-yl ' 156 benzoxazol-2-yl 2R-Me 6S-Me i26-127 382 157 4-cyanophenyl 2R-Me 6S-Me 90-a00 366 158 6-hydroxy-pyridazin-3-yl2R-Me 6S-Me 359 Example 159 1-f4-f2-l1 R-Hvdroxv-ethyl)-ovrimidin-4-vll-2R.6S-dimethvl-oioerazin-1-vl~-2-(6-methvl-pvridin-3 yloxv)-ethanone.
N \~--N
Me ~~"
~H Me Step A: 1 R-f4-(4-Chloroacetvl-3R.5S-dimethvl-~i~erazin-1-yl?-ovrirnidin-2-vll-ethyl bu te. To a solution of 1 R-(4-(3R,5S-dimethyf-piperazin-1-yt~pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Preparation Three, 9.69 g, 31.3 mmol) and fiethylamine (4.74 g, 46.9 mmol) in chloroform (150 mL) was added dropwise chloroacetyl chloride (3.00 mL, 37.6 mmol) at 0 °C then stirred at ambient temperature for 12 h under nitrogen atmosphere. The mixture was washed success'rvefy with saturated aqueous sodium bicarbonate and water, and the organic layer was dried over sodium sulfate, treated with activated carbon, and filtered. The filtrate was concentrated to obtain an oil which was purfied by flash chromatography (9:1 dichloromethane:methanol) to give the title compound of Example 159, Step A as an oil, 8.98 g (75%). 'H NMR (CDCI,, 300 MHz) 8 0.96 (d, 3H), 1.32 (d, 6H), 1.59 (d, 3H), 1.71 (m, 2H), 2.40 (t, 2H), 3.28 (m, 2H), 4.28 (s, 2H), 4.35 (m, 4H), 5.68.(q, 1 H), 6.41 (d, 1 H), 8.23 (d, 1 H); MS (CI) 383, 385 (MH').
Step B: 1 R-l4-f3R.5S-Dimethvl-4-fl6-methyl-pvridin-3-vloxv~-acetvll-pioerazin-pvrimidin-2-v1)-ethyl butyrate. To a suspension of sodium hydride (60%
dispersion in oil, 0.05 g, 1.3 mmol) in tetrahydrofuran (2 mL) was added a solution of 6-methyl-3-pyridinol (0.14 g, 1.3 mmol) in tetrahydrofuran (3 mL) at 0 °C under nitrogen atmosphere and stirred for 0.5 h warming to ambient temperature. Next, a solution of 1R-[4-(4-chloroaoetyl-3R,5R~iimethyl-piperazin-1-yl)-pyrimidin-2-yQ-ethyl butyrate (prepared according to the method of Example 159, Step A, 0.40 g, 1.1 mmol) in tetrahydrofuran (2 mL) was added and fefluxed for 1 h. The mixture was diluted with dichloromethane.and washed with saturated aqueous sodium bicarbonate; dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash chromatography (91 dichloromethane:methanol) to give the title compound of Example 159, Step B as an oil, 0.31 g (66%). 'H NMR (CDCI,, 300 MHz) b 0.96 (d, 3H), 1.32 (d, 6H), 1.59 {d, 3H), 1.71 (m, 2H), 2.40 (t. 2H), 2.46 (s, 3H), 3.28 (m, 2H), 3,78 (s, 2H), 4.35 (m, 4H), 5.68 (q, 1 H), 6.41 (d, 1 H), 6.83 (m, 1 H). 7.14 (m, 1 H), 8.08, (d, 1 H), 8.23 (d, 1 H); MS (CI) 456 (MH').
Step C: 1~4-f2-l1R-Hvdroxy-ethvl~oyrimidin-4-vll-2R.6S-dimethvl-oiDerazin-1-v(1-2-(6-methyl-pyridin-3-vloxv~ethanone. 1 R-(4-{3R,5S-Dimethyl-4-[(6-methyl-pyridin-3-yioxy)-acetylj-piperazin-1-yl}-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Example 159, Step B, 0.30. g, 0.65 mmol) was combined with concentrated hydrochloric aad (3 mL) and stirred at ambient temperature for 6 h. The mixture was neutralized with 6 N aqueous sodium hydroxide to pH 9 and extracted twice with ethyl acetate. The organic extract was washed once with water, dried over sodium sulfate and filtered. The filtrate was concentrated to an oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound as a white foam, 0.14 g (55%). 'H NMR (CDCI,, 300 MHz) 8 1.38 (d, 6H), 1.55 (d, 3H), 2.46 (s, 3H), 3.28 (m, 2H), 3.76 (s, 2H), 4.35-4.65 (m, 4H), 4.67 (q, 1 H), 6.38 (d, 1 H), 6.83 (m, 1 H), 7.11 (m, 1 H), 8.08, (d, 1 H), 8.21 (d, 1 H); mp: 55-65 °C; MS
(CI) 330 (MH'); [ajD
+16.0 (c 1.0, MeOH).
Example 160 1-(4-(2-(1R-Hydroxy-ethvl~oyrimidin-4-yft-2R 6S-dimethyt-oioerazin-1-vll-2-(ovrimidin 2-vlsulfanvll-ethanone.
Me S
N~ ~ N
\ N ~ ~\
~ O N
Me "' ~ tulea OH
Example 160 was prepared from the appropriate starting materials in a manner analogous to example 159. 'H NMR (CDCI3, 300 MHz) 81.38 (m, 6H),1.48 (d, 3H), 3.28 (m, 2H), 3.96 (s, 2H), 4.35 (m, 4H), 4.65-4.97 (m, 3H), 6.28 (d, 1 H), 6.93 (m,1 H), 7.11 (m,1 H), 8.21 (d,1 H), 8.45, (m, 2H); mp: 60-70 °C; MS (CI) 389 (MH'); [aJ~ +16.8 (c 1.0, MeOH).
pCTIIB00f00296 lExamole i 61 4-[2-f 1 R=Hvdroxv-ethyl)-ovrimidin-4-v(1-2R.6S-dimeth~l-pioerazine-1-carboxylic acid , , phenW ester.
~~~~Me Me Step A: 4-I2-f 1 R-Butyrvloxy-ethvll~avrimidin-4-vll-2R.6S-dimethyf-oioerazine-carboxvlic acid ohenvl ester. To a solution of 1 R-[4-(3R,5S-dimethyl-piperazin-1 yl~
pyrimidin-2-ylj-ethyl butyrate (prepared according to the method of Preparation Three, 0.30 g, 0.98 mmol) and triethytamine (0.20 g, 1.9 mmof) in dichloromethane (5 m~) was added phenyl chloroformate (0.76 g, 4.8 mmot) and stirred at ambient temperature for 2 h under nitrogen atmosphere. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain an oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound of Example 161, Step A as an oil, 0.35 g (84%). 'H NMR (CDCh, 300 MHz) S 0.96 (d, 3H), 1.32 (d, 6H), 1:59 (d, 3H), 1.71 (q, 2H), 2.40 (t, 2H), 3.28 (m, 2H), 4.35 (m, 4H), 5.68 (q, iH), 6.41 (d,1H), 7.12 (d, 2H), 7.22 (m,1 H), 7.35 (m, 2H), 8.23 (d,1 H); MS (CI) 427 (MH');
[a]~ +39.6 (c 1.0, MeOH).
Step 8: 4-f2-(1 R-Hydroxy-ethvl~-oYrimidin-4-vll-2R.6S-dimeth~l-nioerazine-'~
carboxylic aad ohenvl ester: 4-[2-(1 R-Butyryloxy~thyl)-pyrimidin-4-y(}-2R,6S-dimethyt-piperazine-1-carboxylic add phenyl ester (prepared according to the method of Example 161, Step A, 0.31 g, 0.70 mmol) was combined with concentrated hydrochloric add (5 mL) and stirred at ambient temperature for 6 h. The macbune was neutralized with 6 N aqueous sodium hydroxide to pH 9 and extracted twice with etfiyl acetate: The organic extract was washed once with water, dried over sodium sulfate and filtered. The filtrate was concentrated to an oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound as a white solid, 0.12 g (81 %). 'H NMR (CDC13, 300 MHz) 81.41 (d, 6H),1.51 (d, 3H), 3.34 (m, WO 00/59510 PCT/IB00~0296 2H), 4.43 (m, 2H), 4.52 (m, 2H), 4.71 (q, 1 H), 6.46 (d, 1 H), 7.12 (m; 2H), 7.23 (m, 1 H), 7.35 (m, 2H), 8.23 (d, 1 H); MS (CI) 357 (MH'); [aJp +16,9 (c 1Ø MeOH).
Example 162 4-f2-l1 R-H~droxv-ethyl)-avrimidin-4-vll-2R.6S-dimethyl-oioerazine-1-carboxylic acid g~ridin-3-yl ester.
HO
Me ~~~~Me / \ o ~ N_ N- h--N N \ / N
Me Step A: 4:I2-l1 R-Hvdroxv-ethyl)-QVrimidin-4-vll-2R.6S-dimethvl-fli~erazine-1-carbonyl chloride. To a solution of 1 R-[4-(3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Preparation Three, 3.61, 11.8 mmol) and pyridine (0.93 g, 11.8 mmol) in dichioromethane (50 mL) was added triphosgene (1.17 g, 3.9 mmol) and stirred at ambient temperature for 16 h under ri~trngen atmosphere. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain an oil which was purified by flash chromatography (ethyl acetate) to give the title compound of Example 162, Step A as a yellow oil, 2.12 g, (51 %). 'H NMR (CDCI,, 300 MHz) 8 0.90 (t, 3H),1.31 (d, 6H), 1.56 (d, 3H), 1.68 (m, 2H), 2.38 (t, 2H), 3.21 (m, 2H), 3.88-4.40 (m, 4H), 5.66 (q, 1H), 6.43 (d, 1 H), 8.22 (.d, 1 H); MS (CI) 369, 371 (MH').
Step B: f4-I2-(1R-Butvrvloxv-ethyl?-DVrimidin-4-vl1-2R.6S-dimeth~r!-oiDerazine~-1-carboxylic add oyridin-3-v! ester. To a suspension of sodium hydride (60%
dispersion in oil, 0.046 g, 1.15 mmol) in anhydrous tetrahydrofuran (8 mL) was added 3-hydroxypyridine (0.11 g,1.15 mmol) at 0 °C. After a homogeneous solution was obtained, a solution of 4-[2-(1 R-hydroxy-ethyl)-pyrimidin.~-ytj-2R,6S-dimethyl-piperazine-1-cariaonyl chloride (prepared according to the method of Example 162, Step A, 0.36 g, 0.96 mmol) in tetrahydrofuran (3 mL) was added at 0 °C
and this mixture was warmed to ambient temperature, then heated to reflux far 6 h. The mixture was quenched in water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated to obtain an oil, which was purified by flash chromatography (ethyl acetate) to give the title compound of Example 162, Step B as a semi-solid, 0.31 g (78%). 'H NMR (CDCI,, 300 MHz) 8 0.90 (t, 3H), 1.35 (m, 6H), 1.61 (d, 3H), 1.69 (m, 2H), 2.41 (t, 2H), 3.30 (m, 2H), 4.11-4.38 (m, 4H), 5.69 (q, 1 H), 6.41 (d, 1 H), 7.32 (m;
1 H), 7.52 (m, 1 H), 8.22 (d, 1 H), 8.46 (s, 1 H), 8.48, (d, 1 H); MS (CI) 428 (MH').
Step C: 412-f 1 R-Hvdroxv-ethvl~ovrimidin-4-yt1-2R.6S-dimethv!-nioerazine-1-carboxylic acid ovridin-3-of ester. {4-[2-(1R-Butyryloxy-ethyl~pyrimidin-4-yl]-2R,6S-dimethyi-piperazine}-1-carboxylic acid pycidin-3-yl ester (prepared according to the method of Example 162, Step B, 0.31 g, 0.T0 mmol) was combined with concentrated hydrochloric acid (5 mL) and stirred at ambient temperature for 6 h. The mixture was neutralized with 6 N aqueous sodium hydroxide,to pH 9 and extracted twice with ethyl acetate. The extract was washed once with water, dried over sodium sulfate and filtered. The filtrate was concentrated to an oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to give. the title compound as a white solid, 0.12 g (81 %). 'H NMR (CDCI,, 300 MHz) b 1.41 (d, 6H), 1.51 (d, 3H), 3.33 (m, 2H), 4.25-4..45 (m, 4H), 4.71 (q, 1 H), 6.43 (d, 1 H), 7.33 (m, 1 H), 7.56 (m, 1 H), 8.23 (d, 1H), 8.25 (d, 1H), 8.48 (d, 1H); MS (CI) 358 (MH'); [a]o +18.5 (c 1.0, MeOH).
Example 163 4-(2-f1 R-Hvdroxv-ethvl~ovrimidin-4-vIl-2R-phenyl-pioerazine-1-carboxylic aad p~rridin-3-vl ester.
HO
~~~~Me Step A: 1 R-f4-l3R-Phenyl-o oerazin-1-vll-ovrimidin-2-v>t-ethyl butyrate. To a solution of (R~2-phenylpiperazine (0.48 g, 3.0 mmol, Indian J. Chem. Sect B 1994, 33.
285) and triethylamine (1.21 g, 12.0 mmol) in tetrahydrofuran (10 mL) was added (R}-1-(4-chloropyrimidin-2-ylrethyl butyrate (prepared according to the method of Preparation Seven, 0.68 g, 3.0 mmot) and stirred at ambient temperature for 18 h. The mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl ' WO 00/59510 PGT/IB00/00296 acetate. The combined organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product which was purified by flash chromatography (95:5 dichloromethane:methanol) to give the title compound of F~cample 163, Step A as a viscous oil, 0.70 g (67%). 'H NMR (CDCI,, 300 MHz) 8 0.95 (t, 3H), 1.56 (d, 3H), 1.67 (m, 2H), 2.40 (t, 2H), 3.55 (m, 2H), 4.0 (m, 2H), 4.32 (m, 2H), 4.70 (m, 1 H), 5.69 (q, 1 H), 6.49 (d, 1 H), 7.40 (m, 5H), 8.21 (d, 1 H); MS (CI) 355 (MH').
Step B: 4-f2-(1 R-Butvrvloxv-ethvl~pvrimidin-4-vfl-2R-phenyl-piperazine-1-carboxylic acid pvridin-3-vl ester. To a solution 1R-[4-(3R-phenyl-piperazin-1-yl)-pyrimidin-2-yi3 ethyl butyrate (prepared according to the method of Example 163, Step A,~~0.22 g, 0.6 mmol) and triethylamine (0.31 g, 3.1 mmol) in toluene (5 mL) was added dipyridin-3-yl carbonate (0.67 g, 3.1 mmol) and.heated to reflex for 3 h. The mixture was poured into saturated aqueous sodium bicarbonate, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound of Example 163, Step B as a yellow oil, 0.22 g (73%). MS
(CI) 476 (MH').
Step C: 4-f'2-l1R-Hvdroxv-ethvf~ovrimidin-4-vf1-2R=ohenvl niperazine 1-carboxylic add pvridin-3-vl ester. 4-[2-(1 R-Butyryfoxy-ethyl)-pyrimidin-4-yt]-2R-phenyt-piperazine-1-carboxylic aad pyridin-3-yl ester (prepared according to the method of Example 163, Step B, 0.21 g, 0.4.4 mmol) was combined with concentrated hydrochloric aad (2 mL) and stirred at ambient temperature for 6 h. The mixture was neutralized with 6 N aqueous sodium hydroxide to pH 9 and extracted twice with ethyl acetate. The combined extracts were washed once with water; dried over sodium sulfate and filtered. The ftltrate was concentrated to an oil which was purifted by flash chromatography (9:1 dichloromethane:methanol) to give the title compound as a white solid, 0.13 g (73%). 'H NMR (CDCI,, 300 MHz) 81.55 (d, 3H), 3.55 (m, 2H), 4.0 (m, 2H), 4.32 (m, 2H), 4.71 (m, 1 H), 4.75 (q, 1 H), 6.40 (d, 1 H), 7.18-7.41 (m, 7H), 824 (d, 1 H), 8.35 (br s, 1 H), 8.45 (d, 1 H); MS (Ct) 408 (MH').
Examples 164 to 173 Examples 164 to 173 were prepared from the appropriate starting materials in a manner analogous to the method of Example 163.
wo oo~s9sio rc~rnBOOioo2~
HO
Ar' , Rs . ..., Me O ~ N-~N N ~ / N
O
R' Example , R' R Ar' mp (C) MS (MH') 164 3R-Me 5S-Me phenyl 357 165 3R-Me 5S-Me 2-methyl-pyridin-3-yl65-75 372 166 H H ~ pyridin-3-yl 107-110 330 167 3R-Me 5S-Me 2-d~ioro-pyridin-3-yl60-70 392, 394 168 3R-Me 5S-Me 5-chloro-pyridirr3-yl65-69 392, 394 169 3R-Me 5S-Me isoquinolin-5-yl60-70 407 170 3R-Me 5S-Me 4-chloro-pyridin-3-yl60-70 392, 394 171 3R-Me 5S-Me 6-methyl-pyridin-3-yl60-70 372 172 2RS- H pyridin-3-yl 388 CHZOMe 173 2RS-COzEt H' pyridirr3-yl 4p2 Example 174 (Rl~-Benzvl-1-f2-( 1-hvd roxv~thvtl-ovrtmidin-4-vt1-oioeridin-4-ot.
~~»Me Step A: (R>-1.-(4-(4-Benzvl-4-hvdroxv-oic~eridin-1 vll-ovrimidin-2-vll-ethv) acetate. To a solution of 4-tienzy!-4-hydroxypiperidine (0.95 g, 5.0 mma<) and triethytamine (0.51 g, 5.0 mmol) in dichioromethane (10 mL) was added (R)-1-(4-methanesulfonyloxy-pyrimidin-2-yly-ethyl butyrate (prepared according to the method of Preparation Eight, 1.23 g, 4.0 mmol) and stirred at ambient temperature for 18 h. The mixture was WO 00/59510 pCT/IB00100296 washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filten:d. The filtrate was evaporated to an oil which was purified by flash chromatography (95:5 dichloromethane:methanol) to give the title compound,of Example 174, Step A as a viscous oil, 0.99 g (52%). 'H NMR (CDCIS, 300 MHz) s 0.95 (t, 3H),1.53 (d, 3H), 1.65-1.78 (m, 4H), 1.88 (m, 2H), 2.08 (m, 2H), 2.48 (t, 2H), 3.45 (m, ZH), 4.42 (tar s, 1 H), 5.68 (q, 1 H), 6.41 (d, 1 H), 7.30-7.48 (m, 5H), 8.18 (d, 1 H); MS (Cl) 384 (MH').
Step B: (R~4-Benzvl-1-f2-(1-hvdroxv-ethvl~-ovrimidin-4-vIl-oioeridin~-ol. To a solution of (R~1-[4-(4-benzyl-4-hydroxy-piperidin-1-y(~pyrimidin-2-ytJ-ethyl butyrate (prepared accordEng to the method of Example 174, Step A, 0.20 g, 0.52 mmol) in methanol (5 mL) was added 1 N aqueous sodium hydroxide (1 mL) and timed for 4 h at ambient temperature. The mixture was diluted with dichloromethanq and washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate v~ras evaporated to give the title compound as a foam, 0.12 g (68%). 'H NMR (CDCI', 300 MHz) s 1.49 (d, 3H),1.74 (br s, 2H),1.82 (m, 2H), 2.08 (m, 2H), 3.42 (m, 2H), 4.42 (br s, 1 H), 4.7i (q, i H), 6.43 (d, 1 H), 7.33-7.48 (m, 5H), 8.21 (d, 1 H); MS (Cl) 314 (MH').
Example 175 fR?-4-Phenv!-1-f2-( 1-hvdroxv~thvl~-ovrimidin-4-yp-nineridin-4-ol.
Me Example 175 was prepared from the appropriate starting materials in a manner analogous to the method of Example 174. mp: 114 °C; MS (CI) 300 (MH*).
Example 176 (R~1-f4-f4-(3-Chlorobenzvtidene?-niperidin-1- ~rr~midin-2 vll-Methanol.
HO
CI ~ / ....Me N
N ~ 'N
Step A: 1-f4-~3-Chlorobenzvlidene)-oioeridine-1-v(1-1~-carboxylic acid tert-butyl ester.
To a suspension of 4-chlorobenryltriphenylphosphonium chloride (4.23 g, 10.0 mmol) in tetrahydrofuran (40 mL) was added n-butyllithium in hexanes (2.5 M in hexanes, 4.4 mL, 11.0 mmol) at 0 °C under nitrogen atmosphere and stirred 0.5 h. A
solution of 4-oxo-piperidine-1-carboxylic aad tert-butyl ester (prepared according to the method of Example 101, Step A, 1.99 g, 10.0 mmol) in tetrahydrofuran {10 mL) was added at 10-°C and warmed to ambient temperature. The mixture was evaporated to an oil which was purified by flash chromatography (9:1 hexanes:ethyl acetate) to give the title compound of Example 176, Step A as an oil, 2.63 g (85%). 'H NMR (CDCI,, 10 MHz) 8 1.39 (s, 9H), 2.48 (m, 2H), 2.57 (m, 2H), 3.68-3.82 (m, 4H), 6.36 (s, 1H), 7.08 (m, 1 H), 7.12-7.28 (m, 3 H); MS (CI) 308 (MH').
Step 8: 4-l3-Chloro-benzviidene>-piperidine hydrochloride. To a solution of 1-[4-(3-chlorobenzylidene)-piperidine-1-y(j-1-carboxylic aad tert-butyl ester (prepared according to the method of Example 176, Step A, 2.5 g, 8.1 mmol) in dichloromethane 15 (20 mL) was added hydrogen chloride (4 M in dioxane, 4.0 mL, 16.0 mmol) at ambient temperature and stirred for 4 h. The mixture was evaporated to dryness, suspended in ethyl ether and filtered to give the title compound of Example 176, Step B
as a white solid. 1.63 g (82%). 'H NMR (CDCh/D20, 300 MHz) b 2.48 (m, 2H), 2.57 (m, 2H), 3.63 (m, 2H), 3.77 (m, 2H), 6.36 (s,1 H), 7.10 (m, 1 H), 7.12-728 (m, 3H);
rr~: u~-~s~ ~c.
Step C: IR?-1-f4-f4-l3-Chloro-benzvlidenel-piperidin-1-vl1-ovrimidin-2-vll-ethyl butyrate. To a solution of 4-(3-chlorobenzylidene~piperidine hydrochloride (prepared according to the method of Example 176, Step B, 0.46 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) in dichloromethane (10 mL) was added (R}-1-(4-chloropyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Five, 0.54 g, 22 mmol) and stirred at ambient temperature for 12 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product which was purified by flash chromatography (95:5 dichforomethane:methanol) to give the title compound of Example 176, Step C as a viscous oil, 0.64 g (80%). 'H NMR (CDCI,, 300 MHz) 8 0.95 (d, 6H),1.51 (d, 3H), 1.68 (m, 2H) 2.35 (m, 2H), 2.47-2.64 (m, 4H), 3.67-3.75 (m, 4H), 5.68 (q, 1 H), 6.36 (s, 1 H), 6.40 (d, 1 H), 6.98 (m, 1 H), 7.12-7.28 (m, 3H), 8.18 (m,1 H); MS (CI) 400 (MH').
WO 00/59510 PCTIIBOOf00Z96 Step D: lR)-1-~-[4-(3-Chloro~enzYtid~,ne~viperidin-1=3~(-vvrimidin-2-vl~-ethanol. To a ,"
solution of (R}-1-{4-[4-(3-chforo-benzylidene~piperidin-1 yfJ-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 176, Step C, 0.62 g, 1.55 mmol) in methanol (8 mL) was added 1 N aqueous sodium hydroxide (1 mL) then stirred for 4 h at ambient temperature. The mixture was diluted with chlorofom~ and washed once with water, once with saturated aqueous sodium chloride,and.the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product which was purified by flash chromatography (95:5 dichloromethane:methanol) to give the title compound as a white solid, 0.31 g (61 %).
'H NMR (COCI,, 300 MHz) b 1.51 (d, 3H), 2.46 (m, 2H), 2.56 (m, 2H), 3.07 (m, 2H), 3.77 (m, 2H), 4.35 (d,1 H), 4.69 (q,1 H), 6.36 (s, 1 H), 6.40 (d,1 H), 7.07 (m, 1 H), 7.12-7.28 (m, 3H), 8.18 (m, 1H); mp: 45-S5 °C; MS (CI) 330 (MH'); [a]o +16,8 (c 1.0, MeOH).
Examples 177 to 181 ' 15 Examples 177 to 781 were prepared from the appropriate starting materials in a manner analogous to the method of Example 176.
HO
~~~~Me R'z N ..
N ~ ,N
R
Example R'~ it's' mp (C) MS ~M(~
177 4-chlorophenyi H 33p, 332 178 (E}-2-phenyl-ethen-1-ylH
179 benzoyl H 44-59 324 180 phenyl phenyl 108-109 372 181 . phenyl Pyrid-2-yl98-101 373 Example 7 82 jR~,l~4-L4-P~rridin-2-vlmethvl-niflera~in-1-vl~vvrimidin-2-yg-ethanol.
N
N ~--J N
Me ~,..
OH
Step A: (R>-1-f4-l4-Pvridin-2-vlmethvl-nioerazin-1-vl)wrimidin-2-vll-ethyl acetate. To a solution of (Rj-1-[4-piperazin-1 yl~pyrimidin-2-ytj-ethyl acetate (prepared according to the method of Preparation Two, 1.55 g, 6.2 mmol) and triethyfamine (0.86 mL, 6.2 mmol) in tetrahydrofuran (20 mL) was added 2-picoylchloride hydrochloride (1.01 g, 6.2 mmol) at ambient temperature and stirred for 1 h. The mixture was diluted with water and extracted twice with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered, and the filtrate was concentrated to an oil which was purified by flash chromatography (95:5 dichtoromethane:methanol) to give the title compound of Example 182, Step A, 0.98 g (46%). 'H NMR (CDCl3, 300 MHz) 8 1.58 (d, 3H), 2.15 (s, 3H) 2.62 (t, 4H), 3.72 (t, 4H), 3.75 (s, 2H), 5.67 (q, 1 H), 6.35 (d, 1 H), 7.22 (m, 1 H), 7.46 (d, 1 H), 7.73 (m,1 H), 8.21 (d, 1 H), 8.62 (d,1 H); MS
(CI) 342 (MH').
Step B: iR)-1-f4-(4-Pvridin-2ylmethvl-pioerazin-1-vl)-ovrimidin-2-vll-ethanol.
To a solution of (R)-t-(4-(4-pyrtdin-2-ylmethyl-piperazin-1-yl}-pyrimidin-2-yQ-ethyl acetate (prepared acxording to the method of Example 182, Step A, 0.14 g, 0.33 mmot) in dioxane (6 mL) was added at ambient temperature 6 N aqueous potassium hydroxide (0.5 mL). After stirring for 3 h the solution was diluted with ethyl acetate and washed twice with water. The organic Layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound as a white solid, 0.09 g (69%). 'H NMR (CDCI,, 300 MHz) b 1.52 (d, 3H), 2.38-2.59 (m, 4H), 3.72-3.77 (m, 6H), 4.69 (q, 1 H), 6.37 (d, 1 H), 7.22 (d,1 H), 7.41 (d, 1 H), 7.69 (m, 1 H), 8.21 (d, 1 H) 8:58, (d,1 H); mp: 68-70 °C; MS (CI) 300 (MH'); [a]~ +162 (c 1.0, MeOH).
Examples 183 to 187 Examples 183 to 187 were prepared from the appropriate starting materials in a manner analogous to the method of Example 182.
HO , ~~~~Me N_ R°- ~ N
Example R' mp (C) MS (MH7 183 phenylmethyl 299 184 ' isoquinolin-2-yl-methyl' 350 185 benzothien-2-yl-methyl 355 186 benzothiazot-2-yl-methyl356 187 benzofuran 2-yl-methyl v 339 Example 188 1 R-f4-f2R.6S-Dimethvl-.4-l2-f1.2.41triazof-1-vl-ovrimidin-4-yl~oiaerazin-1-vl1-nvrimidin-2-vtl-ethanol.
~~Me Step A: 4-(3R.5S-Dimethvl-oioerazin-1-v1~2-methanesulfonvl-ovrimidine. To a solution of cis-2,6-dimethylpiperazine (10.7 g, 94.1 mmol) and triethylamine (9.52 g, 94.1 mmol) in chloroform (300 mL) was added 4-chloro-2-methanesulfonylpyrimidine (15.1 g, 78.4 mrnol; Hetemcycles 1985, 23, 611) at ambient temperdbime and stin~ed for 1 h. The mixture was partitjoned with saturated aqueous sodium bicarbonate and the separated organic layer was washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filten:d: The filtrate was evaporated to an orange solid which was slurried in ethyl ether and filtered to give the title compound of Example 188, Step A as a white solid.
15.4 g (73%). 'H NMR (CDCI,, 400 MHz) 81.01 (m, 6H), 2.35-2.78 (m, 4tfi), 2.85 (s, 3H), 3.32 (m, 2H), 6.81 (d, 1 H), 8.2 (d, 1 H); mp: 182-9 ~3 °C; MS
(CI) 301 (MH').
Step B: 4-(3R.5S-Dimethvl-oioerazin-1-vl)-2-f1.2.41triazol-1-vl-o~rimidine. To a slurry of sodium hydride (60% dispersion in oil, 0.37 g; 9.4 mmol) in dimethylfom~amide (5 mL) was added a solution of 1,2,4-triazole (0.67 g, 9.4 mmol) in dimethylformamide (4 mL) at 0 °C under nitrogen atrr~sphere. After 10 min, a solution of 4-(3R,5S-dimethyl-piperazin-1-y1~2-methanesulfonyl-pyrimidine (prepared according to the method of Example 188, Step A, 2.54 g, 9.4 mmol) in warm dimethylfom~amide (5 mL) was added dropwise and stirred at ambient temperature for 2 h then heated to 100 °C
for 0.5 h. Thelmixture was quenched in saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound of Example 188, Step B as an oil, 0.50 g (62%). 'H NMR (CDCI,, 400 MHz) S 1.01 (m, 6H), 2.35-2.88 (m, 5H), 3.32 (m,1H), 6.81 (d,1H), 8.16-823 (m, 2H), 9.25 (d, 1 H); MS (CI) 260 (MN').
Step C: 1R-f4-f2R.6S-Dimethvl-4-l2-(1.2 3]triazol-1-vl-ovrimidin-4-vi)-oioerazin-1-v(1 p~rrimidin-2-vll-ethyl butvrat~. To a solution of 4-(3R,5S-dimethyl-piperazin-1~t)-2 (1,2,4)triazol-1-yl-pyrimidine (prepared according to the method of Example 188, Step B, 0.46 g,1.8 mmol) in acetonitrile (3 mL) was added (R~1-(4-methanesulfonyloxy-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Eight, 0.57 g, 2.0 mmol) and heated to refiux for 6 h under nitrogen atmosphere. The mixture was quenched in saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound of Example 188, Step C as an oil, 0.22 g (54%). 'H NMR (CDCI,, 400 MHz) b 0.95 (t, 3H),1.51 (m; 6H), 1.54 (d, 3H), 1.63 (m, 2H), 2.38 (t, 2H), 3.38 (m, ZH), 4.33-4.64 (m, 4H), 5.68 (q,1 H), 6.28 (d, 1 H), 6.58 (d,1 H), 8.10 (s,1 H), 8.26-8.32 (m, 2H), 9.10 (d, 1 H); MS (Cl) 452 (MH'); [a]p +50.0~(c 1.0, MeOH).
' WO 00/59510 PCTIIB00/00296 Step D: 1R-l4-f2R.6S-Dimethvl-4-l2-f1.2.41triazol-1-vl-pyrimidin-4-vl)-oioerazin-1-vll-pvrimidin-2-vl)-ethanol. 1 R-{4-[2R,6S-Dimethyt-4-(2-j.1,2.3jtriazoi-1-yl-pyrimidin-4-yl)-piperazin-1-y(j-pyrimidin-2-yl}-ethyl butyrate (prepared acxording to the method of Example 188, Step C, 0.18 g, 0.40 mmol) was combined with concentrated hydrochloric acid (2 mL) and stirred at ambient temperature for 4 h. The mixture was quenched in saturated aqueous sodium bicarbonate and extracted twio~ with ethyl acetate. The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash ~
, chromatography (9:1 dichloromethane:methanol) to give the title compound as a white solid, 0.13 g (87%). 'H NMR (CDCI,, 400 MHz) 81.31 (d, 6H), 1.51 (d, 3H), 3.42 (m, 2H), 4.42-4.73 (m, 5H), 6.41 (d, 1 H), 6.56 (d, 1 H), 8.12 (s, 1 H), 8.24 {d;
1 H), 8.30 (d, 1 H), 9.10 (s, 1 H); MS (CI) 382 (MH'); [ajo +18.6 (c 1.0, MeOH).
Examples 189 to 195 Examples 189 to 195 were prepared from the appropriate starling materials in a manner analogous to the method of Example 188.
HO
R" R6 .."Me ~N N-N~ ~ N
s s R' Example R" R' R' mp (C) MS (MH') 189 2-hydroxyphenyl 2R-Me 6S-Me 60-70 407 190 imidazol-1-yl 2R-Me 6S-Me 60-70 381 191 [1,2,3]triazol-1-yl 2R-Me 6S-Me 70-80 382 192 , pyrrol-1-yl 2R-Me 6S-Me 70-80 380 193 4-methylimidazol-1-yl2R-Me 6S-Me 70-80 395 194 2-methylimidazol-1 2RMe 6S-Me 70-80~ 395 yl 195 2.4~imethylimidazol-1-yl2R-Me 6S-Me 70-80 409 Examote 196 , 1R-f4-f2R 6S-Dimethvl-4-(4-f1 2 4ltriazol-1-vl-pyrimidin-2-yll-oioerazin-1-yll-pyrimidin-2-vl?-ethanol. , N~N HO
'N Me ~~~~Me N ~ N-~~N N ~ / N
N
Me Step A: 2-Thiomethvl-4-f1.2.41triazol-1-vl-pvrimidine. To a slurry of sodium hydride (60% dispersion in oil, 24.2 g, 605 mmol) in dimethylformamide (800 mL) was added a solution of 1,2,4-triazole (0.67 g, 9.4 mmol) in dimethylfom~amide (4.0 mL) at 0 °C
under nitrogen atmosphere. After 10 min, a solution of 4-chloro-2-methylthio-pyrimidine (97.2 g, 605 mmol) in dimethyffom~amide (200 mL) was added dropwtse at 10 °C and stirred at ambient temperature for 14 h: The ni~xture was quenched in water and the solid precipitate was filtered off and'~dried under vacuum to give the title compound of t=xample 196, Step A as a white solid, 113.8 (94%). 'H NMR (CDCt,, 400 MHz) b 2.82 (s, 3H), 6.82 (d, 1 H), 8.18 (d, 1 H), 8.19 (s, 1 H), 9.35 (s, 1 H); mp:
125-126 °C; MS (CI) 194 (MH').
Step B: 2-Methanesulfonvl-4-f1.2.41triazol-1-vl-pvrimidine. To a mechanically stirred suspension of 3-chloroperoxybenzoic acid (75%, 127 g, 551 mmol) in chloroform (625 mL) was added a solution of 2-thiomethyl-4-[1,2,4)triazof-1-yl-pyrimidine (prepared according to the method of Example 196, Step A, 50.7 g, 262 mmol) in chloroform (625 mL) and stirred at ambient temperature for 16 h. The mixture was filtered and the filtrate was washed six times with saturated aqueous sodium cartxmate. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the title compound of Example 196, Step B as a white solid, 37.8 g (64%). 'H NMR (CDCI,, 400 MHz) S 3.62 (s, 3H), 6.82 (d, 1 H), 8.19 (s, 1 H), 8.24 (d, 1 H), 9.35 (s,1 H); mp:
135-136 °C; MS (CI) 226 (MH').
Step C: 2-(3R.5S-Dimethvl-oiperazin-1-vl>-4-t1.2.4],fiazol-1-vl-ovrimidine, v2-;, Methanesulfonyi-4-[1,2,4]triazot-7-yhpyrimidine (prepared according to the procedure of Example 196, Step B, 32.5 g, 144 mmol) was combined with cis-2,6-dimethylpiperazine (34.5 g, 302 mmol) and heated neat at 135 °C for i h, cooled, dissolved in 2 N aqueous hydrochloric acid and washed once with ethyl acetate.
The acidic aqueous layer was basified to pH 9 with 6 N aqueous sodium hydFoxide at 0 °C
then extracted four times with ethyl acetate. The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to pn oil which crystallized from hexanes to give the title compound of Example 196, Step C as a white solid, 31.8 g (71 %). 'H NMR (CDCI,, 400 MHz) b 0.99 (d, 6H), 2.38 (m, 4H), 3.30 (s, 2H), 6.82 (d, 1 H), 8.18 (d, 1 H), 8.19 (s, 1 H), 9.35 (s, 1 H); mp:
14~-145 °C; MS
(CI) 260 (MH').
Step D: 1R~4-f2R.6S-Dimethvl-4-(4-f1.2.41triazol-1-vl-p"~imidin-2-vl~pioerazin-1-vl1-wrimidin-2-vl1-eth~f but~rrate. To a solution of 2-(3R,5S-dimethyl-piperazin-1 ylr4~-[7,2,4jtriazol-1-yl-pyrimidine (prepared according to the method of Example 196, Step C. 8.33 g, 32.1 mmol) in acetonitrile (30 mL) was added (R}-1-(4-trifluoromethanesutfonyloxy-pyrimidin-2-yl)-ethyl butyrate (prepan:d according to the method of Preparation Nine, 5.50 g, 16.1 mmol) and heated to reflux for 3 h under nitrogen atmosphere. The tooted mixture was filtered and the solids were washed twice with ethyl acetate. The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash chromatography (99:1 dichloromethane:methanol) to give the title compound of Example 196, Step D as an oil, 3.61 g (50%). 'H NMR (COCI,, 400 MHz) b 0.91 (d.
6H), 1.26 (t, 3H), 7.59 (d, 3H), 1.69 (q, 2H), 2.40 (m, 2H), 3.40 (d, 2H), 4.60 (m, 4H), 5.70 (q,1 H), 6.39 (d, 7 H), 6.58 (d, 1 H), 8.12 (s,1 H), 8.25 (d, 1 H), 8.31 (d,1 H), 8.35 (s, 1 H); MS (CI) 452 (MH').
Step E: 1R-f4-T2R.6S-Dimethvl-4-(4-f1 2 4ltriazol-1 yl-ovrimidin-2-vl>-ninerazin-1-vt1-gyrimidin-2-vl~-ethanol. 1R-{4-[2R,6S-Dimethyl~-(4-j1,2,4]triazol-1-yl-pyrimidin-2-yl~
piperazin-1 yQ-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 196, Step D, 3.60 g, 8.0 mmol) was combined with concentrated hydrochloric aad (10 mL) and stirred at ambient temperature for 4 h. The mixture was WO 00l595I0 PCTIIBOOI00296 ~217-quenched in saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oi! which was purified by flash chromatography (99:1 dichloromethane:methanol) to give the title compound as a white solid, 2.35 g (77%). 'H NMR (CDCI,, 400 MHz) 81.31 (d, 6H), 1.51 (d, 3H), 3.34 (m, 2H), 4.42 (m, 2H), 4.68.82 (m, 3H), 6.42 (d, 1 H), 7.11 (d, 1 H), 8,11 (s, 1 H), 8.23 (d, 1 H), 8.49 (d, 1 H), 9.12 (s, 1 H); mp: ~s~-Fez ~c; MS (CI) 382 (MH').
Examples 197 to 200 Examples 197 to 200 were prepared from the appropriate starting materials in a manner analogous to the method of Example 196.
HO
Rs ..
R"
N-- ~---N N ~ / N
N s s R' Example R" R' R" mp (~C) MS (Mti~
197 imidazol-1-yl 2R-Me 6S-Me 60-70 381 198 morphQlin-4-yl 2R-Me 6S-Me 70-80 400 199 pyrrolidin-1-yl 2R-Me 6S-Me 70-80 384 200 4-methylpiperazin-1-yl3R-Me 5S-Me 168-170 413 ~xamale 201 1R-f4-t2R.fiS-0imethvl-4-!2-ovridin-3-y!-ovrimidin~l-vl>~oiperazin-1-vl~-ovrimidin 2 vll' ethanol.
wo oors9s><o rcrr><aoorooZ9s -21 &
,, ~~~~Me ' Step A: 2-Pvridin-3-vl-pvrimidin~-vl fifluoromethanesulfonate. To a solution of 2-pyridin-3-yi-3H-pyrimidin-4-one (150 mg, 0.87 mmol; J. Med. Chem. 1990, 33, 1230) and triethytamine (Q.13 mL, 0.95 mmol) in dichloromethane (3 mL) was added dropwise a solution of trifiuoromethanesulfonic anhydride (0.22 mL, 0.91 mmol) in dichloromethane (2 mL) at 0 °C under nitrogen atmosphere. The mixture was allowed to stir for 30 min at 0 °C then diluted with dichloromethane and washed qnce with water and the aqueous layer was extracted twice with dichloromethane. The organic extracts were combined, washed sequentially with saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over sodium sulfate and filtered. The filtrate was evaporated to give the tifle compound of Example 201, Step A as an orange oil, 0.22 g (95%), that was used without further purifrcation.
Step B: 1 R-f4-f2R.6S-Dimethvl-4-!2-ovridin-3-vt-pvrimid'm-4-vl~oioerazin-1 v11-eyrimidin-2-yll-ethanol. A solution of 2-pyridin-3-yl-pyrimidin-4-yl trifiuoromethanesulfonate (prepared according to the mett~d of Example 201, Step A, 0.15 g, 0.5 mmol) in tetrahydrofuran (3 mL) at 0 °C was added dropwise to a solution of 1R-[4-(2R,6S-dimethyl-piperazin-1yl)-pyrmidin-2-ytJ~thyl butyrate (prepared according to the method of Preparation Four, 0.15 g, 0.45 mmol) in tetrahydrofuran (2 mL) and stirred for 1 h at ambient temperature. The mixture was quend~ed in saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate.
The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil and dissolved in concentrated hydrochloric aad (3 mL) and stirred at ambient temperature for 4 h. The mixture was quendied in saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate.
The combined Extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to give the title compound as a white foam; 0.091 g (48%). 'H
NMR (CDCI,, 400 MHz) 81.31 (d, 6H), 1.51 (d, 3H), 3;,34 (m, 2H), 4.42-4.70 (m, 4H), 4.71 (q, 1 H), 6.40 (d, 1 H), 6.56 (d,1 H), 7.37 (m, 1 H), 8.22 (d, 1 H), 8.36 (d, 1 t;), 8.62-8.68 (m, 2H), 9.53 (m, 1H); mp: 61-70 °C; MS (Ct) 392,(MH').
Examcle 202 1 R-(4-f2R.6S-Dimethvl-4-f2-l4-methyl-oiaerazin-1-vil-avrimidin-4-v11-oioerazin-1-vlf-pvrimtdin-2-vll-ethanol.
Me HO
Me ~~~~Me N
N~ N ~ ~ N
Me Step A: 1 R-f4-f4-(2-Methanesulfonvl-ovrimidin~-vll-2R 6S-dimethvl-oioerazin-1 v11=
pvrimidin-2-vf!-ethyl butyrate. To a solution of 4-(3R,5S-dimethyl-piperazin-1-yl}-2-methanesulfonyl-pyrimidine (prepared according to the method of Example 188, Step A, 7.70 g, 14.3 mmol) in aoetonitrile (30 mL) was added 1 R-(4-trifluoromethanesulfonyloxy-pyrimidin-2-yl~thyl butyrate, (prepan:d according to the method of Preparation Nine, 5.50 g, 16.1 mmol) and heated to reflux for 3 h under nitrogen atmosphere. The cooled mixture was filtered and the solids were washed twice with ethyl acetate. The combined extracts were washed once with water;
once with saturated aqueous sodium chloride and the organic tayer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash chromatography (98:2 dichloromethane:methanot) to give the tifle compound of Example 202, Step A as an oil, 4.01 g (62%). 'H NMR (CDCI,, 400 MHz) 8 0.93 (t, 3H},1.21 (d, 6H),1.55 (d, 3H),1.64 (q, 2H), 2.36 (t, 2H), 3.25 (s, 3H), 3.37 (m, 2H), 4.5-4.7 (m, 4H), 5.65 (q, 1 H), 6.33 (d,1 H), 6.68 (d,1 H), 8.22 (d,1 H), 8.28 (d,1 H); MS
(Cl} 463 (MH').
Step B: 1 R-f4-f4-(2-Methanesulfonvl-pvrimidin-4-yl~2R 6S-dimethyl-o~~erazin-1 vtl-pvrimidin-2-vIt-ethanol. 1 R-(4-[4-(2-Methanesulfonyl-pyrimidin-4-yIr2R,6S~imethyl-piperazin-1 y(]-pyrimidin-2-yI}-ethyl butyrate (prepared according to the method of W~ 00/5951 ~~~~Z~
Example 202. Step A, 0.42 g, 0.9 mmol) was combined with concentrated ~' hydrochloric acid (3 mL) and stirred at ambient temperature for 4 h. The mixture was '' quenched in saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic' layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash .
chromatography (99:1 dichloromethane:methano!) to give the title compound of Example 202, Step B as a white foam, 0.25 g (71 %). 'H NMR (CDCI,, 400 MHz) 8 1.26 (d, 6H).1.50 (d, 3H), 325 (s, 3H), 3.41 (m, 2H), 4.5-4.7 (m, 5H), 6.37 (d, 1 H), 6.71 (d, 1 H), 8:24 (d, 1 H), 8.30 (d, 1 H); MS (CI) 393 (MH').
Step C: 1 R-l4-f2R.6S-Dimethvl-4-f2-!4-methyl-oioerazin-1 of ~nvrimidin-4-vl1-pic~erazin-1-yl?-wrimidin-2-vl>-ethanol. 1 R-{4-(4-(2-Methanesulfonyf-pyimidin-4-yt}-2.6-dimethyl-piperazin-1-yQ-pyrimidin-2-yf}-ethanol (prepared according to the method of Example 202, Step B, 0.25 g, 6.4 mmol) was combined with N-methylpiperazine (2.0 mL) and heated at 80 °C for 1 h under nitrogen atmosphere. The mixture was quenched in water and extracted twice with ethyl acetate. The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash chromatography (96:4 chlorofortn:methanol) to give the title compound as a white foam, 0.11 g (41%). 'H NMR (CDCI,, 400 MHz) 1.31 (d, 6H),1:51 (d, 3H), 2.47 (s, 3H), 2.63 (m, 4H), 323 (m, 2H), 3.94 (m, 4H), 4.33 (m, 2H), 4.57 (m, 2H), 4.71 (q, 1 H), 5.96 (d, 1 H), 6.46 (d, 1 H), 7.98 (d, 1 H), 823 (d, 1H); mp: 60-70 °C; MS (CI) 413 (MH').
Examples 203 to 207 Examples 203 to 207 were prepared from the appropriate starting materials in a manner analogous to the method of Example 202.
pCTIIB00/00296 HO
R6 I ' ..., Me // N ~ ~ N-N~N N ~ / N
s ' s .
R' Example R" R' R° mp (°C) MS (MH') 203 morpholin-4-yl 2R-Me fiS-Me 70-80 400 204 pyrrolidin-1-yl 2R-Me 6S-Me 70-80 ~ 384 205 2,6-dimethylmorpholin-4-yi 2R-Me 6S-Me 42g 206 3,5-dimethylpiperidin-1-y1 2R-Me 6S-Me 426 207 5-methyl-furan-2-yl 2R-Me 6S-Me 123-128 395 Example 208 1 R-f4-f3R.5S-Dimethyl~-l2-(4-methyl-piaerazin-1-vl)-ayrimidin-4-v(i-oiperazin-1-vi>'-gvrimidin-2-vl~thanol.
~~~Me Me Step A: ~Benzyl-2R.6S-dimet~l-piperazin-1-vl~-2-methanesulfonvl-vvrimidine.
To a solution of as-1-benzyl-3,5-dimethylpiperazine (24.9 g, 122 mrnol, O~g.
Prep.
Proceed. Int 1976, 8,19) in dimethylacetamide (60 mL) was added 4-.chloro-2-methanesulfonyl pyrimidine (11.8 g, 61.3 mmol) and stirred for 16 h at 120 °C. The mixture was partitioned between water and ethyl acetate and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed three times with 1% aqueous copper sulfate, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an orange solid which was slurried in isopropyl ether (100 mL) and filtered to give the title compound of E~cample 208, Step A as an orange solid, 16.5 g PC'fIIB00/00296 (75%). 'H NMR (CDCI,, 300 MHz) b 1.35 (d, 6H), 2.25 (m, 2H); 2.76 (m, 2H), 3.23 (s, 3H), 3.53 (s, 2H), 4.35-4.65 (m, 2H), 6.51 (d, 1 H), 7.26 (m, 2H), 7.34 (m, 3H), 8.24 (d, 1 H); MS (CI) 361 (MH').
Step B: 4-(4-Benzyl-2R.6S-rJimethvl-piaerazin-1-yl~-2~4-methvlpiperazin-1-vl~
evrimidine.4-(4-Benzyl-2R,6S-dimethyipiperazin-1-y1~2-methanesulfonylpyrimidine (prepared according to the method, of Example 208, Step A, 11.5 g, 31.9,mrnol) was combined with N-methylpiperazine (15 mL, 128 mmol) and heated to 120 °C
for 2 h.
The mixture was diluted with ethyl acetate and washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filteted. The filtrate was evaporated to give the title compound of Example 208, Step 8 as an orange solid, 14.7 g (84%). 'H NMR (CDCI,, 300 MHz) 81.30 (d, 6H), 2.21 (m, 2H), 2.33 (s, 3H), 2.46 (m, 4H), 2.72 (d, 2H), 3.53 (s, 2H),~~.78 (m, 4H), 4.31 (m. 2H), 5.79 (d, 1 H), 7.24 (m, 2H), 7.31' (m, 3H), 7.90 (d, 1 H); MS
(Cl) 381 (MH').
Step C: 4-(2R.6S-Dimethvl-oiperazin-1-vl~-2-(4-methvloiaerazin-1-vl~-ovrimidine. To a solution of 4-(4-benzyl-2R,6S-dimethyipiperazin-1-yl)-2-(4-methyl-piperazin-1-ylr pyrimidine (prepared according to the method of Example 208, Step B. 9.8 g, 25.8 mmol) in methanol (200 mL) and hydrochloric acid (1 N in ethyl ether, 38.7 mL, 38.7 mmol) was added ammonium fom~ate (16.3 g, 25.8 mmol). After stirring at ambient temperature for 5 min, 10% palladium on carbon (1.96 g, 20 wt% pre-wetted with isopropanol) was added and this mixture was heated to reflux for 2 h. The cooled reaction was filtered and the filtrate was concentrated to a solid, which was diluted with ethyl acetate and washed twice with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to give the tide compound of Example 208, Step C as a dear oil, 6.01 g (81%). 'H NMR (CDCI,, 300 MHz) b 1.25 (s, 6H), 2.31 (s, 3H), 2.24-2.44 (m, 4H), 2.90 (m, 4H), 3.76 (m, 4H), 4.25 (m, 2H), 5.79 (d,1 H), 7.90 (d, 1 H); MS (C1) (MH').
Step D: 1 R~4-f3R.5S-Dimethvl-4-f2-l4-meth~rl-piperazin-1-vl~-nvrimidin-4-y,11-pioerazin-1-yll-pvrimidin-2-vl)-ethyl butyrate. To a solution of 4-(2R,6S-dimethyl-piperazin-1-yl)-2-(4-methyl-piperazin-1-yl)-pyrimidine (prepared according to the method of Example 208, Step C, 9.0 g, 31.1 mmol) and triethylamine (6.5 g, 46.5 mmol) in dimethytforrnamide (90 mL) was added (R}-1-(4-chloro-pyrimidin-2-yl)-ethyl WO 00159510 ~2~
butyrate (prepared according to the method of Preparation Seven; 7.78 g, 34.1 mmol) and heated to reflux for 3 h under nitrogen atmosphere, The cooled mixture was filtered and the solids were washed twice with ethyl acetate. The combined extracts were washed once with water; once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered: The filtrate was evaporated to an oil which was purified by flash chromatography (95:5 chlorofortn:methanol) to give the title compound of Example 208, Step D as an oil, 11.4 g {76%). 'H
NMft (CDCI,, 300 MHz) s o.95 (t, 3H), 1.18 (d, 6H), 1.54 (d, 3H), 2.23-2.35 (m, 7H), 2.51 (m, 4H), 3.21 (m, 2H), 3.81 (m, 4H), 4.32 (m, 2H), 4.52 (m, 2H), 5.65 (q, 1 H), 5.82 (d, 1 H), 6.38 (d, 1 H), 7.39 (d, 1 H), 8.18 (d, 1 H); MS (CI) 483 (MH').
Step E: 1 R-(4-f3R.5S-Dimethvl-4-12-f4-methyl-ninerazin-1 girl)-ovrimidin-4-,y11-piperazin-1-vl~-oyrimidin-2-vll-ethanol. 1 R-(4-{3R,5S-dimethy(~-[2-(4-methyl-piperazin-1-yl)-Pyimidin-4-yf)-piperazin-1-yl}-pyrimidin-2-yl)-ethyl butyrate {prepared according to the method of Example 208, Step D, 11.3 g; 23.5 mmol) was combined i 5 with concentrated hydrochloric acid (60 mL) and stirred at ambient temperature for 4 h. The mixture was quenched in saturated aqueous sodium bicarbonate and extracted five times with 10~ isopropanoUchlorofortn. The combined extracts v~re washed once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil and crystallized from isopropanol to give the title compound as a white solid, 7.34 g (76%). 'H
NMR
(CDCI,, 300 MHz) 81.21 (d, 6H), 1.51 {d, 3H), 234 (s, 3H), 2.45 (m, 4H), 3.24 (m, 4H), 3.76 (m, 2H), 4.30.53 (m, 4H), 4.68 (q, 1 H), 5.82 (d, 1 H), 6.42 (d,1 H), 7.94 (d, 1 H), 8.21 (d, 1 H); rr~: ~s~-~e2 ~c; MS (CI) 413 (MH').
Examples 209 to 211 Examples 209 to 211 were prepared from the appropriate starting materials in a manner analogous to the method of Example 208.
P~'~I00296 .."Wle .
Example R" R' R mp (Cj ~ ' MS (MH'j 209 2,6-dimethyfmorpholin-4-yf3R-Me 5S-Me 428 210 4-ethyfpiperazin-1-yl3R-Me 5S-Me 144-146 427 211 4-isopropylpiperazin-1-yl3R-Me 5S-Me 137-139 ' 441 Example 212 1 R-f4-f2R.6S-Dimethvl-4-(4-mornho(ino~-yl-f1.3.51triazin-2-yl~aioe zin-1-vt1-oyrimidin-2-yl~-ethanol.
~~~Me Me Step A: 1R~4-f4-(4-Chloro-6-morphoiino-f1.3.51triazin-2-vl~2R.6S-dimethyloioerazin-1-vt~-nvrimidin-2-vl1-~thvl butyrate. To a solution of 1R-[4-(2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yq-ethyl butyrate (prepared according to the method of Preparation Four, 0.31 g, 1.0 mmol) and sodium bicarbonate (0.17 g, 2.0 mmol) in dimethyffomiamide (3 mL) was added 2,4-dichloro-6-morpholino-[1,3,5jtriazine (0.24 g,1.0 mmol; Chem. Pharm. Bull.1997, 45, 291 ) and stirred at ambient temperature for 2 hours. The mixture was diluted with ethyl acetate and washed twice with water, once with saturated aqueous sodium chloride, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to an oil, which was purified by flash chromatography (99:1 chlorofortn:methanol) to give the title compound of Example 212, Step A as a white solid, 0.19 g (37%). 'H NMR (CDCIs, 300 MHz) b 0.93 (t, 3H), 1.23 (d, 6H), i :53 (d, 3H), ,1.66 (m, 2H), 2.37 (t, 2H), 3.16 (m, 2H), 3.72-pCTIIB00100296 WO 00!59510 3.78 (m, 10H), 4.12-4.78 (m, 2H), 5.65 (q, 1 H), 6.34 (d,-1 H). 8.1~, {m, 2H);
MS (CI) 505, 507 (MH').
Step B: 1R-~4=f2R.fiS-Dimethv!-4-(4-morahofino-4-vl-f1.3.51triazin-2-vl)-o'roerazin-1-yj]wrimidin-2-vll-ethanol. To a solution of 1 R-{4-[4-(4-chloro-6-morphotino-[1,3,5]triazin-2-yIr2R,6S-dimethyl-piperazin-1-y~-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 212, Step A, 0.15 g, 0.35 mmo() in ethanol (10 mL) was added 10% palladium on carbon (0.75 g, 500 wt %) and hydrogenated at 45-50 psi using a Parr apparatus for 12 hours. The catalyst was fettered off and the filtrate was concentrated to an oil which was added to concentrated hydrochloric acid (2 mL) and stirred at ambient temperature for 6 hours. The mixture was diluted with chloroform and washed twice with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to give the title compound as a white solid, 0.47 g (40%). 'H NMR (CDCI3, 300 MHz) b 1.23 (d, 6H), 1.53 (d, 3H), 3.16 (m, 2H), 3.72-3.78 (m, 10H), 4.12-4.78 (m, 3H), 6.34 (d,1 H), 8.19 (m, 2H); mp: 78-82 °C; MS (C1) 401 (MH'); [a]o +15.1 (c 1Ø MeOH).
Example 213 1 R~4-f4-l4-Methoxv-6-methyl-f 1.3.51triazin-2-yl)-3R.5S-dimethyloioerazin-1~~
pyrimidin-2-vff-ethanol.
HO
Me0 Me ~~~~Me N-N ~N N ~ / N
~N
Met Me Step A: 1 R-(4-f4-(4-Chlpro-6-methyl-f1.3.51tciazin-2-vl~3R.5S-dimethylninerazin-1-vfi-pvrimidin-2-vl)-ethyl butyrate. To a solution of 1R-[4-(3R,5S-dimethyl-piperazin-1 ylr pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Preparation Three, 1.47 g, 6.43 mmol) and sodium bicarbonate (2.25 g, 26.8 mmol) in dimethylfomiamide (10 mL) was added 2,4-dishloco-6-methyl-[1,3,5]triazine (0.88 g, 5.3 mmol; Monatsh. Chem.1970, 101, 724) and stirred at ambient temperature for h. The mixture was diluted with ethyl acetate (150 mL) and washed twice with water, once with 10% aqueous CuSO,, once with saturated aqueous sodium chloride, and pGTIIB00100296 the organic layer was dried over sodium sulfate and filtered. The filtrate was ;
concentrated to give the title compound of Example 213, Step A as a tan soi'~d, 2.12 g (91%). 'H NMR (CDCI,, 300 MHz) b 0.93 (t, 3H), 1.23 (m, 6H), 1.54 (d, 2H), 1.fi6 (m, 2H), 2.31 (s, 3H), 2.37 (m, 2H), 2.41 (s, 1H), 3.19 (m, 2H); 4.22-4.55 (m, 2H), 4.91 (m, 2H), 5.65 (q, 1 H), fi.40 (d, 1 H), 820 (d,1 H); MS (CI) 434, 436 (MH').
Step B: 1 R-14-f4-(4-Methoxv-6-methyl-f1.3.5ltrtazin-2-yl)-3R.5S~iimethvtoiDerazin-1-vll-ovrimidin-2-vl)-ethanol. A solution of sodium methoxide in methanol was freshly prepared by allowing sodium metal (0.4 g, 17.3 mmol) to dissolve in methanol (40 mL). To this mixture was added 1R-{4-[4-(4-chloro-6-methyl-[1,3,5)triazin-2-yf}-3R,5S-dimethyl-piperazin-1-ylj-pyrimidin-2-yl}~thyl butyrate (prepared according to the method of Exarnpie 213, Step A, 1.5 g, 3.46 mmol) which was stirred at ambient temperature for 76 h. The reaction mixture was evaporated to an oil, diftrted with chloroform and washed twice with water, once with saturated aqueous sodium chloride, and the organic layer was dried over sodium sulfate and filtered.
The filtrate was concentrated to a dear oil which was crystallized ft~om isopropyl ether to give the title compound as a white solid, 0.85 g (72%). 'H NMR (CDCI,, 300 MHz) 81.23 (d, 6H), 1.48 (d, 3H), 2.36 (s, 3H), 3.20-3.26 (m, 2H), 3.90 (s, 3H), 4.18.43 (m, 2H), 4.63 (m, 2H), 4.68 (q, 1 H), 4.85 (d, 1 H), 6.42 (d, 1 H), 8.18 (d, 1 H); mp:
161-162 °C;
MS (CI) 360 (MH'); [ajo +16.8 (c 1.0, MeOH).
Example 214 1 R-f4-f4-14.6-Dimethoxv-f1.3.51triazin-2-vI)-3R.5S-dimethyl-oiDerazin-1-vI1-9vrimidin-2-vl)-ethanol.
Me0 ~~Me r--N
N~~
~N
Me0' Me Step A: 1 R-f4-f4-f4.6-Dichloro-f 1.3.51triazin-2-v1)-3R.5S-dimethvl-Dioerazin-1-vIt-p~rrimidin-2-vll-ethyl butyrate. To a solution of 1R-[4-(3R,5S-Dimethyl-piperazin-1-yl)-pyrimidin-2-yf)-ethyl butyrate (prepared according to the method of Preparation Three, 3.25 g, 10.5 mmol) and sodium bicarbonate (1.01 8,19.2 mmol)~ in dimethylfomlamide (8 mL) was added cyanuric chloride (1.76 g, 9.6 mmol) and stirred -227_ at ambient temperature for 2 h. The mixture was diluted with ethyl acetate and washed twice with water, onoe with saturated aqueous~,sodium diloride, and the organic layer was dried over sodium sulfate and flitered. The filtrate was concentrated to give the title compound of F~cample 214, Step A,as a white semi-solid, 1.42 g (68%). 'H NMR (CDCl3, 300 MHz) 8 0.93 (i, 3H), 1.23 (m, 6H), 1.54 (d, 3H), 1.66 (m, 2H), 2.37 (m, 2H), 3.19 (m, 2H), 4.42-4.55 (m, 2H), 4.91 (m, 2H), 5.65 (q,1 H), 6.40 (d, 1 H), 820 (d, 1 H); MS (Ci) 446, '448 (MH').
Step B: 1R-f4-f4-(4 6-Dimethoxv-f1 3 5ltriazin-2-vll-3R 5S-dimethvl-oinerazin 1 vi1 wrimidin-2-vlf-ethanol. A solution of sodium methoxide in methanol was freshly prepared by allowing sodium metal (0.18 g, 8.0 mmol) to dissolve in methanol (16 mL). To this mixture was added 1R-{4-(4-(4,6-dichloro-[1,3,5)triazin-2-yl}-3R,5S-dimethyt-piperazin-1-ylj-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 214, Step A, 0.91 g, 2.0 minoi) at 0 °C, then wam~ed to ambient temperature for 1 h. The mixture was evaporated to an oil, diluted with chloroform and washed once with water, once with saturated aqueous sodium chloride, dried over sodium sulfate and filtered. The filtrate was concentrated to a dear oil which crystallized from isopropyl ether to give the title compound as a white solid, 0.54 g (72%). 'H NMR (CDCl3, 300 MHz) b 1.23 (d, 6H), 1.50 (d, 3H), 3.20 (m, 2H), 3.95 (s, 6H), 4.32 (m,1 H), 4.67-4.86 (m, 4H), 6.34 (d, 1 H), 8.22 (d,1 H); mp:187-188 °C; MS
(CI) 376 (MH').
Example 215 1R-f2R 6S-Dimethvl-4-(4-phenyl-f1 3 5ltriazin-2vl~oiDerazin-1-vl1-nvrimidin 2 vt>~-ethanol.
HO
Me ~~~~Me N----N N
N
Me Step A: 1 R-f4-f4-l4-Chloro-6-phenyl-f1 3 5ltriazin-2-vl~-2R 6S-dimethvl-oin~erazin-1 ~~pyrimidin-2y11~-ethyl butyrate. To a solution of 1 R-(4-(2R,6S-dimethyl-piperazin-1yl}-pyrmidin-2yf}~thyl butyrate (Prepared according to the method of Preparatron WO 00!59510 PCTIIB00/00296 Four, 2.35 g, 7.67 mmol) and sodium bicarbonate (1.29.8,15.3 mmol) in ~ ,, dimethylformamide (25 mL) at 0 °C was added 2,4-dichloro-6-phenyl[1,3,5)trtazine (1.73 g, 7.67 mmol; Helv. Chim. Ada 9950, 33, 1365) portionwise. The reaction mixture was allowed to warm to room temperature and stir under nitrogen for 4 h, poured into water then filtered to give the title compound of F~cample 215, Step A as a light tan solid, 1.99 g (51 %). 1 H NMR (CDCI,, 400 MHz) S 0.94 (t, 3H),1.25 (d, 6H), 1.57 (d, 3H), 1.68 (m, 2H), 2.40 (t, 2H), 327 (d, 2H), 4.65 (m, 2H), 4.82 (d, 1H), 5.00 (d,1 H), 5.68 (q,1 H), 6.34 (d,1 H), 7.46 im, 3H), 821 (d,1 H), 8.40 (d, 2H);
MS (CI) 496, 498 (MH'). ,, Step B: 1 R-f4-f4-(6-Phenyl-f1.3.51trtazin-2-vIJ-2R.6S-dimethyt-cioerazin-1 yl1-pvrimidin-2-vll-ethyl buivrate. To a solution of 1 R-{4-[4-(4-chloro-6-phenyl-[1,3,5]triazin-2-yl~2R,6S-dimethyl-piperazin-1-yQ-pyrimidin-2-yI}-ethyl butyrate (prepared according to the method of Example 2i 5, Step A, 4.81 g, 9.7 mmol) in methanol (50 mL) was added 10% palladium on carbon (940 mg, 20 wt%), ammonium fom~ate (5.98 g, 97 mmol), and hydrochloric aad (2 M in ethyl ether, 7.1 mL,14.2 mmol) and refluxed for 1.5 h. The mixture was allowed to cool, then filtered.
The filtrate was concentrated and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered, and the filtrate was evaporated to an oil which was purified by flash chromatography (99:1 chlorofortn:methanol) to give the tithe compound of Example 215, Step B as a dear oil, 2.69 g (59%). 1 H NMR (CDCI3, 400 MHz) b 0.95 (t, 3H), 125 (d, 6H), 1.57 (d, 3H),1.68 (m, 2H), 2.40 (t, 2H), 3.2? (d, 2H), 4.65 (m, 2H), 4.82 (d, 1 H), 5.00 (d, 1 H), 5.68 (q, 1 H), fi.34 (d, 1 H), 7.46 (m, 3H), 821 (d, 1 H), 8.40 (d, 2H), 8.66 (s, 1 H); MS (CI) 462 (MH').
Step C: 1 R--f2R 6S-Dimethvl-4-(4-ohenvl-f1 3 5ltriazin-2vlMioerazin-1 v(1-ovrimidin 2 thanol. Concentrated hydrochloric add (10 mL) was added to 9 R-{4-[4-(6-phenyl-[1.3.5]triazin-2-Y1~2R.6S~limethyl-piperazin-1 y(j-pyrimidin-2y(j-ethyl butyrate (prepared according to the method of Example 215, Step B, 2.69 g, 5.8 mrnol) and alla~nred to stir for 5 h at ambient temperature. The reaction mixture was cooled to 0 °C, diluted with chloroform, and 6 M aqueous sodium hydroxide was added slowly until basic (pH 9). The layers were separated and the aqueous layer was extracted lwioe with chloroform. The combined organic extracts were washed once with saturated aqueous sodium chloride, dried over sodium sulfate, filtered; and the filtrate WO 00!59510 was concentrated to an oil which was purified by flash chromatography (97:3 chloroform:methanol) to give a white foam that crystallized from isopropyl ether to give the title compound as a white solid, 1.55 g (68%). 1 H NMR (CDCI,, 400 MHz) a 1.28 (d, 6H), 1.54 (d, 3H), 3.31 (d; 2H), 4.63 (m, 2H), 4'.77 (q, 1 H), 4.85 (d, 1 H), 5.50 (d, 1 H), 6.42 (d, 1 H), 7.50 (m, 3H), 8.25 (d,1 H), 8.41 (d, 2H), 8.68 (s, 1 H);
mp: 133-134 °C; MS (CI) 392 (MH'); [aJo +18.7 (c 1.07, MeOH).
Examples 216 to 235 Examples 216 to 235 were prepared from the appropriate starting materials in a manner analogous to the method of Example 215.
~~~~Me R
WO 00!59510 PCT/IB00/00296 ExampleR" R'= R6 R' , mp (C) MS (MHO
~ , , 216 C7 morpholin-4-yl 2R-Me 6S-Me 138-141435; 437 217 H morpholin-4-yl 3R-Me 5S-Me 152 401 218 OMe morpholin-4-yl 2R-Me, 6S-Me 176-178431 219 Me 4-methyl-piperazin-3R-Me 5S-Me 428 1-yl " . , 220 Me H 2R-Me 6S-Me 91-94 330 221 OMe OMe ~ 2R-Me 6S-Me 128-129376 222 OEt Me 3R-Me 5S-Me 141-1~2374 223 OiPr Me 3R-Me 5S-Me 87-91 388 224 phenyl H 3R-Me 5S-Me 154-1<55392 225 phenyl OMe 3R-Me 5S-Me , , 4~
226 phenyl OMe ~ 2R-Me6S-Me 135-138'422 227 iPr H 2R-Me 6S-Me 122-124358 228 iPr OMe 3R-Me 5S-Me 75-80 388 229 phenyl H H H 115-117364 230 OMe Me H H 173-175332 231 o-tolyl H 3R-Me 5S-Me 123-125406 232 o-tolyl OMe 3R-Me 5S-Me 143-145436 233 cydopropylH 3R-Me 5S-Me 134-135356 234 cydopropylH 2R-Me 6S-Me 133-134356 235 OMe CH=OMe 3R-Me 5S-Me 104-105390 Example 236 1R-f4-f4-(4-Hvdroxvm ethvl~-methoxv-f1.3.5itriazin-2-yl)-3R
erazin-1-5S-dimeth io vIl-avrimidin-2-vll-ethanol.
~Me _ Step A: 1 R-f4-t4-(4-Chloro-6-diazomethvl-I1.3.51triazin-2-vi~3R.5S-dimethvt-oiaerazin-1-vll-ovrimidin-2-vll-ethyl butyrate. To a solution of 1R-[4-(3R.5S-dimethyl-piperazin-1-yl)-pyrimidin-2-y~-ethyl butyrate (prepared according to the method of Preparation Three, 3.06 g, 10.0 mmol) and sodium bicarbonate (1.68 g, 20.0 mmol) in dimethylformamide (10 mL) was added 2,4-dichloro-6-diazomethyl-[1,3,5jtriazine (1.90 g, 10.0 mmol; J. Am. Chem. Soc. 1957, 79, 94.4) and stirred at ambient temperature for 2 h. The mixture was diluted with ethyl acetate, washed twice with water, once with saturated aqueous sodium chloride, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated and purified by flash 1fl chromatography (ethyl acetate) to give the title impound of Example 236, Step A as a foam, 1.84 g (4i °~). 'H NMR {CDCh, 300 MHz) 8 0.94 (t, 3H), 1.23 {m, 6H), 1.55 (d, 3H), 1.66 (m, 2H), 2.38 (m, 2H), 3.19 (m, 2H), 4.22-4.45 (m, 2H), 4.86 (m, 2H), 5.10 (s, 1 H), 5.65 (q, 1 H), 6.40 (d, 1 H), 8.20 (d, 1 Hj; ~mp: 106-108 °C;
MS (CI) 461, 463 (MH').
Step B: 1R-f4-f4-l4-Hvdroxvmethvl-6-methoxv-f1.3.51triazin-2-vllr3R 5S-dimethvl-vioerazin-1-vl1-ovrtmidin-2-vl1-ethanol. 1 R-{4-[4-(4-Chtoro-6-diazomethyl-[1,3,5]triazin-2 yl)-3R,5S-dimethylpiperazin-1 ylJ-Pyrimidin-2-yt}-ethyl butyrate (prepared according to the method of Example 23fa, Step A,1.5 g, 3.2 mmoi) was dissolved in ethyl acetate (20 mL) and 10% aqueous sulfuric acid {5 mL) was added slowly at ambient temperature, stirred 5 min then basfied to pH 9 with 6 N
aqueous sodium hydroxide. The separated ethyl acetate layer was washed once with brine, dried over magnesium sulfate, and conoenVated to a semi-solid. To a freshly prepared solution of sodium methoxide, generated by dissolving sodium metal (0.92 g, 4.0 mmol) in methanol (6 mL), was added the crude solid (0.89 g, 2.0 mmol).
This mixture was stirred for 4 h at ambient temperature then evaporated to dryness.
The residue was purified by flash chromatography (95:5 dichiorornethane:methanoi) to give the title compound as a white solid, 0.084 g (13%). 'H NMR (CDCI,, 300 MHz) 8 1.23 (d, 6H),1.49 (d, 3H), 3.14-3.21 (m, 2H), 3.96 (m, 2N), 3.90 (s, 3H), 4.18-4.38 (m, 2H), 4.69 (q, 1 H), 4.97 (m, 2H), 6.44 (d,1 H), 820 {d, 1 H); mp:170-171 °C; MS (CI) 376 (MH'); [a]o +16.6 (c 1.0, MeOH).
~amDle 237 1 R-t4-(4-(4-Methoxvmethvl-f 1 3 5ltriazin-2-vl1-3R 5S-dimethvl-niaerazin 1 v0-pyrimidin=2-vll~-ethanol.
pCTIIB00100296 ' HO '.
Me w~~~Me ' ~ ~ , N-N ~N N ~ / N
~N , MeO~ Me Step A: 1 R-(4-f4-(4-Chloro-6-methoxvmethvl-f1.3.51triazin-2-vl)-3R.5S-dime pperazin-1-vll-ovrimidin-2-vl~-ethyl butyrate. 1R-(4-[4-(4-Chloro-6-diazomethyl-(1,3,5]triazin-2-yl}-3R,5S-dimethylpiperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 236, Step A, 1.5 g, 3.2 mmol) was dissolved in methanol (10 mL) and 10% aqueous sulfuric acid (3 mL) was added.
This mixture was stirred at ambient temperature for 1 h then diluted with ethyl acetate.
The separated ethyl acetate layer was washed once with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated to an oil which was purified by flash chromatography (99:1 dichloromethane:methanol) to give the title compound of Example 237, Step A as an oil, 1.02 (60%). 'H NMR (CDCI,, 300 MHz) 8 0.95 (t, 3H), 1.26 (d, 6H), 1.58 (d, 3H), 1.67 (q, 2H), 2.41 (t, 2H), 3.24 (m, 2H), 3.51 (s, 3H), 4.18-4.38 (m, 4H), 4.69 (q, 1 H), 4.92 (m, 2H), 6.47 (d, 1 H), 8.24 (d, 1 H);
MS (CI) 464, 466 (MH').
Step B: 1 R-f4-f4-(4-Methoxvmethyl-f1.3.51triazin-2-vl)-3R,.5S-dimethvl-oinerazin-1-v(1-pvrimidin-2-vl''-ethanol. To a solution of 1 R-{4-(4-(4-chloro-6-methoxymethyl-[1,3,5]triazin-2-yIr3R.5S-dimethpiperazin-1-yi]-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 237, Step A, 0.43 g, 0.92 mmol) in methanol (8 mL) and hydrochloric acid (2 M in ethyl ether, 0.7 mL, 1.37 mmol) was added ammonium formate (0.58 g, 9.2 mmol) and 10% palladium on carbon (0.085 g, 20 wt%) and heated to reflux for 3 h. The solvents were removed and concentrated hydrochloric aad (2 mL) was added and stirred at ambient temperature for 16 h, based to pH 9 with 6 N aqueous sodium hydroxide and diluted with ethyl acetate.
The separated ethyl acetate layer was washed once with saturated aqueous sodium chloride; dried over magnesium sulfate, and concentrated to an oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound as a whitesolid, 0.12 g (36%). 'H NMR (CDCI,, 300 MHz) 81.25 (d, 6H),1.49 (d, 3H), 3.24 (m, 2H), 3.51 (s, 3H), 4.18-4.38 (m, 4H), 4.72 (q, 1 H), 4.97 (m, 2W), 6.47 (d, , 1 H), 8.22 (d, 1 H), 8.57 (s, 1 H); MS (CI) 3fi0 (MH'). ,, , Exarrroles 238 to 240 Examples 238 to 240 were prepared from the appropriate starting materials in a manner analogous to the method of Exariiple 237.
~~~~Me Example R" Ru R' R mp (C) MS (MHO
238 CHZOH H 3R-Me 5S-Me 173=175 346 239 OMe CHZOMe 3R-Me 5S-Me 143-145 390 240 CHZOH phenyl 2R-Me 6S-Me 173-175 422 ' Example 241 1R-(4-f4-(4 6-Dimethvl-f1 3 5ltriazin-2-vtl-2R 6S~iimethvic~ioerazin-1 yl]-nvrimidin-2-th nol.
'Me Step A: 1R-(4-L4-l4-Methyl-6-trichloromethyl-f1 3 5ltriazin-2-vl1-2R 6S-dimethyl-eoerazin-1-vf1-pyrimidin-2-vl>~-ethyl butyrate. To a solution of 1R-[4-(2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl]-ethyl butyrate dibenzoyl-L-tartrate salt (prepared according to the method of Preparation Fifteen,1.33 g, Z.0 mmol) and sodium bicarbonate (0.34 g, 4.0 mmol) in dimethylfomiamide (S mL) was added 2-methyl-4,6-R
pCT/IB00100296 bis-trichloromethyt-[1,3,5jtriazine (1.00 g, 3.0 mmol; Butl. Chem. Soc., Jpn.
"1969, 42, 2924) and stirred at ambient temperature for 14 h. The mixture was diluted with ethyl 1I
acetate and washed twice with water and the organic layer was dried over magnesium sulfate and concentrated. The crude oil was purified by flash chromatography (95:5 dichloromethane:methanoi) to give the title compound of Example 241, Step A as a foam, 0.71 g (69%). 'H NMR (CDC13, 300 MHz) 8 p.95 (t, 3H), 1.22 (m, 6H), 1.56 (d, 3H), 1.66 (m, 2H), 2.37 (m, 2H), 2.55 (s,1 H), 3.27 (m, 2H), 4.48-4.78 (m, 2H), 4.84 (m, 2H), 5.fi7 (q, 1 H), 6.32 (d, 1 H), 8.22 (d,1 H);
MS (CI) 517, 519 (MH').
Step B: 1R-f4-f4-(4:6-Dimethvhf1.3.51triazin-2-vl~-2R.6S-dimeth~~lnioerazin-1-vI)-ovrimidin-2-vI>'-ethanol. A suspension of 1 R-{4-[4-(4-methyl-6-trichloromethyl-[1,3,5jtriazin-2-yl~2R.6S dimethyl piperazin-1-yfj-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 241, Step A, 0.65 g, 1.2 mmol) and 10°~ palladium on carbon (0.2 g) in triethylamine (1 mL) and methanol (20 mL) was hydrogenated at 40 psi for 0.5 hours using a Parr apparatus. The catalyst was filtered and the filtrate was concentrated to a solid which was dissolved in concentrated hydrochloric aad (2 mL) and stirred for 6 hours. This mixture was diluted with water, basified to pH 9 with 6 N aqueous sodium hydroxide, and extracted into dichloromethane. The extract was washed twice with water, once with saturated.
aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to a dear oil which crystallized from isopropyl ether to give the title compound as a white solid, 0.25 g (58%). 'H NMR
(CDCI,, 300 MHz) 8 1.21 (d, 6H), 1.49 (d, 3H), 2.40 (s, 6H), 3.16 (m, 2H), 4.45-4.68 (m;
2H), 4.71 (q, 1 H), 4.84 (m, 2H), 6.42 (d, 1 H), 8.20 (d, 1 H); mp: 172-173 °C;
MS (CI) 344 (MH');
[a)o +17.2 (c 1.0, MeOH).
Example 242 1R-f4-f4-14.6-Dimethvl-f1.3.51triazin-2 vf~3R.5S~iimethvl-oioerazin-1-vil~rimidin-2-thano .
HO
Me Me , ~~~~Me ~N ~ N-N'/ ~~N N ,,~ '/N
~N
Me/ Me pCT/IB00/00296 Step A: 4-Methyl-6-trichloromethvl-f1.3.51triazin-2-vl methanesuffonate. To a solution of 2-hydroxyl-methyl-6-trichloromethyi-[1,3,5]triazine (1.74 g, 5.0 mmol; J.
Amer. Chem. Soc. 1956, 78, 2447) and triethylamine (0.51 g, 5.5 rnmol) in dichloromethane was added methanesulfonyl chloride (0.57 g, 5.0 mmol) at 0 °C and stirred for 1 h then quenched in saturated aqueous sodium bicarbonate. The separated organic layer was washed once with saturated sodium chloride, dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound of Example 242, Step A as an orange oil, 0.98 g (65%) which was used directly without any further purification. MS (CI) 291,293 (MH').
Step B: 1R-(4-f3R.5S-Dimethvt-4-f4-methyl-6-trichloromethvl-f1.3.51triazin-2-vll-yiperazin-1-vfl-ovrfmidin-2-vl~thvl butyrate. To a solution of 1R-[4-(3R,5S-dimethyl-piperazin-1-yl~-pyrimidin-2-y(j-ethyl butyrate (prepared according to the method of Preparation Three; 0.62 g, 2.0 mmol) and sodium~bicarbonate (0.34 g, 4.0 mmol) in dimethylfomiamide (5 mL) was added 4-methyl-6-trichloromethyl-[1,3,5]triazin-2-yl methanesuifonate (prepared according to the method of Example 242, Step A, 1.00 g, 3.0 mmol) and stirred at ambient temperature for 14 h. The mixture was diluted with ethyl acetate and washed twice with water and the organic layer was dried over magnesium sulfate and concentrated. The crude oil was purified by flash chromatography (ethyl acetate) to give the title compound of Example 242, Step B as a dear oil, 0.41 mg (96%). 'H NMR (CDCI,, 300 MHz) b 0.95 (t, 3H), 7.22 (m, 6H), 1.56 (d, 3H), 1.66 (m, 2H), 2.37 (m, 2H), 2.55 (s, 3H), 327 (m, 2H), 4.48-4.78 (m, 2H), 4.84 (m, 2H), 5.67 (q, 1 H), 6.32 (d, 1 H), 8.22 (d, 1 H); MS (CI) 517, 519 (MH').
Step C: 1R-f4-f4-~4.6-Dimethvl-f1.3.51triazin-2-vl1-3R.5S-dimethvl-oinerazin-1-yfl-pyrimidin-2-vll-ethanol. A suspension of 1 R-{4-[3R,5S~irr~thyt-4-(4-methyl-6-trichloromethyl-[1;3,5jtriazin-2-yl)-piperazin-1-y(j-pyrimidin-2-yt}-ethyl butyrate (prepared according to the method of Example 242, Step B, 0.65 g, l2.mmol) and 10% palladium on carbon (0.2 g, 30 wt%) in triethylamine (1 mL) and methanol (20 pCTIIB00/00296 mL) was hydrogenated at 40 psi for 0.5 h using a Parr apparatus. The catalyst was , , filtered off and the filtrate was concentrated to a solid which was dissolved in concentrated hydrochloric aad (3 mL) and stirred for 6 h. This mixture was diluted with water, basified to pH 9 with ~6 N aqueous sodium hydroxide, and extracted into dichloromethane. The extract was washed twice with water and once with saturated aqueous sodium chloride and the organic Payer was dried over sodium sulfate and concentrated to a Gear oil which crystallized from isopropyl ether to give the title compound as a white solid, 025 g (23%). 'H NMR (CDCt,, 300 MHz) 8121 (d, 6H), 1.49 (d, 3H), 2.40 (s, 6H), 3.16 (m, 2H), 4.45-4.68 (m, 2H), 4.71 (q, 1 H), 6.4~ (d, 1 H), 8.20 (d, 1 H); MS (CI) 344 (MH'); mp: 157-159 °C; taJ~ +17.2 (c 1.0, MeOH).
Examples 243 to 246 Examples 243 to 246 were prepared from the approprtate starting materials in a manner analogous to the method of Example 242.
~~~~Me Example R". R'= ~ R' R mp (C) MS (Mli~
243 Me phenyl 2R-Me 6S-Me 406 244 Me phenyl 3R-Me 5S-Me 132-134 _ 406 245 Me tetrahydrofuran-2-yl2R-Me 6S-Me 428 246 Me o-tolyl ZR-Me 6S-Me 14&150 436 Example 247 (Rl-2-f2-(1-Hvdro~cv-ethvl~ovrimidin-~-vt1-1.2.3 4-tetrahvdro-isoouinoline-7-sulfonic aad dimethvlamide.
R
Me= \ i0. , , o ~S HO , .."Me \ ''v ~ N-N ~ ~N
Step A: 2-Trifiuoroacetvl-1.2.3.4-tetra~dn~-isoauinoline-7-sulfonic acid dimethvlamide. A mixture of 2-fifluoroacelyl-1,2,3,4-tetrahydro-isoquinolirte-sulfonyl chloride (400 mg, 1.22 mmo(, .l. Med Chem.1980, 23, 837), dimethylamine hydrochloride (150 mg,1.83 mmol), and triethy(amine (0.50 mL, 3.66 mmol)~in dioxane (10 mL) was refluxed with stirring for 30 min, cooled to room temperature, concentrated, and purified by flash column chromatography (10-X50% ethyl acetate/hexanes) to give 337 mg (82%) of the title compound of Example~247, Step A
as a yellow oil. 'H NMR (CDC13, 300 MHz, 9:5 mixture of rotamers) 8 7.67-7.52 (c, 2H), 7.36 (t, 1 H), 4.87 (s,1.3H), 4.81 (s, 0.7H), 3.96-3.86 (c, 2H), 3.08-3.02 (c, 2H), 2.72 (s, 6H); MS (TS) 337 (MH').
Step B: 1.2.3.4-Tetrahvdnrisoauinoline-7-sulfonic aad dimethvlamide. A mixture of 2-trif(uoroacetyt-1,2,3,4-tetrahydro-isoquinotine-7-suffonic aad dimethylamide (prepared acxording to the method of Example 247; Step A, 337mg,1.0 mmol) and potassium carbonate (207 mg,1'.5 mmol) in a 3:1 mixture of methanollwater (10 mL) was stirred at room temperature for 1 h and concentrated. The remaining aqueous residue was extracted with 10% isopropanoUchloroform (7x) and the combined organic extras were dried over sodium sulfate, filtered, and evaporated to give 214 mg (89%) of the title compound of Example 247, Step B as a white solid. 'H NMR
(CD,OD, 300 MHz) b 7.52 (d, 1 H), 7.48 (s,1 H), 7.36 (d, 1 H), 4.90 (s, 2H), 3.11 (t, 2H), 2.91 (t, 2H), 2.65 (s, 6H); MS (CUNH,) 241 (MH').
Step C: fR~1-f4-t7-0imethvlsulfamovl-3.4-dihvdr~o-1 H-isoouinolin-2-vll-rnrrimidin-2-yt~-ethyl acetate. To a solution of 1,2,3,4-tetrahydro-isoquinofine-7-sulfonic aad dimethylamide (prepared according to the method of Example 247, Step B, 210 mg, 0.88 mmol) in isopropanol (5 mL) was added (R}-1-(4-chloro-pyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation five,175 mg, 0.88 mmol) followed by triethylamine (0.24 mL, 1.75 mmol). This mbchrre was stirred at room temperature for 1.75 h then heated to retlux for 1.5 h, cooled to room temperature, WO 00159510 PCTIIBOOIOOZ96 .
evaporated, and purified by flash column chromatography (1%
methanoUcHlbrofonn) to give 327 mg (92%) of the title compound of Example 247, Step C as a white solid.
'H NMR (CDCI,, 250 MHz) 8 8.28 (d,1 H), 7.68-7.58 (c, 2H), 7.47 (d, 1 H), 6.44 (d, '1 H), 5.72 (q, 1H), 4.86 (s, 2H), 3.92 (t, 2H), 3.05 (t, 2H), 2.73 (s, 6H), 2.19 (s, 3H), 1.62 (d;
3H); MS (TS) 431 (MH').
Step D: (Rl-2-T2-(1-H~droxv~thvll-ovrimidin-4-of1-1.2.3.4-tetrahvdro-isoauinoline-7-sulfonic acid dimethylamide. To a solution of (R)~1-j4-(7-dimethylsulfamoyl-3,4-dihydro-lH-isoquinolin-2-yl)-pyrimidin-2-yt]-ethyl acetate (prepared according to the method of Example 247, Step G, 326 mg, 0:81 mmol) in a 4:1 mixture of methanolMrater~(8 mL) was added t'~thium hydroxide hydrate (170 mg, 4.0 mmol).
This mixture was stirred at room temperature for 50 min, concentrated, n.-suspended in water, and extracted with 10% isopropanoUchlorofortn (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified 1by flash column chromatography (1 % methanoUchloroform) to give a white foam which was further purified by recrystallization from ether/methanol to give 90 mg (31%) of the title compound as a white solid: mp: '120.5-122 °C;'H NMR (CDCI,, 300 MHz) 8 8.24 (d, 1 H), 7.62-7.59 (c, 2H), 7.35 (d,1 H), 6.44 (d, 1 H), 4.83 (s, 2H), 4.73 (q,1 H), 4.34 (br s, 1 H), 3.93-3.85 (c, 2H), 3.03-(t, 2H), 2.71 (s, 6H), 1 X52 (d, 3H); MS (TS) 363 (MHO.
Example 248 1-f4-(6-Thioohen-3-vt-3.4-dihvdro-1 H-isoauinoGn-2-vll-dvrimidin-2-vil-ethanol.
HO
~~~~Me S ~ ~ ~ N-N ~ /N
Step A: 6-Thioohen-3-vt-3,4-dihvdro-1 H-isoauinoline-2-carbox~c acid tert-butyl gster. A mixture of bis(benzonitrile)palladium(II) chloride (30 mg, 0.079 mmof) arid 1,4-bis(diphenyiphosphino)butane (33.6 mg, 0.079 mmol) in toluene (3 mL) was stirred at room temperature for 20 min. To this mixture was added &
trifluoromethanesulfonyloxy-3,4~ihydro-1 H-isoquinoline-2-carboxylic aad tart-butyl ester (300 mg, 0.79 mmol, Synth. Common. 1995, 25, 3255), thiophene-3-boronic aad (131 mg,1.02 mmol), 1 M aqueous sodium carbonate (1.57 mL,1.57 mmol), and ethanol (2 mL). This dark mixture was heated to reflux with stirring under nitrogen pCT/IB00/00296 overnight, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (4x). The,combined organic extracts ;
were dried over sodium sulfate, filtered through Celite, evaporated, and purified by flash column chromatography (hexanes-->5% ethyl acetate/hexanes) to give 252 mg (100%) of the title compound of Example 248, Step A as a pale yellow waxy solid. 'H
NMR (CDCI,, 250 MHz) b 7.47-7.38 (c, 5H), 7.14 (d, 1 H), 4.60 (s, 2H), 3.~2-3.64 (c, 2H), 2.95-2.82 (c, 2H), 1.52 (s, 9H); MS (TS) 316 (MH'). , Step B: 6-Thioohen-3-vl-3.4-dihvdro-1 H-isoauinofine ~drochloride. A mixture' of 6-(thiophen-3-yl-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tart-butyl ester; (prepared 7 0 according to the' method of Example 248, Step A, 250 mg, 0.79 mmol) and hydrochloric aad (4 M in dioxane, 6 mL, 23.8 mmol) was stir-ed at room temperature for 1 h and concentrated to give 170 mg (86%) of the title compound of F~cample 248, Step B as a yellow solid that was used without purification in the next step.
'H NMR
(CD,OD, 250 MHz) 8 7.66 (m,1H), 7.61-7.53 (c, 2H), 7.51-7.42 (c, 2H), 7.23 (d, 2H), 4.38 (s, 2H), 3.52 (t, 2H), 3.16 (t, 2H); MS (TS) 216 (MH').
Step C: (R~-1-f4-f6-ThioDhen-3-vl-3.4-dihvdro-1 H-isoauinolin-2-vl~pvdmidin-2-y(~-ethvl acetate. To a solution.of 6-thiophen-3-yl-3,4-dihydro-lH-isoquinoline hydrochloride (prepared according to the method of Example 248, Step B, 170 mg, 0.68 mmol) in isopropanol (6 mL) was added (R~1-(4-chloro-pyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Five; 136 mg, 0.68 mmol) followed by triethylamine (0.28 mL, 2.04 mmol). This mixture was stirred at reflux for 7 h, cooled to room temperature overnight, evaporated, and purified by flash column chromatography (0.51 % methanoUchlorofoml) to give 253 mg (98%) of the title compound of Example 248, Step C as a yellow solid. 'H NMR (CDCI,, 250 MHz) E
8.26 (d, 1 H), 7:52-7.36 (c, 6H), 6.43 (d, 1 H), 5.73 (q, 1 H), 4.76 (s, 2H), 3.96 3.82 (c, 2H), 3.02 (t, 2H), 2.21 (s, 3H), 1.63.(d, 3H); MS (TS) 380 (MH').
Step D: 1~4-f6-'Thioahen-3-vl-3 4-dihydro-1 H-isoauinolin-2-vl1-ovrimidin-2-yf1-ethanol.
To a solution of (R}-1-(4-(6-thiophen-3-yl-3,4-dihydro-l H-isoquinolin-2-yl)-pyrimidin-2-y(j-ethyl acetate (prepared according to the method of Example 248, Step C, 253 mg;
0.67 mmol) in a 3:1,:1 mixture of methanoUtetrahydrofuranlwater (5 mL) was added lithium hydroxide hydrate (84 mg, 2.0 mmol). This mixture was stirred at room temperature for 1 h, concentrated, re-suspended in water, and extracted with .
chloroform (4x). The combined organic extracts were dried over sodium sulfate, pC'TIIB00/00296 filtered, evaporated, and purifed by flash column chromatography (2% ~ , methanoUchloroform) to give a yellow solid which was further purified by recrystallization from ether/methanol to give 163 mg (72%) of the title compound as a white solid. mp: 125.5-127.5 °C; 'H NM,R (CDCI,, 300 MHz) S 8.22 (d, 1 H), 7.47-7.35 (c, 5H), 7.22 (d, 1 H), 6.42 (d, 1 H), 4.78.72 (c, 2H), 4.46 (br s, 1 H), 3.93-3.84 (c, 2H), 2.99 (t, 2H), 1.54 (d, 3H); MS (APCI) 338 (MH'). , , Examples 249 to 252 Examples 249 to 252 were prepared from the appropriate starting materials in a manner analogous to the method of Example 248.
' Rza H O
..... Me N
N ~ ~N
Example . R= " mp (C) MS (MH') _ 249 6-thiophen-2-yl i 04-105 338 250 6-pyrimidin-5-yl ~ 334 251 7-pyrimidin-5-yl 135-137 334 252 6-hydroxy 272 Examples 253 to 258 Examples 253 to 258 were prepared from the appropriate starting materials in a manner analogous to the method of Example 86.
:
HO
~ ...., Me Rza~~ ,.. ~ ~- .
N N ~ ~ ~N
Example Rz' mp (C) MS (MHO
253 H _ 79-82 258 254 Me ~ 272 ~
256 NHz 20&210 273 257 Ph 128-131 334 258 pyridin-4-yl ~ Exarrrole 259 (Rl-1-f4-(3-Benzothiazot-2-vt-5 6-dihvrd~o-8H,~1 2 4Ltriazolof4 3-alo~razin-7~r1~
pvrimidin-2-vll-e~anol.
Me Step A: 5-Ethoxy 3.6-dihvdro-2H-nvrazine-1-carboxylic acid benzvi ester. To a i0 solution of 3-oxo-piperazine-1-carboxylic aad benzyl ester (2.0 g, 8.54 mmol, Maybridge) in dichioromethane (18 mL) at room temperature was added triethyloxonium tetrafluoroborate (4.1 g, 21.3 mmol). This mixture was allowed to stir for about 3 days then quenched by the addition of ice chips followed by saturated aqueous sodium bicarbonate until a neutral pH was obtained. The organic layer was separated and the aqueous layer was extracted with chloroform.(3x). The aimbined organic extracts were washed with brine (1 x), dried over sodium sulfate, and concentrated to give 2.11 g (95%~ of the title compound of .Example 259, Step A as a slightly yellow oil that was sufficiently pure,~to carryon to the next step.
'H NMR
(CDCI,, 300 MHz) b 7.43-6.97 (c, 5H), 5.17 (s, 2H), 4.i0 (q, 2H), 3.98 (s, 2H), 3.60-3.40 (c, 4H),1.27 (t, 3H); MS (APCI) 263 (MH').
Step B: 3-__Benzothiazol-2 vl-5.6-dihvdn3-8H-f1.2.41triazolot4.3-alovrazine-7-carboxylic acid benzvl ester. A mixture of 5-ethoxy-3,6-dihydro-2H-pytazine-1-carboxylic~acid benzyl ester (prepared according to the method of Example 259, Step A, 490 mg, 1.87 mmol) and benzothiazole-2-cart~oxylic aad hydrazide (360 mg, 1.87 mmot;
J.
Org. Chem.1958, 23, 134.4) in n-butanol (2 mL) was stirred at reflux overnight, cooled to room temperature, concentrated, arid purified by flash column chromatography (1 methanoUchloroform) to give 580 mg of the tibe compound of F-xample 259, Step B
(contaminated with an equimolar amount of benzothiazole-2-carboxylic aad hydrazide which was removed in the subsequent step) as a yellow solid.
Step C: 3-Benzothiazol-2-vl-5.6-dihvdn~-8HJ1.2.41triazolof4 3-alovrazine. To a solution of 3-benzotniazol-2-y!-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-carboxylic aad benzy! ester (prepared according tQ the method of Example 259, Step B, 580 mg, contaminated with bdnzothiazole-2-carboxylic aad hydrazide) in dichioromethane (10 mL) at 0 °C was added a solution of boron tribromide (1 M in dichloromethane, 4.45 mL, 4.45 mmol). This mixture was warmed to room temperature overnight, quenched by addition of water, and cflncentrated. The residual aqueous layer was washed with ether (6x), neutralized with saturated aqueous sodium bicarbonate, and extracted with 10% isopropanoUchloroform (3x).
The combined organic extracts v~re dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1-X10% metharioUchlorofom~) to give 175 mg (36%, two steps) of the title compound of Example 259, Step C as a white solid. 'H NMR (CDCh; 300 MHz) 8 8.05 (d,1 H), 7.96 (d, 1 H), 7.57-7.41 (c, 2H), 4.62 (t, 2H), 4.36 (s, 2H), 3.35 (t, 2H); MS (APCI) 258 (MH').
Step D: (Rl-1-(4-(3-Benzothiazol-2-vl-5 6-dihvdro-8H~1 2 4lhiazolol4 3-aiovra rr7 ~rt~-ovrimidin-2-yfl~thvl butyrate. A mixture of 3-benzothiazol-2-yl-5,6-dihydro-8H-[1.2.4]triazolo[4,3-a]Pyrazine (prepared according to the method of Example 259, Step C, 170 mg, 0.66 mmol), (R)-1-(4-chloro-pyrimidin-2-y1)-ethyl butyrate (prepared according to the method of Preparation Seven, 150 mg, 0.66 mmvl), and triethylamine (0.28 mL, 1.98 mmo() in n-butanol (2.2 mL) was heated to reflux overnight, cooled to room temperature, evaporated, and purified by flash column chromatography (1 %
methanol/chloroform) to give 224 mg (76%) of the title compound of Example 259, Step D as a colorless solid. 'H NMR (CDCI,, 300 MHz) s 8.37 (d, 1 H), 8.08 (d, 1 H), 7.97 (d, 1 H), 7.57-7.43 (c, 2H), 6.53:(d, 1 H), 5.71 (q,1 H), 5.09 (s, 2H), 4.82 (t; ~2H), 4.33-4.26 (c, 2H),.2.42 (t, 2H), 1.78-1.64 (c, 2H),1.61 (d, 3H), 0.99 (t, 3H);~MS (APC1) 450 (MH'). .
Step E: (R~-1-t4-f3-Benzothiazo(-2-v(-5.6-dihvdero-8H-I1.2.41trfazolo14.3-alovr'azin-7-vll-ovrimidin-2-vl1-ethanol. To a solution of (Ry-1-[4-(3-benzothiazol-2-yl-5,6-dihydro-8H-[1,2,4)triazolo[4,3-a]Pyrazin-7-YI)-Pyrimidin-2 ytj-ethyl butyrate (prepared according to the method of Example 259, Step 0, 220 mg, 0.49 mmol) in a 3:1:1 mixture of tetrahydrofuraNmethanoUwater (5 mL) was added lithium hydroxide hydrate (62 mg, 1.47 mmol). This mixture was stined at room temperature for 3 h, concentrated, and extracted with chloroform (3x). The combined organic extracts were died over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (5%
methanollchioroform) to give 192 mg (100%) of the title compound as a cotortess solid. mp: 216.5-218.5 °C;'H NMR (CDCI,; 300 MHz) S 8.37 (d, 1 H), 8.06 (d, 1 H), -7.97 (d, 1 H), 7.56-7.45 (c, 2H), 6.56 (d, 1 H), 5.11 (s, 2H), 4.83 (t, 2H), 4.77 (m, 1 H), 4.35-4.25 (c, 2H), 4.16 (s, 1 H), 1.54 (d, 3H); MS (APCI) 380 (MH-), [a]p +14,2 (c 1.0, CHCt,).
Examples 260 to 263 Examples 260 to 263 were prepared from the appropriate starting materials in a manner analogous to the method of Example 259.
WO 00!59510 HO ' ~N .,...Me j ~~ . N_ ~~N N N
\ ~
xampte R"_ mp (C) MS (MHO
260 phenyl 161-164 ~ 323 261 quinoxalin-6-yl 212-215 375 262 benzothiophen-2-yl 224-226 , 379 263 biphen-4-yl 123-i25 399 Example 264 (Rl-1-14-(Soirofbenzothiaaoline-2.4'-oioeridinel?-pyrimidin-2-v11-ethanol. ' HO
.... Me _ S N-W l N \ ~N
N
H
Step A: Soirofbenzothiazolip-2.4'-oioeridinel hydrochloride. To a solution of 1'-benzylspiro[benzothiazoline-2,4'-piperidine) (500 mg, 1.69 mmol; Indian J.
Chem.
19T6, X48, 984) in acetone (5 mL) at 0 °C was added 1-chloroethyl chlorofom~ate (0.37 mL, 3.38 mmol). This mixture was stirred at 0 °C for 2 h, warmed .to room temperature, and concentrated. The residue was purified by flash column chromatography (1025% ethyl acetatelhexanes) to give the intem~ediate carbamate which was refluxed in methanol (2 mL) for 30 min. Evaporation of the reaction mixture provided 128 mg (31 %) of the title compound of Example 264, Step A as a white solid.
'H NMR (CD30D, 400 MHz) 8 6.98 (dd,1 H), 6.88 (t,1 H), 6.68-6.64 (c, 2H), 3.48-3.34 (c, 2H), 3~5-3.11 (c, 2H), 2.39-220 (c, 4H); MS (APCI) 207 (MH').
WO 00!59510 pG"f/IB00/00296 Step B: (R~1-f4-(Soirofbenzofhiazoline-2.4 -niperidinej~nyrimidin-2-vIl-Ethyl butyrate.
To a solution of spiro[benzothiazolin-2,4'-piperidine] hydrochloride (prepared ' according to the method of ExaFnple 264, Step A, 147 mg, 0.60 mmol) in isopropanol (4 mL) was added (R~1-(4-chloro-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Preparation Seven, 140 mg, 0.60 mmol) followed by triethylamine (0.25 mL, 1.8 mmol). This mixture was stirred at reflux for 2 h, concentrated, and purified by flash column chromatography (1%-~2% methanollchforoform) to give mg (88%) the title compound of Example 264, Step B as a yellow oil. 'H NMR
(CDC13, 300 MHz) 8 8.20 (d,1 H), 7.09 (dd,1 H), 6.95 (t, 1 H), 6.78 (t, 1 H), 6.68 (d, 1 H), 6.40 (d, 1 H), 5.68 (q, 1 H), 4.32-4.18 (c, 2H), 4.02 (s, 1 H), 3.38-3.25 (c, 2H), 2.39 (t, 2 h), 2.36-2.25 (c, 2H), 1.99-1.83 (c, 2H), 1.75-1.64 (c, 2H);'1.57 (d, 3H), 0.9fi (t, 3H); MS (APCI) 399 (MH').
Step C: (Rl-1-f4-(Soirofbenzothiazoline-2.4'-piperidinel~nyrimidin-2-yfl-ethanol. A
mixture of (R}-1-[4-(spiro[benzothiazoline-2,4'-piperidine]}-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 264, Step B; 204 mg, 0.51 mmol) and lithium hydroxide hydrate (65 mg, 1.53 mmol) in a 2:2:1 rtiucture of tetrahydrofuraNmethanoUwater (5 mL} was stirred at room temperature for 1 h.
The organic solvents were evaporated and the residue was extracted with 10%
isopropanol/chlaroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2%
methanol/chlorofoml, 2x) to give a red foam which was further recyrstall'~zed (ethyl acetate) to give 42 mg (25%) of the title compound as a yellow solid. 'H NMR
(CDCI,, 400 MHz) b 8.18 (d, 1 H}, 7.07 (d, 1 H), 6.93 (td, 1 li), 6.78 (td, 1 H), 6.69 (d, 1 H), 6.42 (d, 1 H), 4.69 (m, 1 H); 4.35-4.16 (c, 3H), 4.02 (s, 1 H), 3.41-3.28 (c, 2H), 2.37-2.24 (c, 2H), 1.99-1.85 (c, 2H), 1.49 (d, 3H); MS (APCI) 329 (MH'); [a]o +17.3 (c 1.0, MeOH).
wo oo~s9sio rcr~soomo2~s Example 265 , , 4-f2-l1 R-Hvdroxv-ethvl~ovrimidin-4-v(t-3R.5S-dimethyl-piperazine-1-carboxylic acid methyl, ester. :~_ HO
."~ Me N-~ IN , , To a solution of 9 R-[4-(2R,fiS-dimethyl-piperazin-1-yt)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the procedure of Preparation Four, 70 mg, 23 Nmol) in tetrahydrofuran (2 mL) at room temperature under nitrogen was added triethylamine (63 NL; 46 Nmol) followed by methyl chiorofom~ate (21 IrL, 27 Nmol): This mixture was stirred for 1 h and concentrated. The residue was dissolved in a 3:1:1 mixture of methanoUtetrahydrofuran/water (2 mL) and lithium hydroxide hydrate (29 mg, fig pmol) was added. This mixture was stirred for 1 h, concentrated, re-suspended in water, and extracted with 1 d% isopropanoUchlorofonn (4x). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (1x), dried over sodium sulfate; filtered, and evaporated to give 50 mg (74%, 2 steps) of the tifae compound as a colorless oil. 'H NMR (CDCh, 400 MHz) 8 8.2i (d,1 H), 6.33 (d,1 H), 4.70 (m, 1 H), 4.63-3.92 (c, SH), 3.76 (s, 3H), 3.20-3.02 (c, 2H), 1.50 (d, 3H),1.25 (d, 6H); MS (APCI) 295 (MH'); [aJo +19.0 (c 0.9, MeOH).
Example 26~
1 R,~4~4-(2-f 1 R Butvnrloxv~thvll-pvrimidin~ vtl 2R 6S~imethvl-flioerazin 1 ~rl,~
nvrimidin-2-vll-ethyl but)rrate.
Me To a solution of 1 R-[4-(2R,6S-dimethyl-pipen~zin-1 yi)-pyrimidin-2-yIJ-ethyl butyrate (prepared according to the procedure of Preparation Four, 200 mg, 0 65 mmol) in isopropanot (2 mL) at room temperature was added triethylamine (0.18 mL, 1.31 mmol) followed by (Rr1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the procedure of Preparation seven, 150 mg, 0.65 mmol). This mixture was heated to reflex for 18 h, cooled to room temperature, concentrated and purified by flash column chromatography (1% methanoUchlorofortn) to give 321 mg (99%) of the title compound as a yellow oil. 'H NMR (CDCI3, 400 MHz) 8 8.22 (d, 2H), 6.43 (d,1 H), 6.32 (d, 1 H), 5.68 (q, 2H), 4.72-4.24 (c, 4H), 3.30-3.12 (c, 2H), 2.39 (t, 4H); 1.77-1.63 (c, 4H), 1.57 (d; 6H),1.28-1.17 (c, 6H), fl.96 (t, 6H); MS (APCI) 499 (MH').
yxamole 267 4-(4-f2-(1R-Hvdroxv-ethvll-pvrimidin-4-vl1-2R.6S-dimethYl-oinerazin-1-vl~-6-methyl I1.3.5~triazin-2-ol.
Me Me ,, N
N~N N~ -.- ~N
N ~ N
Meln~,..
Me OH
OH
1R-[4-[4-(4-Chloro-6-methyl-[1,3,5jtriazin-2 yl~3R,5S-dimethylpiperazin-1-yQ-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of t=xample 213, Step A, 0:30 g, 0.70 mmol) was added to concentrated hydrochloric aad (3 mL) and heated to reflex for 12 h. The mixture was neutralized to pH 7 with solid sodium bicarbonate and extracted into chloroform. The organic extract was dried over sodium sulfate and filtered. The filtrate was concentrated to an oil which was purified by flash chromatography (92:8 chloroform:methanol) to give the title compound as a white solid, 0.15 g (64%). 'H NMR (CDCI,, 300 MHz) 81.21 {d, 6H), 1.49 (d, 3H), 236 (s, 3H), 3.21-3.27 (m, 2H), 4.22-4.43 (m, 2H), 4.63 (m, 2H), 4.69 (q,1 H), 6.42 (d,1 H), 8.18 (d,1 H); mp: 247-248 °C; MS (CI) 346 {MH').
Examotes 268 to 275 Examples 268 to 275 were prepared from the appropriate starting materials in a manner analogous to the method of Example 267.
HC .
HO ~, Rs ..nMe !=N x/12 ,N~ ' N~N ~~~ ~~ /N
R" . sR78 , Example R" ~ R' R' mp (C) ~ MS (MHO
268 , , H 3R-Me 5S-Me > 250 332 _ 269 isopropyl 3R-Me 5S-Me > 250 374 ' 270 cydohexyl 3R-Me 5S-Me > 250 414 271 phenyl 3R Me 5S-Me >: 250 408 272 cydopropyl 3R-Me 5S-Me > 250 ~ 372 273 methyl 2R-Me 6S-Me > 250 346 274 cydopropyl 2R-Me 6S-Me > 250 372 275 phenyl 2R-Me 6S-Me > 250 408 Examoie 27~
(El-f4-Oxo-3-!5-trifiuoromethvl-benzothiaZOl-2-vimethvl~-3 4-dihvdro-ohthafazin-1-yl1-acetic acid 1R-f4-f4-l3-thioahen-2-vl-acrvlovfl-oioerazin-1-vft-ovrimidin 2 ytl-ethyl ester.
. O
~N r ~N, J -ON N
O CH
~N 3 ..
O N.~_ F F
To a solution of {4-oxo-3-(5-trifluoromethyl-benzothiazo!-2-yimethyl~3,4-dihydro-phthalazin_1-ylJ-acetic add (0.59 8,1.41 mmoi) in dichloromethane (30 mL) and dimethyiaminopyridine (0.18 g,1.41 mmol) was added 1-(3-dimethytaminopropyl~3-ethylcarbodiimide hydrochloride (0.54 g, 2.82 mmol) followed by (E}-1-(4-(2-(1R-wo oors9s><o rcrnsooiooz~
hydroxy-ethyl)-pyrirnidin-4-ylj-piperazin-1-y1}-3-thiophen-2-yl-propenone (prepared according to the method of F~cample 127, 0.49 8,1.41 rr~mo() at ambient temperature and stir-ed for 20 h. The mixture'was washed once with saturated aqueous sodium bicarbonate, once with saturated aqueous podium chloride, dried over magnesium sulfate and filtered. The filtrate was concentrated to an oil which was purified by flash chromatography (ethyl acetate) to give the title compound as a white foam, 0.65 g (62%). 'H NMR (CDCI,, 300 MHz) S 1.51 (d, 3H), 3.41-3.77 (m, 8H), 4.28 (m, 2H), 5.18 (q, 1 H), 5:79 (d, 1 H), 6.35 (d, 1 H); 6.68 (d, 1 H), 7.05, (m, 1 H), 7.32 (d, 1 H), 7.68 (m, 1 H), 7.71-7,90 (m, 5H), 8.18 (d, 1 H), 8.27 (d, 1 H), 8.46 (m, 1 H); mp:
105-109 °C;
MS (CI) 746 (MH'); ja]p +49.2 (c 1.0, MeOH).
Example 277 IE~f4-Oxo-3-l5-trifluoromethvl-benzothiazol-2-vlmethvl~-3.4-dihvdro-ot~i~thalazin-1-ytl-acetic acid 1R-f4-(4-ouinoxalin-2-vl-pioerazin-1-vl)-DVrimidin-2-vIl-ethyl ester.
Example 277 was prepared from the appropriate starting materials in a manner analogous to the method of Example 276. 'H NMR (CDCI,, 300 MHz) 81.53 (d, 3H), 3.38-3.87 (m, 8H), 4.28 (ms 2H), 5.18 (q, 7 H),. 6.35 (d, 1 H); 7.68 (m, 1 H), 7.58-?.94 (m, 8H), 8.18~(d, iH), 8.21-8.37 (m, 2H), 8.46 (m,1H); mp: 108-112 °C;
NIS (Ct) 738 (MH').
2-Methoxvmethvl-4-~inerazin-1-vl-wrimidine.
Step A: 2-Methoxvmethvl-pyrimidin-4-vl-methanesulfonate. To an ice cold solution of 2-methoxymethyl-3H-pyrimidin-4-one (35.0 g,~250 mmoi; US 5,215,990) and triethylamine (25.6 g, 250 mmol) in dichloromethane (250 mL) was added methanesuffonyl chloride (28.6 g, 250 mmol) dropwise. This mixture was allowed to warm slowly to room temperature over 1 h then washed successivelysroith saturated aqueous sodium bicarbonate and water. The organic layer was dried ~rer magnesium sulfate, filtered, and evaporated to give the title compound of Preparation One, Step A as a tan solid, 49.2 g (90%). 'H NMR (CDC4~, 300 MHz) 8 3.55 (s, 3H), 3.82 (s, 3H), 4.42 (s, 2H), 6.36 (d; 1 H), 8.12 (d,1 H); mp: 39-40 °C;
MS (TS) 219 (MH'). , ~ , Step B: 2-Methoxvmethyl~-Diberazin-1-vl-ovrimidine. To a solution of 2-methoxymethyl-pyrimidin-4-yl-methanesulfonate (prepared acdrding to the method of Preparation One, Step A, 43.6 g, 200 mmol) in tetrahydrofuran (400 mL) was added piperazine (34.4 g, 400 mmoi). This mixture was heated to reflux for 0.5 h, cooled to room temperature, and filtered. The filtrate was concentrated and dried under reduced pressure to give the title compound as a semi-solid, 36.6 g (85%). 'H
NMR
(CDCI,, 300 MHz) b 2.45 (br s,1 H), 2.88 (m, 4H), 3.45 (s, 3H), 3.72 (m, 4H), 4.46 (s, 2H), 6.38 (d, 1 H), 8.22 (d, 1 H); MS (TS) 209 (MH'). , Preparation Two ~Rl-1-(4-Pioerazin-1 vl-pyrimidin-2-vll-ethvi acetate. A mixture of (R)-i-(4-methanesulfonyloxy-pyrimidin-2-ylrethyl acetate (prepared according to the method of Preparation Six, 24.1 g; 92 mmol) and piperazine (16.0 g, 184 mmol) in tetrahydrofuran (200 mL) was heated at reflex for 1 h. This mixture was doled, 8ltEred, dncentrated, and purified by flash dlurtm chromatography (9:1 dichloromethanelmethanol) to °give 24.4 g (88%) of the title dmpound as an oil. 'H
NMR (CDCI,, 300 MHz) 81.56 (d, 3H), 2.25 (s, 3H), 2.83 (m, 4H), 3.63 (m, 4H), 5.54 (q, 1 H), 6.38 (d, 1 H), 8.24 (d, 1 H); MS (CI) 251 (MH').
Preparation Three 1R-f4-l3R.SS-Dimethvl-oioerazin-1-vl~-oyrtmidin-2-v0-ethvt butyrate. A mixture of (R~ .
1-(4-chloro-pyrimidln-2-yl)-ethyl butyrate (prepared acdniing to the method of Preparation Seven,18.5 g, 80.9 mmol) and as-2,6-dimethytpiperazine (18.6 8,162 mmol) in tetrahydrofuran (400 mL) was stirred at room temperature overnight, diluted with ether, and washed with saturated aqueous sodium bicarbonate (1x) and water (3x). The dmbined aqueous extracts were bade-extracted with 10°~
isopropanoUchloroform (6x). The cornbined~organic extracts were dried over sodium sulfate, filtered; evaporated, and purified by flash dlumn chromatography (1.-~5°h methanoUchloroform) to give 20.9 g (84°~) of the title compound as a waxy yellow solid. 'H NMR (CDCI,, 400 MHz) S 8.14 (d, 1 H), 6.31 (d, 1 H), 5.65 (q, 1 H), 4.53.16 -25i-(c, 2H), 2.89-2.78 (c, 2H), 2.47-2.33 (c, 2H), 2.38 (t, 2H).1.73-1.60 (c, 2H), ~f.55 (d, . 3H), 1.11 (d, 6H), 0.94 (t, 3H); MS (APCI) 307 (MH').
Precaration Four 1 R-f4-12R,.6S-Dimethvl-oioerazin-l:ylj~~rtimidin-2-vli-ethyl butyrate.
Step A: 114-(4-Benzvl-2R.6S-dimethv!-oiderazin-1-vl~dvrimidin-2-vli-ethyl butyrate.
A mixture of (R)-1-(4-trifluoromethanesulfonyloxy-pyrimidin-2-ylrethyl butyrate .. , (prepared according to the method of Preparatioh Nine, 84.8 g, 248 mmol) and cis-1-benzyl-3,5-dimethy1-piperazine (101 g, 496 mmol, Org. Prep. Proceed. Int.1976, 8, 19) in aoetonitrile (310 mL) was stirred at reflex for 15 h, concentrated, and purified by flash column chromatography (15% ethyl acetatelhexanes) to give 52 g (53°~) of the title compound of Preparation Four, Step A as an, orange oil. 'H NMR (COCI3, MHz) 8 8.15 (d,1 H), 7.39-7.24 (c, 5H), 6.25 (d,1 H), 5.66 (q,1 H), 4.45 (m,1 H), 4.24 (m, i H), 3.52 (s, 2H), 2.73 (d, 2H), 2.37 (t, 2H), 2.22 (d, 2H),1.70-1.60 (c, 2H),1.55 (d, 3H), i.30 (d, 3H), 127 (d, 3H), 0.93 (t, 3H); MS (APCI) 398 (MH').
Step B: 1 R-f4-(4-Benzvl-2R.6S-dimethvl-oioerazin-1-vl~vrimidin-2-v(l.ethvl but~rr a and 1S-f4-l4-Benzvl-2R 6S-dimethvl-eioerazin-1-v11-oyrimidin-2- -ethyl bulb. 1-I4-(4-Benzyl-2R,6S-dimethyl-piperazin-1-yl~pyrimidin-2-Y(J-ethyl butyrate (Prepared according to the method of Preparation Four, Step A,131 g, 79% ee) was purified by chiral HPLC under the following conditions (column:15 an id x 25 cm Prochrom column packed with Chiracel AD obtained from Chiral Technologies inc., 730 Springdale Dr., Exton, Pennsylvania,19341; mobile phase: 90:10 n-heptanefsopropanol; flow rate: about 1 Umin; loading: 4.2 glcycle) to provide the title compounds of Preparation Four, Step B (109 g, >98°~ ee) and (12.6 g, 93% ee), respectively, both as yellow oils. The 'H NMR and MS data for the preceding impounds were in agreement with that for scalemic material of Preparation Four, Step A.
Step C: 1R-f4-L4-Benzvl-2R 6S-dimethyl~ieerazin-1-vl~-nvrimidin-2-vi1-ethv!
bu~rrate t~rdrochloride. To a solution of i R-I4-(4-benzyl-2R,6S-dimethyl-piperazin-1 yI~ .
pyrimidin-2-ylJ-ethyl butyrate (prepared according to the method of Preparation Four, Step 8,109 g,. 275 mmot) in methanol (500 mL) was added hydrogen chloride (5 M
in methanol, 56 mL, 278 mmol). This mixture was stirred at room temperature for 5 n~ira and concentrated to give 118 g (990) of the title compound of Preparation four, Step C as a slightly yellow foam.
Step D: 1 R-14-(2R 6S-Dimethyl-oiperazin-1-vl)-pvrimidin-2-vll-ethyl butyrate.
To a solution of 1 R-[4-(4-benzyi-2R,6S-dimethyl-piperazin;l yl)-pyrimidin-2-ylJ-ethyl butyrate hydrochloride (prepares! according to the method of Preparation Four, Step C, 54.2 g, 125 mmol) in methanol (200 mL) was added ammonium formate (79 g, 1.25 mol) followed by a slurry of 10% palladium on carbon (13.5 g, 25 wt%) in methanol (200 mL). This mixture was stirred at reflux for 1 h and filtered through Celite. The filtrate was concentrated, diluted with saturated aqueous sodium bicarbonate, and extracted with chloroform (2x). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give 40.8 g of the title compound as a yellow oil.~'H NMR (CDCl3, 400 MHz) 8 8.16 (d, 1H), 6.26 (d, 1H), 5.66 (q, 1H), 4.39 (m, 1 H), 4.22 (m, 1 H), 2.93 (app s, 4H), 2.38 (t, 2H),1.71-1.62 (c, 2H),1.56 (d, 3H), 1.27 (d, 3H), 1.24 (d, 3H), 0.94 (t, 3H); MS (APC!) 307 (MH').
Preparation Five fR~-1-(4-Chloro-avrimidin-2-vl)~thvf acetate. (R)-2-(1-Acetoxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Thirteen, 3.00 8,16.5 mmol) was added to phosphorus oxychloride (10 mL) at ambient temperature and stin~ed for 3 h. Excess phosphorus oxychloride was removed under vacuum and the resulting oil was partitioned between chloroform and saturated aqueous sodium carbonate.
The layers were separated and °the organic layer was washed twice with water, once with saturated aqueous sodium chloride and dried over magnesium sulfate and filtered. The fltrate was evaporated to give the title compound as an orange oil, 288 g (87%). 'H.NMR (CDCI,, 300 MHz) b.1.56 (d, 3H), 2.18 (s, 3H), 5.68 (q,1 H), 6.32 (d, 1 H), 821 (d, 1 H); MS {CI) 201, 203 (MH'); [ajo +27.6 (c 1.0, MeOH).
Preparation Six (R~-1-l4-Methanesulfonvloxv-oyrimidin-2y11-et~rl acetate. To an ice cold solution of (Rj-2-(1-acetoxy-ethyl)-3H-pyrimidin-4-0ne (prepared according to the method of Preparation Thirteen, 258 g, 142 mmol) and triethylamine (1.43 g, 142 mmol) in dichloromethane (20 mL) was added methanesutfonyl chloride (1.63 g, 14.2 mmol) dropwise and stir-ed for 1 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate and filtered.
The filtFate was evaporated to give the title compound as an oil, 3.15 g (85%). 'H
NMR (CDCI,, 300 MHz) 81.56 (d, 3H), 2.i8 (s, 3H), 3.82 (s, 3H), 5.56 (q, 1H), 6.38 (d, 1 H), 8.24 (d, 1 H); MS (Cl) 261 (MH'); [a]o +53.8 (c 1.1, MeOH).
WO 00!59510 PGT/IBOOI00296 Preparation Seven iRl-i-l4-Chloro-ovrimidin-2-vtl-ethyl butyrate. (R~2-(1-Butyryloxy-ethyl~3H-pyrimidin~-one (prepared accorrJing to the method of Preparation Fourteen, 3.OO g, 16.5 mmol) was added to phosphorus oxychloride (10 mL) at ambient temperature and stirred for 3 h. Excess phosphonrs oxychtoride was removed under vacuum and the resulting oil was partitioned between dicttloromethane and saturated aqueous sodium carbonate. The layers were separated and the organic layer was,washed once with water, once with saturated aqueous sodium chloride and dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound as an orange oil, 3.19 g (85%). 'H NMR (CDCI,, 300 MHz) S 0.98 (t, 3H),1.54 (d, 3H), 1.67 (m, 2H), 2.48 (t, 2H), 5.68 (q,1 H), 6.36 {d, 1 H), 8.21 (d,1 H);
[ajo +27.6 (c 1.0, MeOH ).
Preparation Eiaht (Rl-1-(4-Methanesulfon~x~ pyrimidin-2-vl)~thvl butvr-ate. To an ioe cold solution of (Rr2-(1-butyryloxy-ethyl}-3H-pyrimidin-4-one (prepared according to the method of Preparation Fourteen, 17.8: g, 97.8 mmol) and triethylamine (9.9 g, 97.8 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (11.21 g, 97.8 mmol) dropwise and stirred for 1 h. The mixture was washed successively with saturated aqueous sodium bicarbonate arid water, dried over magnesium sulfate and filtered.
The filtrate was evaporated to give the title compound as an oil, 24.1 g (94%). 'H
NMR (CDCI,, 300 MHz) b 0.99 (t, 3H), 1.54 (d, 3H), 1.68 (m, 2H), 2.48 (t, 2H), 3.81 (s, 3H), 5.54 (q, 1 H), 6.38 (d, 1 H), 8.24 (d, 1 H); MS (CI) 281 {MH'); [ajo +28.8 (c 1.0, MeOH).
Preparation Nine (Rl-1-(4-Triftuoromethanesulfonvloxv-~yrimidin-2-vll-ethyl butyrate. ' Method 1: To a solution of (R~2-(1-bufyryfoxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Fourteen, 52 g, 248 mmol) and triethylamine (36.2 mL, 260 mn~l) in dichloromethane (830 mL) at 0 'C with stirring under nitrogen atmosphere was added a solution of trifluoromethanesulfonic anhydride (44 mL, mmot) in dichloromethane (70 mL) dropwise via addition funnel over 30 min, maintaining an internal temperature of 4-8 °C. This mixture was allowed to stir an additional 15 min at 4 °C, then quenched with water. After stirring for 10 min, the layers were separated and the aqueous layer was extracted with dichloromethane pCT/IB00/00296 (3x). The combined organic extracts were dried over sodium sulfate, filterad, and concentrated to give 47.2 g (-100°~) of the tifie compound as a dark oil which was used immediately in the next step. 'H NMR (CDCI3, 400 MHz) b 8.83 (d, 1H), 7.03 (d, 1 H), 5.82 (q,1 H), 2.41-2.32 (c, ZH),1.72-1.60 (c, 2H),1.62 (d, 3H), 0.95 (t, 3H); MS
(APCI) 343 (MH'). ' Method 2: To a solution of (R~2-(1-butyryloxy-ethyl~3H-pyrimidin-4-one (prepared according to the method of Preparation Fourteen, 4.20 g, 20.0 mmol) and, triethyfamine (2.02 g, 20.0 mmol) in dichloromethane (20 mL) was added trifluoromethanesulfonyl chloride (3.37 g, 20.0 mmol) dropwise, maintaining an intemaf temperature less than -20 °C, and stir=ed for 0.5 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, dried over sodium sulfate and filtered. The filtrate was evaporated to give the title compound as a dark oil, 6.42 g (94%), which was used immediately in the next step. 'H NMR
and MS data were were in agreement with that from Preparation Nine, Method 1.
Preparation Ten lRl-1-(4-Chloro-pvrimidin-2;yl~thanol. To a solution of (R)-i-(4-chioro-pyrimidin 2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 250 mg, 1.1 mmol) in dioxane (0.9 rizL) was added concentrated hydrochloric add (0.9 mL).
This mixture was allowed to stir,at room temperature for 5 h, quend~ed with saturated aqueous sodium bicarbonate followed by solid,sodium bicarbonate until no more gas evolution was evident Dichloromethane was added and the layers were separated.
The aqueous phase was extracted with dichloromethane (3x) and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give 125 mg (71%) of the title compound as a pale yellow oil. 'H NMR (CDCt,, 400 MHz) 8 8.59 (d, 1 H), 7.25 (d, i H), 4.92 (q,1 H), 3.81 (br s, 1 H),1.5fi (d, 3H); MS
(APCI) 159, 161 (MH').
Prenarat;on Eleven fR?-(+1-2-l1-Hvdroxv-ethvll-3H-ovrimidin-4-one hprdro-.
Step A: R-(+~-2-Hvdroxv-orooionamidine hvdrochioride. To a 22L, 3-neck round bottom flask equipped with reflux condenser, mechanical stirrer, themvometer and nitrogen inlet was added tetrahydrofuran (7.3 l-), R-(+~2fiydroxy-propionamide (T31 g, 82 mol) and triethyloxonium tetrafluorQborate (95°x,1.97 kg, 9.8 mol). The resulting yellow solution was allowed to stir at room temperature for 2 h, at which time an NMR sample indicated consumption of starting material and the presence of the desired imidate. The solution was concentrated under vacuum to provide a yellow oil which was taken up in methanol..(2 L). This solution was cooled to 15 °C and anhydrous ammonia was bubbled through the solution for 5 h. The resulting suspension was allowed to stir for 2 h. concentrated to a thick mixture, diluted with ethyl acetate and filtered through Celite. The filtrate was then cooled to ~0 °C, anhydrous hydrogen chloride was bubbled through the solution for 2 h, warmed to room temperature, and filtered to provide 418 g (41 %) of the title compound of Preparation Eleven, Step A. mp: 134-i38 °C;'H NMR (DMSO-ds, 300 MHz) S
1.33 (t, 3H), 4.42 (q, 1 H), 625-6.88 (br s, 1 H), 8.72-9.25 (br s, 3H).
Step B: fR~f+~2-(1-Hydroxv-ethvl~-3H-avrimidin-4-one hydrochloride. To a 22 L, nedc round bottom flask equipped with a reflux condenser, mechanical stirrer, thermometer and nitrogen inlet was added methanol (8 L), potassium hydroxide (946 g, 14.7 mot), R-(+}-2-hydroxy-propionamidine (prepared according to the method of Preparation Eleven, Step A,1848 g, 14.7 mot) and ethyl 3-hydroxy-acrylate sodium salt (prepared according to, the method of Preparation Twelve, Step C, 2030 g, 14.7 mot). The resulting slurty was stirred at room temperature for 3 h. The pH was adjusted from 125 to 7 by the addition of concentrated hydrochloric acid (1.32 L).
The solids were filtered off and washed with isopropanol. The filtrate was concentrated to an oil, diluted with isopropanol.(4 L), cooled to 10 °C
and anhydrous hydrogen chloride was bubbled through the solution for 4 h. The resulting suspension was filtered and the solids were dried to provide 2242 g (87%) of the title compound.
mp: 180-184 °C (dec);'H NMR (DMSO-db, 400 MHz) b 1.46 (d, 3H), 4.84 (q, 1H), 6.52 (d, 1 H), 8.00 (d, 1 H). -Preparation Twelve 2-(1-Hvdroxv-ethyl)-3H-oyrimidin-4-one.
Step A: 2-Hvdroxv-orooionimidic aad ethyl ester hydrochloride. A solution of lactonitrile (378 g, 5.32 mot) in ethyl ether (1.46 L).and ethanol (0.34 L) was saturated with hydrogen chloride gas at 0-5 °C for 0.5 h and kept at 5 °C
for 60 h. The resulting preapitate was filtered off and washed twice with ethyl ether to give the title compound of Preparation Twelve, Step A as a solid, 815 g (99%). mp: 165-168 °C;'H NMR
(CD,OD. 250 MHz) 8 1.45-1.53 (c, 6H): 4.40-4.61 (c, 3H).
p~~B00/00296 -25&
Step B: 2-Hvdroxv-orooionamidine hvdrochioride. A suspension of 2- ~ ~ , , hydroxypropionimidic acid ethyl ester hydrochloride (prepared according to the ..
method of Preparation Twelve, Step A, 751 g, 4.87 mol) in ethanol (3.75 L) at 0 °C
was saturated with ammonia gas, maintajning an ~intemal temperature < 5 °C, for 1 h then sorted at ambient temperatun: for 18 h. The solid was filten:d off and dried under vacuum at 40 °C to give an initial crop of material. The filtrate was concentrated to one-half volume and a second crop was collected and dried under vacuum. The first and second crops were combined to give the title compound of Preparation Twelve, Step B as a yellow solid, 608 g (99%). mp:134-138 °C;'H NMR (DMSO-dg, 400 MHz) s 1.30 (d, ~3H), 4.38 (q,1 H), 6.23 (br s, 1 H), 7.35 (br s, 1 H), 8.78 (br s, 3H).
Step C: Ethv13-hvdroxv-acrvlate sodium salt. To a suspension of sodium hydride (60°!° dispersion in oil, 269 8,16.7 mol) in isopropyl ether (12 L) was addBd slowly ethyl acetate (1280 g, 14.2 moi) at a rate which maintained an internal temperature of 45 °C. This mixture was stin~ed for and additional 0.5 h, then ethyl formats (2232 g, 30.1 mol) was added dropwise at 42 °C and stirred at ambient temperature for i 8 h.
The mixture was filtered and the solids v~re washed twice with ethyl ether and once with hexanes and dried to give the title compound of Preparation Twelve, Step C as a white solid, 1930 g (99%). 'H NMR (DMSO-a16, 300 MHz) b 1.03 (t, 3H), 3.86 (q, 2H), 4.08 (d, 1 H), 8.03 (d, 1 H).
Step D: 2-l1-Hvdroxv~th~rll-3H-ovrfmidin-4-one. To a solution of ethyl 3-hydroxy-acrylate sodium salt (prepared according to the method of Preparation Twelve.
Step C,1301 g, 9.42 rrml) in water (1.3 L) was added a solution of 2-hydroxy-propionamidine hydrochloride (prepared according to the method of Preparation Twelve, Step B, 610 g, 4.9 mol) in water (1.3 L) at ambient temperature and stirred for 48 h. The soluticn was adjusted to pH 7.0 with acetic aad then continuously extracted with chloroform for 48 h. The extract was dried over sodium sulfate and filtered. The filtrate was concentrated to a solid, slurried in ethyl ether, filtered, and dried to give the title compound as a solid, 232 g (38%). mp:121-124 °C;'H NMR (DMSO-de, MHz) S 1.30 (d, 3H), 4.46 (q, 1 H), 5.62 (br s, 1 H), 6.13 (d, 1 H), 7.80 (d, 1 H).
~ Preparation Thirteen 1R~2-l1-A~etoxv-ethvll-3H-ovrimidin-4-one. Ta a solution of vinyl acetate (4.3 g, 50 mmol) in dioxane (63 mL) was added 2-(1-hydroxy-ethyl~3H-pyrimidin-4.~one pCTIIB00/00296 (prepared according to the method of Preparation Twelve, 2.1 g, 15.1 mmol), and the ,, mixture was heated to 50 °C. To the resulting solution was added lipase P30 (0.21 g, , wt%) and the heating was continued for 24 h. The reaction mixture was filtered and the filtrate was evaporated to obtain a thick synrpy,liquid residue. The residue 5 was purified by flash column chromatography (95:5 dichloromethane:methanol) to give the title compound as a colorless liquid, 0.97 g (92% of theory). 'H
NMR.(CDCI,, 300 MHz) 81.61 (d, 3H), 2.20 (s, 3H), 5.65 (q, 1H), 6.35 (d, 1H), 7.97 (d, 1H), 11.94 (s, 1 H); [a]o +39.9 (c 1.0, MeOH).
Preparation Fourteen 10 (R~2-l1-Butvnrloxv-ethyl?-3H-ovrimidin-4-one.
Method 1: To a solution of vinyl butyrate (17.7 g, 310 mmol) in dioxane (650 mL) was added 2-(1-hydroxy-ethyl~3H-pyrimidin-4-one (prepared according to the method of Preparation Twelve, 21.8 g, 155 mmol), and the mixture was heated to 50 °C. To the resulting solution was added lipase P30 (4.35 g, 20 wt%) and the heating was continued for 24 h. The reaction mixture was filtered and the filtrate was evaporated to obtain a thick syrupy liquid residue which was partitioned between dichloromethane and water. The layers were separated and the organic layer was dried over sodium sulfate, filtered, and evaporated to give the title compound as a colorless liquid, 9.35 g (86% of theory). 'H NMR (CDCI,, 300 MHz) 0.95 (t, 3H), 1.65 (m, 5H), 2.40 (m, 2H), 5.65 (q, 1 H), 6.45 (d, 1 H), 8.00 (d, 1 H); [a]o +29.5 (c 1.0, MeOH).
Method 2: To a chilled (5 °C) solution of (R)-(+~2-(1-hydroxy-ethylr3H-pyrimidin-4-one hydrochloride (prepared according to the method of Preparation Eleven, 750 g, 4.3 mol) in dichloromethane (8 L) was added triethylamine (1216 mL, 8.7 mol) followed by 4-dimethylaminopyridine (25.9 g, 0.21 mol). A solution of butyric anhydride (730 mL, 4.4 mol) in dichloromethane (730 mL) was then slowly added over a period of 5 h, keeping the temperature <3 °C. The mixture was washed twice with half saturated brine (4 L) and once with saturated aqueous sodium bicarbonate (4 L), dried over sodium sulfate, filtered, and concentrated under vacuum to give 869 g (96%) of the title compound as an oil. The'H NMR and MS data for this compound are in agreement with that of Preparation Fourteen, Method 1.
Preparation Fifteen 1 R-T4-(2R.6S-Dimethvl-oiperazin-1-vl~-ovrimidin-2-v(l-ethyl butyrate dibenzovl-L-tartrate salt.
pCT/IBOOI003'96 Step A: 1R~4-Benzvl-2R 6S-dimethvl-oioerazin-1-vl)-ovrimidin-2-vl1-ethyl butyrate bis dibenzov!-L-tartrate salt. To a solution of (R)-2-(1-~utyrytoxy-ethyl}-3H-pyrimidin-4-one (prepared according to the method of Preparation Fourteen, 254 8,1.25 mol) and triethylamine (176 mL, 1.3 mol) in dichloromethane (23 L) at 5 °C
was slowly added a solution of trifluoromethanesulfonic anhydride (211 mL, 1.25 mol) in dichloromethane (355 mL) over a period of 3 h. The reaction was then quenched by the addition of cold water (1.4 L) and the layers were separated. The organic taye~
was washed once with saturated aqueous sodium bicarbonate (1.5 L), once with saturated aqueous sodium chloride (1 L), and the solvent was removed under vacuum. The resulting oil was dissolved in dimethylacetamide (890 mL) and added slowly to a solution of as-1-benzy!-3,5-dimethyl-piperazine (735 g, 3.6 mol) in dimethytacetamide (1.3 L) at 80 °C over a 1 h period. Heating at 80 °C was continued for 3.5 h, at which time the reaction was judged complete by gas chromatography:
After cooling to room temperature, water (2.5 L) and isopropyl ether (25 L) were added, the layers were separated, and the organic layer was washed once with water (2 L). The isopropyl ether layer was then mixed well with a solution of CuSO, (126 g) in water (3 L) and filtered through a layer of Celite, washing the filter cake with isopropyl ether (1 L). The aqueous layer of the filtrate was drained off, and the remaining organic.tayer was washed with water (ZL) and treated with a solution of dibenzoyl-L-tartaric acid (619 g, 2.4 mol) in isopropyl ether (5:3 L). The resulting thick white slurry was stirred for 16 h and the solids were filtered off, washed with isopropyl ether (2 L), and vacuum dried at 50 °C to yield 854 g (71 %) of the title compound of Preparation Fifteen, Step A as a white solid.'H NMR (DMSO-ds, 400 MHz) 8 0.89 (t, 3H),1.23 (d, 3N), 1.25 (d, 3H), 1.48 (d, 3H), 1.54 (dd, 2H), 220 (dd, 2H), 2.31 (dt, 2H), 2T7 (d, 2H), 3.57 (s,1 H), 4.45 (m, 1 H), 4.24 (m, 1 H), 5.51 (q, 1 H), 6.60 (d, 1 H), 7.30 (m, 1 H), 7.39 (m, 4N), 7.64 (m, 7H), 7.77 (m, 4 H), 8.05 (c, 7H), 8.17 (d,1H).
Step B: 1 R-f4-f2R.6S-Dimethyl-pioerazin-1-vl)-ovrimidin-2-vll-ethyl butyrate ., dibenzoyl-L-tartrate salt. To a mixture of 1R-[4-(4-benzyl-2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate bis dibenzoyl-L-tartrate salt (prepared according to the method of Preparation Fifteen, Step A, 50 g, 0.045 mol) and 5% palladium on carbon (50% wet, 10 g, 20 wt%) in methanol (400 mL) under a nitrogen atmosphere was added cydohexene {4.6 mL, 0.045 mol). This mixture was heated to reflux for 6 h, at which time the reaction was judged complete by TLC. After cooling to 40 °C, the mixture was filtered through Celite and washed with methanol (100 mL). The methanol was gradually displaced with isopropanol by atmospheric pressure distillation until a constant boiling point of 80-82 °C was attained, and the resulting white slung was cooled to room temperature and stirred for 4 h. The solids were filtered off, washed with isopropanol (100 mL), and vacuum dried at 50 °C to yield 25.7 g (86%) of the title compound as a white solid. 'H NMR (DMSO-ds, 400 MHz) b 0.90 (t, 3H), 7.15 (d, 3H), 1.21 (d, 3H), 1.47 (d, 3H), 1.55 (q, 2H), 2.3 (m, 2H), 3.04 (m, 2H), 3.2 (m, 2 H), 4.4 (br s, 1 H), 4.6 (br s, 1 H), 5.5 (q, 1 H), 5.74 (s, 2H), 6.6 (d;1 H), 7.5 (t, 4 H), 7.6 (m, 2H), 8.0 (m, 4H), 8.2 (d, 1 H).
Aitemabvely, according to Scheme V the Formula V-a found, wherein R' is as described above for the compound of formula NHE, is combined with a triethylorthoester (i.e., R'C(OEt), wherein R' is as described above for the compound ,, of formula NHE) and acetic anhydride at a temperature of about 120°C, to about 150 °C for about two to about five hours to prepare the Formula V-b compound.
The Formula V-b compound is cyctized with a Fomluta V-d compound, wherein R2 is as described above for the compound of formula NHE, to form the Formula V-c pyrazole.
The Formula V-c pyrazole is hydrolyzed with a base such as sodium hydroxide or lithium hydroxide in a solvent such as water andlor methanol andlor THF
conveniently at ambient temperature or at elevated temperature (e.g., reflux) for about one hour to about ftve hours to prepare the Fomtuta V-f acrd.
The Formula V-f acrd is coupled with guanidine in the presence of a suitable coupling agent as described for the above coupling of the Fomnula I-a acid and guanidine. In one embodiment, the Formula V-f acrd is activated with thionyl chtoiide at a temperature of about 60°C to about 90°C for about fifteen minutes to about two hours. The resulting activated acid chloride is combined with guanidine hydrochloride and an inorganic base (e.g., sodium hydroxide) in anhydrous tetratrydrof<rran and optionally methanol andlor water. The solution is heated, con~nientiy at reflux, for about one hour to about eight hours to prepare the Fomnula V-g compound.
Alternatively according to Scheme V the Fonnuta V-a compound can be directly converted to the Formula V-g compound by several methods. For example.
the Formula V-a compound can be heated in the presence of excess guanidine, in a polar protic solvent for example, methanol or isopropanol at a suitable temperature conveniently, at reflux for about one to about seventy two hours. This transfomsation may also be performed by repeatedly removing the solvent; for example removing ethanol or toluene about four times, from a mixhrre of the Formula Y-a compound and excess guanidine at a pressure of about one to about 100 mmHg and at a temperature of about 25°C to about 95°C. This reaction may also be performed in the absence of solvent by heating the rrindure of the Fortnuta V-a compound and excess guanidine at a temperature of about 100°C to about 180°C, optionaily at about a pressure of about 1 to about 100 mmHg for about five minutes to about eight hours.
According to Scheme VI, the Formula Vha compound, wherein R' is as described above for the compound of formula NHE, is reacted with the Formula VI-b compound, wherein R' and R2 are as described above for the compound of formula.
WO OOI59510 pGT/IB00/00296 NHE, in an aprotic solvent at a temperature of about 0°C to about 25°C for about two hours to about twenty-four hours in the presence of ah~appropriate amine base, such as triethylamine, to form the Formula VI-c compound.
The resulting Formula VI-c compound is hydrolyzed and coupled with guanidine using one of the methods described in earlier Schemes, such as the method employing carbonyldiimidazole, to form the Formula VI-d compound.
According to Scheme VII, the Formula VII-a hydrazine, wherein R2 is as described above for the compound of formula NHE, is reacted with the appropriate Formula VII-b compound to form the Formula VII-c pyrazote ester wherein R is lower alkyl according to the method of Bajnati, A. and Hubert Habart, M. Bu!!. Soc.
Chim.
France 1988, 540. 'The resulting pyrazole ester is converted to the Formula V11-d aryl guanidine using the hydrolysis and coupling methods described above.
According to Scheme Vlll, the Formula VIII-a compound wherein Rz and' R' are as described above for the compound of formula NHE is transfom~ed to the Formula Vllt-b Lithium salt where R is lower alkyl according to the method described in J. HeL Chem. ?989, 26,1389. the Formula VIII-b lithium salt is combined with the Formula VIII-c hydrazine, wherein R' is as described above for the compound of formula NHE, in an inert solvent such as ethanol, in the presence of a miners( acrd, at a temperatun: of about 20°C to about 30°C for about fare minutes to about one hour followed by heating to a temperature of about 70°C to about 110°C for two hours to about four hours to form both the Formula VIII-d and VIII-e pyrazotes. The Fom~ula Vlll-d and Vlll-e pyrazoles are converted to the Formula Vltl-f and VIII acyl guanidines respectively using the hydrolysis and coupling methods descrtbed above.
Some of the methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in Fom~ula I precursors). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods.
The need for such protection is readily determined by one skilled in the art The use of such protectioNdeprotection methods is also within the skill in the art For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley ~ Sons, New York, 1991.
The compounds of formula I of the present invention, when used in combination with NHE-1 inhibitors, inhibit the sodiumlproton (Na'!H') exchange transport system and hence are useful as a therapeutic or prophylactic agent for , diseases caused or aggravated by the acceleration of,the sodiumlproton (Na'!ti') exchange transport system, for example, cardiovascular diseases [e.g., arteriosclerosis, hypertension, atfiythmia (e.g. ischemic arrhythmia, ant~ythmia due to myocardial infarction, myocardial stunning, myocardial dysfunction, arrhythmia after PTCA or after thrombalysis, etc.), angina pectoris, cardiac hypertrophy,.
myocardial infarction, heart failure (e.g. congestive heart failure, acute heart failure, cardiac hypertrophy, etc.), restenosis after PTCA, PTCI, shock (e.g. hemorrhagic shock, endotoxin shock, etc.)], renal diseases (e.g. diabetes mellitus, diabetic nephropathy, isdlemic acute renal failure, etc.) organ disorders assodated with ischemia or tschemic reperfusion [e.g. heart muscle tschemic reperfusion assodated disorders, acute renal failure, or disorders induced by surgical treatment such as coronary artery bypass grafting (CABG) surgeries, vasarlar surgeries, organ transplantation, non-cardiac surgeries or perartaneous transluminat coronary angioplasty (PTCA)j, cerebrovascutar diseases (e.g. isdzemic stroke, hemorfiagtc stroke, etc.), cerebra ischemic disorders (e.g..disorders associated with cerebral infarction, disorders caused after cerebral apoplexy as sequelae, or cerebral edema.
Preferably, the compounds of fomwia t pf this invention can be used in combination with NHE-1 inhibitors as agents for myocardial protection before, during, or after coronary artery bypass grafting (CABG) surgeries; vascular surgeries, pen~rtaneous transluminat coronary angioplasty (PTCA), organ transplantation, or non-cardiac surgeries.
Preferably, the compounds of formula ! of this invention can be used in combination with NHE-1 inhibitors as agents for myocardial protection in patients presenting with ongoing cardiac (carte coronary syndromes, e.g. rrryocardial infarction or unstable angina) or cerebral ischemic events (e.g. stroke).
Preferably, the compounds of fomwta 1 of this invention can be used in combination with NHE-1 inhibitors as agents for chronic rtryocardial protection in patients with diagnosed coronary heart disease (e.g. previous myocardial infarction or unstable angina) or patients who are at high risk for myocardial infarction (age greater than 65 and two or more risk factors for coronary heart disease).
tn addition, a combination of the compounds of fomwla I of this.invention with NHE-1 inhibitors has a strong inhibitory effect on the proliferation of cells, for exar~le wo oo~s9s~o rcr~BOOiooz~
the proliferation of fibrobtast celis'and the proliferation of the smpQth muscle cells of the blood vessels. For this reason, the combination of the compounds of formula I of this invention with NHE-1 inhibitors of this invention is a valuable therapeutic agent for use in diseases in which cell proliferation fepresents a primary or secondary cause and may, therefore, be used as antiatherosderotic agents, and as agents against diabetic late complications, cancerous diseases, fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, glomerular nephrosderosis, organ hypertrophies or hyperplasias, in particular hyperptasia or hypertrophy of the prostate, pulmonary fibrosis, diabetic complications or recurrent strichrre after PTCA;
or diseases caused by endothelial cell injury.
The utility of the combination of compounds of the present invention with NHE-1 inhibitors as medical agents in the treatment of diseases, such as are detailed herein in mammals (e.g. humans) for example, myocardial protection during surgery or mycardiai protedyon in patients presenting with ongoing cardiac or cerebral isdzemic events or chronic cardioprotection in patients with diagnosed coronary heart disease, or at risk for coronary heart disease, cardiac dysfunction or myocardial stunning is demonstrated by the activity of said combination in conventional predinical cardioprotection assays [see the in vivo assay in Klein, H. et al., Circulation 92:912-917 (1995); the isolated heart assay in Schotz, W. et al., Cardiovascular Research 29:260-268 (1995); the antiacrhythmic assay in Yasutake M: et al., Am. J.
Physiol., 36:H2430-H2440 (1994); the NMR assay in Kolke et at., J. Thorac. Cardiovasc.
Sung.
112 ?65-775 (1996)] and the additional in vitro and in vivo assays described below.
Such assays also provide a means whereby the activities of the compounds of fomwla 1 of this invention can be compared with the activi(ies of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
Measurement of Human NHE-1 Inhibitory Activity Methodologies for measurement of human NHE-1 adtvity and inhibitor potency are based on those published by Watson et at., Am. J. Physiol., 24:6229-6238,1991 ), where NHE-mediated recovery of intracellular pH is measured following intracellular aad~cation. Thus, tabroblasts stably expressing human NHE-1 (Counillon; L et at.,,Mol. Pham~acol., 44:1041-1045 (1993) are plated onto collagen coated 96 well plates (50,QOOiwell) and grown to cont3uence in growth media (DMEM
WO 00/59510 PCTlIB00f00296 high glucose, 10°~ fetal bovine serum. 50 uiml penicillin and streptomyan)' ~ Confluent plates are incubated for 30 minutes at 37°C with the pH sensitive fluorescent probe BCECF (5 ~M; Molecular Probes, Eugene, OR). BCECF loaded cells are incubated for 30 minutes of 37°C in aad loading media (70 mM choline chloride, 50 mM NHCI,; 5 mM KCI, 1 mM MgCI?,1.8 mM CaCl2, 5 mM glucose,10 mM HEPES, pN 7.5), and then placed in a Fluorescent imaging Plate Reader (Mofecuiar Devices, CA):;, BCECF
,, fluorescence is monitored using exatation and emission wavelengths of 485 nM
and 525 nM, respectively. Intracellular aadihcatfon is initiated via rapid replacement of acid loading media with recovery media (120 mM NaCI, 5 mM KCI,1 mM MgCl2, 1.8 mM CaCl2, 5 mM glucose,10 mM HEPES, pH 7.5) ~ test combination, and NHE-mediated recovery of intracellular pH is monitored as the subsequent time-dependent increase BCECF fluorescence. The potency of the combinations of the compounds of formula I of this invention with NHE-1 inhibitors is calculated as the concentration that reduces recovery of intracellular pH by 50% (ICS). Under these conditions reference NHE inhibitors amiforide and HOE-642 had IC~ values for human NHE-1 of 50 ~AII
and 0.5 pM, respectively.
As background infom~ation, it is noted that brief periods of myocardial ischemia fo(iowed by coronary artery reperfusion protects the heart from subsequent severe myocardial ischemia (Muny et al., Circulation 74:1124-1136,1986).
The therapeutic effects of the combination of the compounds of formula 1 of this invention with NHE-1 inhibitors in preventing heart tissue damage resulting from an ischemic insult can be demonstrated in vitro along lines presented in Liu et al.
(Cardiovasc. Res., 28:1057-7061, 1994), as described specifically herein.
Cardioprotection, as indicated by a reduction in infarcted myocardium, can be induced pharrnacologicaNy using adenosine receptor agonists in isolated, retrogradely perfused rabbit hearts as an in vitro model of ~rdial ischemic preconditioning (Uu et al., Cardiovasc. Res., 28:1057-1061,1994). The in vitro test described below demonstrates thata test compound or, in this case a test combination (i.e., a combination of a compound of formula I with an NHE-1 antagonist) can also pham~acoiogically induce carciioprotection, i.e., reduced myocardial ir>tarct size, when administered to a rabbit isolated heart. The effects of the test combination are compared to ischemic preconditioning-and the A1/A3 adenosine agonise, APNEA
(N°-[2-(4-aminophenyl)ethytJadenosine), that has been shown to pharmaootogicatfy WO 00/59510 pCTIIB00I00296 induce cardioprotection in the rabbit isolated heart (Liu~et aL, Cardiovasc.
Res., 28:1057-1061, 1994). The exact methodology is described below.
The protocol used for these experiments closely follows that described by Liu et al., Cardiovasc. Res., 28:1057-1061,1994. Male New Zealand White rabbits (3-kg) are anesthetized with sodium pentobai~bitel (30 mglkg, i.v.). After deep anesthesia is achieved (determined by the absence of an ocular blink reflex) the animal is intubated and ventilated with 100°~ OZ using a positive pressure ventilator. A left thoracotomy is performed, the heart exposed, and a snare (2-0 silk) is placed loosely around a prominent branch of the left coronary artery, approximately 213 of the distance towards the apex of the heart The heart is removed from the diest and rapidly (<30 sec) mounted on a Langendorff apparatus. The heart is retrogradety perfused in a non-rearculating manner with a modified Krebs solution (NaCI
118.5 mM, KCI 4.7 mM, Mg SO, 1.2 mM, KHzPO, t.2 mM, NaHC03 24.8 mM, CaCh 2.5 mM, and glucose 10 mM), at a constant pressure of 80 mmHg and a temperature of 37°C. Perfusate pH is maintained at 7.4-7.5 by bubbling with 95% 015%
CO~. Heart temperature is tightly controlled by using heated reservoirs for the physiological solution and water jacketing around both the perfusion tubing and the isolated heart.
Heart rate and left ventricular pressures an: determined via a latex balloon which is inserted in the left ventride and connected by stainless steel tubing to a pressure transducer. The intraventricular balloon is inflated to provide a systolic pressure of 80-100 mmHg, and a diastolic pressure _< 10 mmHg. Total coronary flow is also continuously monitored using an in-line flow probe and normalized for heart weight The heart is allowed to equilibrate for 30 minutes, over which time the heart must show stable left ventricular pnasures within the parameters outlined above. If the heart rate falls below 180 bpm at any time prior to the 30 minutes period of regional ischemia, the heart is paced at about 200 bpm for the remainder of the experiment. tschemic preconditioning is induced by total cessation of cardiac perfusion (global ischemia) for 5 minutes, followed by reperfusi~ for 10 minutes. The regional ischemia is provided by tightening the snare around the coronary artery branch. Following the 30 minutes regional ischemia, the snare is released and the heart reperfused for an additional 120 minutes.
Pharmacological cardioprotection is induced by infusing the test combination, i.e., a corrrbinafron of a compound of formula I with an NHE-1 inhibitor, at WO 00/59510 PCTIIB00~00296 predetermined concentrations, starting 30 minutes poor to the 30 minutes regional ischemia, and continuing until the end of the 120 minutes reperfuston period.
Hearts which receive the test combination do not undergo the period of ischemic preconditioning. The reference compound, APNF~ (500 nM) is perfused through hearts (which do not receive the test compound) for a 5 minutes period which ends 10 minutes before the 30 minutes regional ischemia. , At the end of the 120 minutes reperfusion period, the coronary artery snare is tightened, and a 0.5% suspension of fluorescent zinc cadmium sulfate par6Ges (1-10 NM) Duke Scientific Corp.(Palo Atto, CA) is perfused through the hearty this stains alt of the myocardium, except that area-at-risk for infarct development (area-at-risk). The heart is removed from the Langendorff apparatus, blotted dry, wrapped in aluminum foil and stored overnight at -20°C. The next day, the heart is sliced into ,~ mm transverse sections from the apex to the top of the ventrides_ The slices are stained v~i~th 1 % triphenyt tetrazotium chloride (TTC) in phosphate-buffered saline for 20 minutes at 37°C. Since TTC reacts with living flssue (containing NAD-dependent dehydrogenases), this stain differentiates between fnring (red stained) tissue, and dead tissue (unstained infarcted tissue). The infarcted area (no stain) and the area-at-risk (no fluorescent partides) are catculated for each slice of left ventride using a precalibrated image analyzer. To normalize the ischemic injury for differences in the area-at-risk between hearts, the data is expressed as the ratio of infarct area vs. area-at-risk (%IAlAAR). All data are expressed as mean t SE and compared statistiraliy using a Mann-Whitney non-parametric test with a Bonfemoni cornection for multiple comparisons. Significance is considered as p < 0.05.
The results from the above in vitro test demonstrate that a combination of a compound of this invention with an NHE-1 inhibitor induce signficartt cardioprotection relative to the control group.
The therapeutic effects of a combination of a compound of formula t of this invention with an NHE-1 inhibitor in preventing heart tissue damage otherwise resulting from an ischemic insult can also be demonstrated in vivo along Unes presented in tau et at. (Circulation, Voi. &4:350-356,1991 ) as described speaficalty herein. The in vivo assay tests the cardioprotedion of the test combination, i.e., a compound of formula ! together with an NHE-1 inhibitor, relative to the control group which receives saline vehide. Cardioprotection, as indicated by a reducfion in pGTIIB00/00296 infarcted myocardium, can be induced pharmacologically using intravenously administered adenosine receptor agonists in intact; anesthetized rabbits studied as an in situ model of myocardial ischemic preconditioning (Liu et af., Circulation 84:350-356, 1991 ). The in vivo assay tests whether the instant combination of a compound of formula I with an NHE-1 inhibitor can phaiinaGOlogicaliy induce cardioprotection, i.e., reduced myocardial infarct size, when parenterally administered to intact, anesthetized rabbits. The effects of the combination of a compound of formula I of this invention with an NHE-11 inhibitor can be compared to ischemic preconditioning using the A1 adenosine agonist, N6-1-(phenyl-2R-isopropyl) adenosine (PIA) that has been shown to phamiacologicaAy induce cardioprotection in intact anesthetized rabbits studied in situ (Liu et al., Circulation 84:350-356, 1991 ). The methodology is described below.
Surcrerv: New Zealand White male rabbits (3-4 kg) are anesthetized with sodium .
pentobarbital (30 mg/kg, i.v.). A tracheotomy is performed via a ventral midline cervical incision and the rabbits are ventilated with 100% oxygen using a positive p pressure ventilator. Catheters are placed in the left jugular vein for dntg administration and in the left carotid artery for blood pressure measurements.
The hearts are then exposed through a left thoracotomy and a snare (00 silk) placed around a prorinent branch of the left coronary artery. lschemia is induced by pulling the snare tight and damping it in place. Releasing the snare allows the affected area to repertuse. Myocardial ischemia is evidenced by regional cyanosis;
reperfusion is evidenced by readive hyperemia.
Protocol: Once arterial pressure and heart rate have been stable for at least minutes the test is started. Ischemic preconditioning is induced by occluding the coronary artery for 5 rtvnutes followed by a 10 minutes reperfusion.
Pharmacological preconditioning is induced by infusing the test combination, i.e., a combination of a compound of formula I of this invention with an NHE-1 inhibitor, over, for example, 5 minutes and allowing 10 minutes before further intervention or by infusing the adenosine agonist, PiA (0.25 mg/kg). Following ischemic preconditioning, pham~acologicat preconditioning or no conditioning (unconditioned, vehicle control) the artery is occluded for 30 minutes and then reperfused for two hours to induce myocardial infarction. The test combination and PIA are dissolved in saline or other suitable vehicle and delivered at 1 to 5 mglkg, respectively.
wo oo~s9sio rcrnsooiooz~
Stainin (Liu et al., Circulation 84:350-356, 7 991 ): At the end of the 2 hour ~ , , reperfusion period, the hearts are quiddy removed, hung on a Langendorff apparatus, , and flushed for 1 minute with normal saline heated to body temperature (38°C). The silk suture used as the snare is then tied tighny to reocdude the artery and a 0.5%
suspension of fluorescent zinc cadmium sulphate particles (1-10 um) Duke Sdentific Corp. (Palo Alto, CA) is infused with the perfusate to stain all of the myocardium except the area at risk (nonfiuorescent ventricle). The hearts are then quiddy frozen and stored overnight at -20°c. On the following day, the hearts are cut into 2 mm slices and stained with 7 % triphenyl tetrazolium chloride (1'TC). Since TTY
reacts with living tissue, this stain differentiates between living (red stained) tissue, and dead tissue (unstained infarcted tissue). The infarded area (no stain) and the area at risk (no fluorescent particles) are calculated for each slice of left ventricle using a pre-calibrated image analyzer. To normalize the ischemic injury for differences in the area at risk between hearts, the data is expressed as the ratio of infarct area vs.
area at risk (%IA/AAR). All data are expressed as MeantSEM and compared statistically using single factor ANOVA or Mann Whitney non parametric test. Signficance is considered as p<0.05.
The combination of a compound of formula I of this invention with an NHE-1 inhibitor can be tested for their utility in redudng or preventing ischemic injury in non-cardiac tissues, for example, the brain, or the liver, utilizing procedures reported in the scientific literature. The combination of a compound of formula I of this invention with an NHE-1 inhibitor in such tests can be administered by the preferred route and vehicle of administration and at the preferred bme of administration either prior to the ischemic episode, during the ischemic episode, following the isdiemic episode (reperfusion period) or during any of the below-mentioned experimental stages.
The benefit of the combination of NHE-1 inhibitors and compounds of fortnuta 1 of this invention to reduce ischemic brain damage can be demonstrated, for example, in mammals using the method of Park, et al (Ann. Neurol.1988;24:543-551 ).
According to the procedure of Park, et al., adult male Sprague Dawley rats are anesthetized initially with 2% halothane, and thereafter by mechanical venWabon with a nitrous oxide-oxygen mixture (70%:30%) containing 0.5-1% halothane. A
tracheostotny is then perfom~ed. The stroke volume of the ventilator is adjusted to maintain arterial carbon dioxide tension at approximately 35 mm Hg and adequate arterial oxygenation (PaOz>90 mm Hg). Body temperature can, be monitofed by a rectal thermometer, and the animals can be maintained normothermic, if necessary, by external heating. The animals next undergo subtemporal cxanieto expose the main trunk of the left middle cerebral artery (MCA) under an operating microscope, and the exposed artery is occluded with microbipolar coagulation to generate large ischemic lesions in the cerebral cortex and basal ganglia.
After three hours of MCA occlusion, the rats are deeply anesthetized with 2% halothane and a thoracotomy is pertormed to infuse heparinized saline into the left ventricle.
The effluent is collected via an indsion of the right atrium. The saline washout is followed by approximately 200 m! of a 40% formaldehyde, glaclal acetic add and absolute methanol solution (FAM;1:1:8, v/vlv), then the animals are decapitated and the head is stored in fixative for 24 hours. The brain is then removed, dissected, embedded in paraffin wax, and sectioned (approximately 100 sections 0.2mm per brain). The sections are then stained with hematoxylin~osin or with a combination of cresyl violet and Luxol fast blue, and examined by light microscopy to identify and quantitate the ischemic damage using a precalibrated image analyzer. The isdzemic volumes and areas are expressed in absolute units (mm' and mmz) and as a peroentage of the total region examined. The effect of the compositions and methods of this invention to reduce ischemic brain damage induced by MCA occlusion is noted based on a reduction in the area or volume of relative or absolute ischemic damage in the brain sections from the rats in the treatment group compared to brain sections from rats in a ptaoebo-treated control group.
Other methods which could alternatively be utilized to demonstrate the benefit of the invention to reduce ischemic brain damage include those described by Nakayama, et al, in Neurology 1988, 38:1667-1673;_ Memezawa, et al. in Stroke 1992, 23:552-559; Folbergrova, et al. in Pros. Natl. Acad. Sd 1995, 925057-5059; and Goth, et al. in Brain Res.1990, 522:290-307.
The benefit of the compositions and methods of this invention to reduce ischemic liver damage can be demonstrated, for example, in mammals using the method of Yokoyama, et al. (Am. J. Physiol.1990~58:G564-G570). According tp the procedure of Yokoyama, et al., fasted adult male Sprague Dawley rats are anesthetized with sodium pentobarbital (40 mglkg i.p.), then the animals are trad~eotomized and mechanically ventilated with room air. The fryer is extirpated and placed in an environmental chamber maintained at constant temperature (37 ~°C), then perfused through the portal vein at a constant pressure pf 15 cm H=0 with a mod~ed, hemoglobin-free Krebs-Henseleit buffer (n mM:118 NaCI, 4.7 KCI, 27 NaHCO', 2.5 CaClz, 1.2 MgSO" 12 KH=PO,, 0.05 EDTA, and 11, mM,glucose, plus 300 U
heparin).
The pH of the perfusate is maintained at 7.4 by gassing the buffer with 95% 02 - 5%
COZ. Each liver is perfused at a flow rate of 20 mUminutes in a single-pass, manner for a 30 minutes washout and equilibration period (preischemic period), followed by a 2 hour period of global ischemia, and then a 2 hour period of reperfusion under conditions identical to the preisdtemic period. Aliquots (20 ml) of the perfusate are collected during the preischemic period, immediately after the occlusive isd~emic period, and every 30 minutes of the 2 hour reperfusion period. The perfusate samples are assayed for the appearance of hepatocellular enzymes, for example, aspartate amino-transferase (AS't~, alanine amino-transferase (ALTS, and lactate dehydrogenase (LDH), which are taken to quantitatively reflect the degree of ischemic liver tissue damage during the procedure. AST, ALT, and LDH activities in the perfusate can be determined by several methods, for example, by the reflectometry method using an automatic Kodak Ektachem 500 analyzer reported by Nakano, et al.
(Hepatology 1995;22:539-545). The effect of the compositions and methods of this invention in reducing ischemic liver damage induced by occlusion is noted based on a reduction in the release of hepatooelluiar enzymes immediately following the ocdus'rve period andlor during the postischemio-reperfusion period in the perfused livers from the rats in the treatment group compared to perfused fivers from rats in a placebo-treated control group.
Other methods and parameters which could alternatively be utifrzed to demonstrate the benefit of the compositions and methods of this invention in redudng isd~emic liver damage include those described by Nakano, et at. (Hepatology 1995;22:539-545).
Any glycogen phosphorylase inhibitor may be used as the second compound of this invention, The term glycogen phosphorylase inhibitor refers to any substance or agent or any combination of substances andlor agents which reduces, retards, or eliminates the enzymatic action of glycogen phosphorytase. The currently known enzymatic action of glycogen phosphorylase is the degradation of glycogen by catalysis of the reversible reaction of a glycogen macrortrolearle and incxganic phosphate to glucose-i-phosphate and a glycogen macromolecule which is one glucosyl residue shorter than the original glycogen macromolecule (forward direction of gfycogenolysis). Such actions are readily determined by those. skilled in the art according to standard assays (e.g., as described hereinafter). A variety of these compounds are inducted in the following published PCT patent applications: PCT
application publication WO 96139384 and W096I39385. However, other glycogen phosphoryiase inhibitors will be known to those skilled in the art Compounds of formula l, prodrugs thereof, mutual prodrugs of the compounds of formula I with aldose reductase inhibitors, pharmaceutically acceptable salts of any of the above and pharmaceutical compositions comprising a compound of formula 1, a prodrug thereof or a pham~aceutically acceptable salt of said compound or said prodrug and either (a) an aldose reductase inhibitor, a prodrug thereof or a pham~aceutically acceptable salt of said aldose reductase inhibitor or said prodrug, (b) a NHE-1 inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said NHE-1 inhibitor or said prodrug, or a glycogen phosphorytase inhibitor, a prodrug thereof or a pham~aoeutically acceptable salt of said glycogen phosphorylase inh~itor or said prodnrg are hereinafter referred to, collectively, as "the active compounds and oomopositions of this invention."
The active compounds and compositions of this invention may be administered to a subject in need of treatment by a variety of conventional routes of administration; inducting orally, parenterally and topically. In general, compounds of the formula I and their pharmaceutically acceptable salts will be administered orally or parenterally at dosages between about 0.001 and about 100 mglkg body weight of the subject to be treated per day, preferably from about 0.01 to 10 mglkg, in single or divided doses. Mutual prodrugs of compounds of the formula Land aldose reductase intu'bitors will generally be administered orally or parenterally at dosages between about O.OOi and about 100 mglkg body weight of the subject to be treated per day, preferably from about 0.01 to about 10 mglkg, in single or divided doses.
Compositions containing both a compound of the fom~ula I and an aldose reductase inhibitor will generally be administered orally or parenterally at dosages between about 0.001 and about 100 mg of each active component (i.e., the cor~ound of fomwia I and the aldose reductase inhibitor) per kg body weight of the subject to be treated per day, preferably from about 0.01 to about 10 mglkg. Compositions containing both a compound of formula I and a NHE-1 inhibitor will generally be administered orally or parenterally at dosages between about 0:001 and 100 mg of said compound of formula I per kg body weight of the subject to be treated per day and about 0.001 to 100 mglkg/day of the NHE-1 inhibitor. An especially preferred dosage contains between about 0.01 anti 10 mglkglday of said compound of formula I
and between about 0.01 and 50 mglkglday of said NHE-1 inhibitor. Compositions containing both a compound of fortiiula I and a gicogen phosphorylase inhibitor will generally be administered orally or parenterally at dosages between about 0.001 and 100 mg of said compound of formula I per kg body weight of the subject to be treated per day and 0:005 to 50 mg/kglday of said glycogen phosphorytase inhibitor, preferably 0.01 and 10 mglkglday of said compound of formula and 0.01 to 25 mglkg/day of said glycogen phosphorylase inhibitor and most preferably 0:01 and 10 mglkg/day of said compound of formula and 0.1 to 15 mglkglday of said glycogen phosphorylase inhibitor. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
The active compounds and compositions of this invention may be administered alone or in combination with pharme~utically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical carriers indude inert solid diluents or fillers, sterile aqueous solutions and various organic solvents_ The pharmaceutical compositions formed by combining the active compounds of formula I
of this invention and the phamnaceutically acceptable carriers are then readily administered in a variety of dosage fom~s such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pham~aceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, exapients and the like.
Thus, for purposes of oral administration, tablets containing various exapients such as sodium citrate, cafaum carbonate and calaum phosphate may be employed along with various disintegrants such as starch, alginic aad and certain complex silicates, together with binding agents such as potyvinylpyrrolidone, sucrose, gelatin and acaaa. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as 511ers in soft and hard filled gelatin capsules.
WO 00159510 pCTIIB00100296 Prefer-ed materials for this indude lactose or milk sugar and high molearlar weight polyethylene gtycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring ri~atter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
For parenteral administration; solutions of the active compounds and compositions of this invention in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be t 0 suitably buffered if necessary and the liquid diiuent first~rendenrd isotonic with sufficient saline or glucose. These partiarlar aqueous solutions are espeaally suitable for intravenous, intramuscxriar, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media employed arse all readily available by standard techniques known to those skilled in the art Administration of the compounds of formula 1 of this inventi~ can be via any method which delivers a compound of this invention preferentially to the desired tissue (e.g., nerve, kidney, retina andlor cardiac tissues). These methods indude oral routes, parenteral, intraduodenal routes; etc. Generally, the compounds of the present invention are administered in single (e.g., once daily) or multiple doses or via ant infusion.
The compositions of this invention comprising a compound of fomu~la I in combination with an NHE-1 inhibitor are useful, for example, in reduang or minimizing damage effected directly to any tissue that may be susceptible to ischemialreperfusion injury (e.g., heart, brain, lung, kidney, Liver, gut, skeletal muscle, retina) as the result of an ischemic event (e.g., myocardial infarction). The composition is therefore usefully employed prophytadically to prevent, i.e.
(P~Pe~IY ~ ProPhY~~~IIY) m blunt or stem, tissue darrrage (eg., rtyoc~rdial tissue) in patients who are~at risk for ischemia (e.g., myocardial ischert~ia).
Generally, a compound of formula I of this invention is adrronistened orally, or parenterany (e.g., intravenous, intramuscutar, subcutaneous or intramedullary).
Topical administration may also be indicated, for example, where the patient is suffering from gastrointestinal disorders or whenever the medication is.best applied to the surface of a tissue or organ as determined by the attending physician.
pCTIIB00/00296 The amount and timing of compounds administered wilt, of course,'be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgement of the prescribing physidan. Thus, because of patient to patient variability, the dosages given below are a guideline and the physician may titrate doses of the drug to achieve the treatment that the physidan considers appropriate for the patient In considering the degree of treatment desired, the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases.
Thus, for example, in one mode of administration the compounds of formula I
of this invention may be administered just prior to surgery (e.g., within twenty-four hours before surgery for example cardiac surgery) during or subsequent to surgery (e.g., within twenty-four hours after surgery) where there is risk of myocardial ischemia. The compounds of formula I of this invention may also'be administered in a chronic daily mode.
The compounds of the present invention are generally administered in the form of a pham~aceutical composition comprising at least one of the compounds of formula I of this invention together with a pham~aceutically acceptable vehide or diluent. Thus, the compounds of formula I of this invention can be administered individually or together in any conventional oral, parenteral, rectal flr transdem~al dosage forma For purposes of transdem~al (e.g.,topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1 % to 5%
concentration), otherwise similar to the above parenteral solutions, are prepared.
Methods of preparing various phamiaceubcal compositions with a certain amount of active ingredient are known, or will be apparent in light of this disdosure, to those skilled in this art For examples of methods of preparing pharmaceutical compositions, see Reminaton's Pharmaceutical Sciences, Madc Publishing Company, Easton, Pa:, '19th Edition (1995).
Pham~aoeutical compositions according to the invention may contain for example 0.0001%-95% of the compounds) of this invention. In any event, the composition or-formulation to be administered wiA contain a quantity of a compounds) according to the invention in an amount effective to treat the diseaselcondition of the subject being treated.
WO 00!59510 PGT/IB00/00296 The two different compounds of this combination of this invention can be co-administered simultaneously or sequentially in any order, or as a single pharmaceutical composition comprising a compound of Formuta I and an aldose reductase inhibitor as described above or a giyoQgen phosphorylase inhibitor as described above or a cardiovascular agent ~"
Since the present invention has an aspect that relates to the treatment of the diseaselconditions described herein with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharrnaceuticai compositions in kit form. The kit comprises two separate pham~aceutical compositions: a compound of formula I a prodnrg thereof or a satt of such compound or prodnrg and a second compound as described above The k'rt comprises means for containing the separate compositions such as a container, a divided bottle 'or a divided foil packet. TypicaNy the kit comprises dir~ec~tions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage fom~.s (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescxibing physican.
An example of such a kit is a so-called blister pads. Blister packs are well known in the packaging industry and are being widely used for the packaging of phamiaoeutical unit dosage fortes (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. the recesses have the size ancJ shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet Preferably the strength of the sheet is such that the tablets or capsules can be removed from tide blister pads by manually applying pressure on the recesses whereby an opening is fom~ed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specfied should be ingested.
Another example of such a memory aid is a calendar printed on the card, e.g., as follows ~Fin;t Wesk, Monday, Tuesday, ...etc.... Second Week, Monday, Tuesday,.. "
etc. Other variations of memory aids will be readily apparent. A "daily dose"~
can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of Formula I compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.
tn another speafic embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use~is provided.
Preferably, the dispenser is equipped with a memory-aid, so as to further facititate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed.
Another example of such a memory-aid is a battery-powered miao-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the fast daily dose has been taken andlor reminds one when the next dose is to be taken.
The compounds of formula I of this invention generally will be administered in a convenient formulation. The following formulation examples are illustrative only and are not intended to limit the scope of the present invention.
In the formulations which follow, "active ingredient" means a compounds) of this invention.
Formulation 1: Gelatin Capsules Hard gelatin capsules are prepared using the following:
Ingredient Quantity (mglcapsule) Alive ingredient 0.25-100 Starch. NF p.65p Starch fiowable powder 0.50 Silicone fluid 350 centistokes o-5 A tablet formulation is prepared using the ingredients below:
' WO 00/59510 pCT/IB00/00296 Formutation 2: Tablets . , Ingredient ' Quantity (mg/tablet) ' Active ingredient 0.25-100 Cellulose, microcrystalline , . , ' ' - 200-650 Silicon dioxide, fumed 10-650 Stearate acid 5-15 The components are blended and compressed to form tablets.
Alternatively, tablets each containing 0.25-100 mg of active ingredients are made up as follows:
Formulation 3: Tablets Ingredient Quantity (mg/tablet) Active ingredient 0.25-100 Starch 45 Cellulose, micxocrystalline 35 Polyvinylpyrrolidone (as 10% solution in water) 4 Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc 1 The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
The granules so produced are dried at 50° - 60°C and passed through a No. 18 mesh U.S:
sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
Suspensions each containing 0.25-100 mg of active ingredient per 5 ml dose are made as follows:
Formulation 4: Suspensions Ingredient Quantity (mgl5 ml) Active ingredient 0.25-100 mg Sodium carboxymethyl cellulose . 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 mL
Flavor q.v.
Color q.v.
Purified Water to 5 mL , The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Suffiaent water is then added to produce the required volume.
An aerosol solution is prepared containing the following ingredients:
Formulation 5: Aerosol Ingredient Quantity (% by weight) Active ingredient X0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane) 74.00 The active ingredient is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to 30°C, and transfer-ed to a filling device. The required amount is then fed to a stainless steel container and diluted with the remaining propellant. The valve units are then fitted to the container.
Suppositories are prepared as follows:
Formulation 6: Suppositories Ingredient Quantity (mglsuppository) Active ingredient 25p Saturated fatty aad glycerides 2,000 The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty aad glycerides previously melted using the minimal _1~
necessary heat. The mixture is then poured into a suppo$i~ry mold of nominal 2.g capacity and allowed to cool.
An intravenous fomwlation is prepared as follows:
Formulation 7: Intravenous Solution Ingredient . Quantity. .
Alive ingredient. 25 mg-10,000 mg Isotonic saline 1,000 mL
The solution of the above ingredients is intravenouslyr administered to a patient.
The active ingredient above may also be a combination of agents.
GENERAL EXPERIMENTAL PROCEDURES
Melting points were determined on a Thomas-Hoover Capillary Melting Point tus*, and are uncorrected. 'H NMR spectra were obtained, on a Bndcer AM-250*
(Broker Co., Billeriaa, Massachusetts), a Broker AM.300; a Varian XL 300 (Vari~tl Co., Palo Alto, Cafifomia), or a Varian Unily 400 at about 23 °C at 250, 300, or 400-MHz for proton. Chemical shifts are reported it parts per million (5) relative to residual chlorofornn (726 ppm), dimethylsulfoxide (249 ppm), or methanol (3.30 ppm) as an internal refen:noe. The peak shapes and descriptors for the peak shapes are der>abed as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, mufflplet; c, oompie~ br, broad;
app, apparent Law-resolution mass spectra were obtained under thertnospray (TS) conditions;on a Fsons-(now Micromass) Trio 1000 Mass Spec~romete~ (Miaornass -Inc., Beverly, Massachusetts); under chemical-ionization (CI) conditions on a Hewlett Padcard 5989A Particle Beam Mass Spectrometer (Hewlett Padcard Co., Palo Al~o, . California), or under atmospheric pressure chemical ion~tion (APCI) on a F~sons .
(now Miaomass) Platform II Spectrometeei optical rotations were obtained on a-Perkin-Elmer 241 MC Polarimete~ (Perkin-Elmer, Norvvalk, Connec~iart),using a standard path length of 1 clan at about 23 °C at the indicated concentration in the ~iaated soiveM.
Liquid column chromatography was performed using foroed flow (flash cluo<natography) of the indicated solvent on either Baker SH~a lief (40 Nm, J:
-T.
Baker, Phillipsburg, New Jersey) or Silica Gel 60~(EM Sclenoes, Gi>abstawa, New Jersey) in glass columns or using low nitrogen or air pressure in Flash 40~ or Flash *Trade-stark 12"" (Biotage; Charlottesville, Virginia) cartridges. Radial chromatography was perfomled using a Chromatrori (Harrison Research, Paio Alto. California). The temvs "concentrated" and "evaporated" refer to removal of solvent using a rotary evaporator ' at water aspirator pressure or at similar pressures generated by a Bi~chi B-Vacobox (Brinkmann Instrumertts, Inc., Westbury, New York) or a Bilchi B~177 -Vacobox with a bath temperature equal to or less than 50 °C. Reactions requiring the use of hydrogen gas at pressures greater than 1 atmosphere were run using a Parr hydrogen apparatus (Parr Instrument Co., Moline, Illinois). Unless otherwise specified, reagents were obtained from commercial sources. The abbreviations "d", "h", and "min" stand for "day(s)", "hour(s)", and "minute(s)", respectively.
~ 1 LRl-1-f4-f4-Quinoxalin-2 vl-~iperazin-1-vll-ovrimidin-2-vil-ethanol.
Me~~~~
Step A: L,RI-1-t4-l4-Quinoxalin-2-vl-oiperazin-1 vll-nyrimidin-2ar11-ethyl acetate. To a solution of (R}-1-(4-chioro-pyrimidin-2-yl}-ethyl acetate (prepared axording to the method of Preparation Five, 7.3 g, 362 mmol) in isopropanol (240 mL) was added triethylamine (10.1 mL, 72.4 mmol) followed by 2-(1-piper~azinyl~uinoxaline (10.1 g, 47.1 mmol; J. Med Chem.~ 1981, 24, 93). This mixture was stirred at room temperature overnight then concentrated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (5x): The combined organic extracts rare dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2% methanoUchloroform) to give 12.4 g t9i %) of the tills oompamd of Example 1, Step A as a yellow foam. 'H NMR (CDC~,, 250 MHz) b 8.61 (s,1 H), 8.27 (d,1 H), 7.91 (dd,1 H), 7.72 (dd, 1 H). 7.61 (td,1 H), 7.44 ~(td,1 H), 6.43 (d,1 H), 5.70 (q,1 H), 3.96-3.84 (c, 8H), 2.18 (s, 3H),1.G1 (d, 3H); MS
(CIINH~
379 (MH').
Step B: fR)-i-f4-(4-Quinoxafin-2-vl-nioerazin-1 vl)wrimidin-~ vll-ethanol. To a solution of(Rr1-[4-(4-quinoxalin-2-yl-piperatin-1-yl~pyrimidin-2-ylj-ethyl aoebte (prepared according to the method of Example 1, Step A, 14.1 g, 372 mirrol) in a *Trade-mark 3:1:1 mixture of tetrahydrofuranlwater/methanol (375 mL) was added lithiuri~
hydroxide hydrate (4.7 g, 112 mmol). This mixture wa$,stirred at room temperature for 1 h 45 min, concentrated, and extracted with chloroform (6x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2x; 2% methanoUchloroform) to give 11.3 g (90%) of the title compound as a pale yellow solid after tritration with hexanes. mp:
106.5-108 °C;'H NMR (CDCI,, 250 MHz) b 8.62 (s, 1H), 8.26 (d, 1 H), 7.92 (dd, 1 H), 7.72 (dd, 1 H), 7.61 (td, 1 H), 7.44 (td, 1 H), 6.45 (d, 1 H), 4.75 (m, 1 H), 3.95-3.85 (c, 8H), 1.54 (d, 3H); MS (CI/NH3) 337 (MH'); [a]o +15:3 (c 2.3, MeOH).
Example 2 (Rl-1-f4-t4-Oxazolof5.4-clpvridin-2-yl-oiperazin-1-yl~-ovrimidin-2-vll-ethanol.
N
Me~
Step A: (R~1-f4-(4-Oxazolof5.4-clpvridin-2-vl-oioerazin-1-vl~ovrimidin-2-vfl-ethyl but)rrate. To a sotu6on of 2-(1-piperazinyl~xazoto[5,4-c]pyridine (775 mg, 3.8 mmol;
J. Org. Chem. 1995, 60, 5721 ) in isopropanol (38 mL) was added (Ry-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 868 mg, 3.8 mmol) followed by triethylamine (1.6 mL, 11.4 mmol). This mixture was sfin-ed at reflux overnight, cooled to room temperature, and evaporated.
The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3x). , The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2x; 3%
methanoUchloroform then 6~8% methanoUethyl acetate, where used herein, the arrow symbol, ~, indicates a gradient) to give 1.2 g (T9%) of the title compound of Example 2, Step A as a pale yellow oil which solidfied upon standing. 'H NMR
(CDCI,, 250 MHz) b 8.57 (s,1 H), 8.39 (d, 1 H), 8.28 (d,1 H), 7.30 (d, 1 H);
6.44 (d, 1 H), 5.70 (q, 1 H), 3.85 (s, SH), 2.42 (t, 2H), 1.78 -1.61 (c, 2H), 1.60 (d, 3H), 0.98 (t, 3H);
MS (APCI) 397 (MH').
Step B: IRS-1-f4-(4-Oxazolof5 4-cjovridin-2-vl-Diperazin-1 yll-ovrimidin 2 vfl~thanol.
To a solution of (Rj'1-[4-(4-oxazolo[5,4-c]pyridin-2-yl-piperazin-1-yl}-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Example 2, Step A, 1.2'g, 3.0 mmol) in methanol (30 mL) was added potassium carbonate (823 rng, 6.0 mmol).
This mixture was stirred at room temperature for 5 h, diluted with saturated aqueous ammonium chloride, concentrated, and extracted with chloroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (6% methanoUchloroform) to give 915 mg,,(94%,) of the title compound as a white solid after tritra6on with hexanes. mp: 181-183 °C; 'H NMR
(CDC13, 300 MHz) b 8.54 (d, 1 H), 8.35 (d, 1 H), 8.25 (d, 1 H), 7.27 (dd, 1 H), 6.44 (d, 1 H), 4.71 (q, 1 H), 4.25 (br s, 1 H), 3.86-3.83 (c, 8H), 1.50 (d, 3H); MS
(APCI) 327 (MH'); (a]D +15.3 (c 0.5, MeOH).
Example 3 1 R-l4-f 1'-f2-f 1 R-Hydroxy-ethyll-avrimidin~-vl1-f4 4'lbipiaeridin~rl-1-vl~-ovrimidir~ 2 v11-ethanol.
N~N N~N
\ N~ ~ ~N
Me~~~~ Me OH OH
A mixture of (R)-1-(4-chloro-pyrimidin-2-ylrethanoi (prepared according to the method of Preparation Ten, 100 mg, 0.63 mmol), 4,4'-bipiperidine dihydrochloride (76 mg, 0.32 mmol), and triethylamine (0.44 mL, 32 mmol) in isopropanol (3 mL) was refluxed overnight and cooled to room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (4x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (Biotage Flash 40S"', 5%
methanoUchlorofortn) to give 110 mg (85%) of the title compound as a white solid.
mp: 144-153 °C,'H NMR (CDCI,, 400 MHz) S 8.14 (d, 2H), 6.36 (d, 2H), 4.67 (q, 2H), 4.53.4.28 (c: 4H), 2.84 (t, 4H), 1.82 (d, 4H), 1.49 (d, 6H), 1.43-1.40 (c, 2H),1.30-1.18 (c, 4H); MS (APCI) 413 (MH'); [a]p +22,6 (c 1.0, MeOH).
Examples 4 to 8 Examples 4 to 8 were prepared from the appropriate starting materials in a manner analogous to the method of Example 3.
Example 4 1 R-l4-f4-f2-( 1 R-Hvdroxv-ethvll-ovrimidin-4-v(1-2R.5S-dimethvl-oiperazin-1-vi~-wrimidin-2-v1)-ethanol.
Me. , N~N N~N
\ N ~---/ ~N
Me~~~~ Me Me OH OH
mp: 153-155 °C,'H NMR (CDCI,, 400 MHz) 8 8.23 (d, 2H), 6.40 (d, 2H), 4.71 (m, 2H), 4.28 (dd, 2H), 3.51-3.45 (c, 4H),1.51 (d, 6H), 1.23 (d, 6H); MS (APCI) 359 (MH'); [ac)p +18.6 (c 1.2, CHCI3).
OH HO
Me .... Me -N N-N ~ / N-linker- N ~ / N
Example N-tinker-N mp (°C) MS (MHO
5 N,N'~thylenediamine 141-143 333 6 [1,4)diazepane 136-138 345 7 4,4'-ethylenebipiperidine 8 methyl-piperidin~-ylmethyl-amine 373 Example 9 IRl-1-f4-(4-Oxazolof5.4-blpyridin-2-yl-~iperazin-1-vll-wrimidin-2-ytl-ethanol.
N
N~n~~ I
\ N ~ O N
Me"..
OH
Step A: 2-l1-Pioerazinvl)oxazolof5 4-bloyridine. A mixture of 2-(thiomethyl~xazolo[5,4-b)pyridine (92 g, 55.5 mmol; J. Org. Chem. 1995, 60, 5721 ) pGTIIB00/00296 and piperazine (23.9 g, 277 mmol), with a small amount of ethyl acetate wHich was ; , used for washing the compound down the sides of the flask, was heated at 90 °C for , , 1.5 h. The reaction mixture was cooled to room temperature, diluted with -20%
saturated aqueous sodium bicarbonate solution, and eXtracted with chiorofortn (4x).
The combined organic extracts were washed with saturated aqueous sodium bicarbonate {1 x), dried over sodium,sutfate, filtered, evaporated, and purified by flash column chromatography (3-~5% methanoUchloroform + 1% ammonium hydroxide) to give 9.1 g (81 °1°) of the title compound of Example 9, Step A
as an off white solid. 'H
NMR (CDCI,, 300 MHz) S 7.92 (dd, 1 H), 7.55 (dd, 1 H), 7.10 (dd, 1 H), 3.74-3.70 (c, 4H), 3.02-2.97 (c, 4H); MS (APCI) 205 (MH').
Step B: (R~1-f4-l4-OxazoloT5.4-blavridin-2-vl-oioerazin-1-vl)-ovrimidin-2-vll-ethyl bu te. To a solution of (R~1-(4-chloro-pyrimidin-2-yl~ethyl butyrate (pfepar~ed according to the method of Preparation Seven, 6.8 g, 29.9 mmol) and triethylamine (12.5 mL, 89.6 mmol) in isopropanol (100 mL) was added 2-(1-piperazinyl)oxazolo[5,4-b]pyridine (prepared according to the method of Example 9, Step A, 6.1 g, 29.9 mmol). This mixture was stirred at reflux overnight, cooled to room temperature, and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform {3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5->2% methanoUchloroform) to give 11.1 g (94%) of the title compound of Example 9, Step B as a yellow oil which solidfied upon standing. 'H
NMR~(CDCI,, 250 MHz) b 8.28 (d, 1 H), 7.97 (dd, 1 H), 7.60 (dd, 1 H), 7.25 (dd, 1 H), 6.44 (d, 1 H), 5.70 (q,1 H), 3.85 (app s, 8H), 2.42 (t; 2H), 1.78 -1.61 (c, 2H),1.60 (d, 3H), 0.98 (t, 3H); MS (APCI) 397 (MH').
Step C: (R)-1-I4-f4-Oxazolof5.4-blpvridin-2-vl-pioerazin-1-vl~ovcimidin-2-vll-ethanol.
To a solution of (Ry-1-[4-(4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2 ylj-ethyl butyrate (prepared according to the method of Example 9, Step B, 11.0 g, 27.6 mmol) in dioxane (11.5 mL) was added concentrated hydrochloric aad (23 mL, 276 mmol). This mixture was stirred at room temperature overnight, neutralized with 6 N
aqueous sodium_hydroxide, and extracted with chloroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purfied by flash column chromatography (3.5% methanoUchloroform) to give 8.4 g (93%) of the title compound as a white solid. mp: 153-156 °C; 'H NMR (CDCIj, 300 MHz) S 825 (d, 1 H), 7.95 (dd, 1 H), 7.58 (dd, 1 H), 7.15 (dd, 1 H), 6.45 (d, 1 H), 4.72 (q, 1 H), 4.25 (br s, 1H), 3.85-3.82 (c; 8H), 7.51 (d, 3H); MS (CIINH,) 327 (MH'); [~ajp +16.1 (c t.0, MeOH) Examoies 10 tol5 Examples 10 to 15 were prepared from the appropriate starting materials in a manner analogous to the method of Example 9.
R~
_ _ ~ N~ , ~N
Example X-Ar' R' nip (C) MS (MH') 10 oxazolo[4,5-c]pytidin-2-yl(R~CH(CH,)OH 178-180 327 11 oxazofo[5,4-c]pyridin-2-yl-C(CH,)ZOH 181-184 341 12 oxazolo[5,4-c]pyridin-2yl(t)-CH(CH3~H 153-758 327-13 oxazolo[5,4-cjpyridin-2-yl{S)-CH(CH,)OH 175-179 327 14 quinoxalin-2-yl (t)-CH(CH,~H 102-105 337 (5-iodorbenzoxazol-2-yl(R)-CH(CH,)OH 452 Example 16 1 R-f4-(3S-Methvl~-oxazolof5.4-blnvridin-2-vi-oinerazin-1 vl1-ovrimidin-2-vll-ethanol.
/~'~ N
N //- ~ --~~
\ N ~ O N
Me~~~~ Me OH
15 Step A: (Sl-2-f4-Benzv!-2-methyl-~ioerazin-1 vll~xazofo~5 4-blQVridine. A
modure of 2-(thiomethyl)oxazolo[5,4-b]pyridine (44 g, 264 mmol; J. Olg. Chem.1995, 60.
5721 ) and (Sy-1-benzyl-3-methyl-piperazine (25 8,132 mmol; J. Org. Chem.1995, 60, 4177) was sflmed at 130 °C for 3 d, cooled to room temperature, and purfied by flash column chromatography (1783% ethyl acetatelhexanes) to give 30 g (74%) of the tatte compound of Example 16, Step A as a dark yellow oil. 'H NMR (COCK, 400 MHz) 8 7.89 (d, 1 H), 7.53 (d, 1 H), 7.34-7.25 (c, 5H), 7.10 (dd, 1 H), 4.45 (m, 1 H), 4.11 (d, WO 00!59510 pCT/IB00/00296 1 H), 3.59 (d, 1 H), 3.52-3.45 (c, 2H), 2.90 (d, 1 H), 2.73 (d, 1 H), 2.32 (dd, 1 H), 2.21 (td, .,, 1 H), 1.41 (d, 3H); MS (APCI) 309 (MH').
Step B: fS)-2-f2-Methyl-oioerazin-1-vl)-oxazolo15.4-blp ny_dine. To a solution of (S)-2-(4-benzyl-2-methyl-piperazin-1-yl}-oxazolo[5,4-b]pyridine (prepared according to the method of Example 16, Step A, 30 g, 97 mmol) in methanol (970 mL) was added hydrogen chloride (5.85 M in methanol, 20 mL, 116 mmol), ammonium folmate (122 g, 1.95 mol), and 10 % palladium on carbon (60 g, 200 wt%). This mixture was stirred at reflux for 50 min, cooled, and filtered through Celite. The filtrate was concentrated, diluted with saturated aqueous sodium bicarbonate, and extracted with chlproform (1x) followed by 10% isopropanoUchloroform (4x). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give 16 g (76%) of the title compound of Example 16, Step B as a green oil. 'H NMR (CDCl,, 400 (MHz) 8 7.89 (m, 1 H), 7.53 (m, 1 H), 7.09 (m, 1 H), 4.42 (m, 1 H), 4.11 (d, 1 H), 3.35 (td, 1 H), 3.09=
3.03 (c, 2H), 2.85 (d, 1 H), 2.82 (td,1 H), 1.38 (d, 3H); MS (APCI) 219 (MH').
Step C: 1 R~4-l3S-Methvl-4-oxazolof5.4-blpvridin-2-vl-oioerazin-1-yl3-ovrimidin-2-v(1-ethvlbutvrate. A mixture of (S}-2-(2-methyl-piperazin-1-yl}-oxazolo[5,4-b]pyridine (prepared according to the method of Example 16, Step B, 10 g, 45.9 mmol), (R~1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 9.5 g, 41.7 mmol), and triethylamine (17.3 mL, 125 mmol) in isopropanol (230 mL) was heated at reflux for 30 h, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, and extracted with chloroform (4x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5% methanoUchlorofortn) to give 16 g (93%) of the title compound of Example 16, Step C as a yellow oil. 'H NMR (CDCI,, 400 MHz) S
8.23 (d, 1 H), 7.93 (dd, 1 H), 7.57 (d, 1 H), 7.13 (dd, 1 H), 6.39 (d, 1 H), 5.67 (q, 1 H), 4.61 (m, 1 H), 4.42 (m, 1 H), 4.28 (m, 1 H), 4.18 (dt, 1 H), 3.51 (td, 1 H), 3.41 (dd, 1 H), 3.17 (td, 1 H), 2.39 (t, 2H), 1.72-1.59 (c, 2H), 1.57 (d, 3H), 1.30 (d, 3H), 0.95 (t, 3H); MS
(APCI) 411 (MH').
Step D: 1 R~4-(3S-Methvl-4-oxazolof5.4-blavridin-2-vl-oioerazin-1 vl~nvrimidin-2 ~~
ethanol. A mixture of 1 R-[4-(3S-methyl-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-ylr pyrimidin-2-y(]-ethyl butyrate (prepared according to the method of Example 16, Step C,16 g, 39.0 mmol) and potassium carbonate (10.8 g, 78.1 mmol) in methanol (195 mL) was stirred at room temperature for 4 h, diluted with saturated aqueous sodium pCTnB00/00296 bicarbonate, and extracted with chforofonn (1x) followed by 10%
isopropanol/chloroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purfied by flash column chromatography (1->2.5%
methanoUchioroform) to give a white foam that was reaystallized from ether/chloroform to give 8.9 g (67%) of the tide compound as a white solid.
mp:147-149 °C; 'H NMR (CDCI,, 400 MHz) S 824 (d,1 H), 7.94 (dd,1 H), 7.58 (d,1 H); 7.14 (dd, 1 H), 6.42 (d, 1 H), 4.72 (m, 1 H), 4.64 (m, 1 H), 4.42 (m, 1 H), 4.32 (m, 1 H), 4.25 (d, 1 H), 4.21 (dt, 1 H), 3.54 (td,1 H), 3.46 (dd, 1 H), 3.24 (td,1 H), i .51 (d, 3H),1.33 (d, 3H); MS (APCI) 411 (MH'); [a]o +70.4 (c 1.1, MeOH).
Examples 17 to 25 Examples 17 to 25 were prepared from the appropriate starting materials in a manner analogous to the method of Example 16.
Examcle 17 i R-f4-(3S-Methvl-4-auinoxalin-2-vl-nioerazin-1 vl~-nvrimidin-2-vlt-ethanol.
Me~
'H NMR (CDC13, 400 MHz) b 8.56 (d, 1 H), 8.23 (d, 1 H), 7.89 (d, 1 H), 7.69 (d,1 H), 7.59 (t, 1 H), 7.41 (t, 1 H), 6.42 (d, 1 H), 4.78 (m, 1 H), 4.73 (m, 1 H), 4.43 (m,1 H), 4.38-4.23 (c, 2H), 3.64-3.52 (c, 2H), 3.38 (m, 1H),1.52 (d, 3H), 1.30 (d, 3H); MS (APCI) (MH'); [a]o +57.0 (c 1.2, CHCI3).
Example 18 1R-(4-f 4.6-Dimethvl-ovrimidin-2-vl~3S-methyl-vioerazin-1-vll-rnrrimidin-2-vt~-ethanol.
Me N-N~N N
N ~--~ \N
Me~~~~ Me Me OH
pCTIIB00100296 'H NMR (CDCI,, 400 MHz) b 8.18 (d, 1 H), 6.37 (d, 1 Hj, 6.30 (s, 1 H), 5.04 (m, 1 H), ~ ' 4.70 (q, 1 H), 4.60 (dt, 1 H), 4.37 (br s, 1 H), 4.36.12 (c, 2H), 3.40 (dd, 1 H), 3.34 (td, 1 H), 3.16 (td, 1 H), 2.28 (s, 6H), 1.51 (d, 3H), 1.16 (d, 3H); MS (APCI) 329 (MH'); (a]o +78.8 (c 1.6, MeOH).
Example 19 1 R-t4-f4-(2-Hvdroxymethvl-6-methyl-oyrimidin-d-vl~-3S-methyl-piperazin-'1-vf1-p~rrimidin-2 yf~-ethanol.
Me Me~~~~ , 'H NMR (CDCI,, 400 MHz) b 8.23 (d, 1 H), 6.38 (d, 1 H), 6.23 (s, 1 H), 4.71 (q, 1 H), 4.58 (s, 3H), 4.36-4.18 (c, 4H), 3.86 (br s, 1 H), 3.57 (dd, 1 H), 3.46 (td, 1 H);
3.32 (td, 1 H), 2.38 (s, 3H), 1.51 (d, 3H), 1.22 (d, 3H); MS (APCI) 345 (MH'); (a]~ +72.6 (c 1.1, MeOH).
Examaie 20 1 R-f4-(3S-Methyl-4-oxazolof4.5-blflvridin-2-yl-pit~erazin-1-~rl~pvrimidin-2-yf1-ethanol.
N N
N~N N---C
N ~ O /
Me~w Me OH
mp: 158-161 °C; 'H NMR (CDCI,, 400 MHz) b 8.22-8.15 (c, 2H), 7.40 (dd,1 H), 6.86 (dd, 1 H), 6.40 (d, 1 Hj, 4.65 (m, 1 H), 4.61 (m, 1 H), 4.44-4.20 (c, 3H), 4.18 (dt, 1 H), 3.50 (td, 1 H), 3.41 (dd, 1 H), 3.19 (td, 1 H), 1.45 (d, 3H), 1.26 (d, 3H); MS
(APCt) 341 (MH'); [aJo +582 (c 1.1, MeOH).
Example 21 1 R-f4-(3S-Methyl-4-oxazolo!'4 5-clpvridin-2 girl-c~ioerazin-1 yl)-nyimidin-2-v(a~thanol.
N ~N
N~/ --N N-~r~
N O I
Me ~". , , Me , OH
rcrnsooroo~
'H NMR (CDCI,, 400 MHz) b 8.68 (d,1 H), 8.32 (d,1 H), 8.24 (d, 1 H), 7.25 (dd,1 H), 6.42 (d, 1 H), 4.71 (m,1 H), 4.60 (m,1 H), 4.42 (m,1 H), 4.32-4.23 (c, 2H), 4.17 (dt,1 H), 3.56 (td, 1 H), 3.47 (dd, 1 H), 3.24 (td, 1,H),1.51 (d, 3H), 1.32 (d, 3H); MS
(APCI) 341 (MH'); [a]o +57.9 (c 1.6, MeOH).
Example 22 1 R-t4-(3S-Methyl~-oxazolof5.4-ciamidin-2-vl-oioerazin-1 vll-ovrimidin-2=vIl-ethanol.
N
N .rl ~ -~r I
N ~ O. /
Me~~~~ Me OH
'H NMR (CDC13, 40D MHz) b 8.56 (s,1 H), 8.37 (d, 1 H), 8.25 (d, 1 H), 7.29 (d, 1 H), 6.43 (d,1 H), 4.72 (m, 1 H), 4.65 (m,1 H), 4.45 (m,1 H); 4.29 (m,1 H), 4.26-420 (c, 2H), 3.58 (td, 1 H), 3.48 (dd, 1 H), 3.26 (td, 1 H), 1.51 (d, 3H), 1.34 (d, 3H); MS
(APCI) 341 (MH');
[a)p +61.1 (c 1.0, MeOH).
HO
Me ~~~~Me N-Ar'-X-N N~ . N
Example X~4~' C' Jo (°C) MS (MH"y 23 quinoxaiin-2-yl R 351 24 _ - (2-[C(CH~)zOH]}- py~imidin~-yi S 359 benzoxazol-2-yi S 340 -i 57-(=xam~le 26 1 R-l4-f4-f2-(1 R-Hvdroxv-ethyl)-pvrimidin-4-vIl-2R.6S-dimethvl-piperazin-1-vlf-pyrimidin-2-vl~ethanol.
Me~
OH OH
Method 1: To a~solution of 1R-[4-(2R,6S-dimethyl-piperazin-1-y!)-pyrimidin-2-yQ-ethyl butyrate (prepared according to the method of Preparation Four, 72.8 g, 238 mmol) and triethylamine (50 mL, 357 mmol) in isopropanol (793 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl~thyl butyrate (prepared according to the method of Preparation Seven, 54.3 g, 238 mmol). This mixture was stirred at reflux for 12 h and concentrated. The residue was dissolved in a 3:1:1 mixture of tetrahydrofuraNmethanoUwater (1200 mL) and lithium hydroxide hydrate (60 g, 1.43 mot) was added. This mixture was stirred at room temperature for 2.5 h, concentrated somewhat, diluted with saturated aqueous sodium bicarbonate, and extracted with 10% isopropanoUchloroform (6x). The combined organic extracts were dried over sodium sulfate; filtered, and evaporated. The residue was diluted with 1:1 ethyl acetatelmethanol (1100 mL) and stirred at room temperature for 1 h. The precipitate was collected by filtration and the filtrate was concentrated to about 850 mL.
After 1 h, more preapitate had formed and this material was collected by filtration. The filtrate was concentrated somewhat and ethyl acetate was added. After 1 h more precipitate had again formed and this material was collected by filtration. This was repeated one more time to give in total 65.9 g (77%) of the title compound as a white solid. mp:
163-164.5 °C; 'H NMR (CDCI,, 400 MHz) S 824 (d, 1 H), 823 (d, 1 H);
6.46 (d, 1 H), 6.36 (d, 1 H), 4.74-4.70 (c, 2H), 4.704.50 (c, 2H), 4.50-4.30 (c, 2H), 4.30 (d, 1 H), 427 (d, 1 H), 3.31 (dt, 2H), 1.51 (d, 6H), 1.26 (d, 6H); MS (APCI) 359 (MH'); [a]o +42.3 (c 1.0, MeOH).
Method 2, Step A: 1 R-(4-f4-f2-(1 R-Buivrvloxv~thvl~pvrimidin-4-vtl-2R 6S-dimethvl-piperazin-1-vl~-ovrimidin-2-vll-ethyl butyrate. To a solution of (R~2-(1-btrtyryloxy-ethylr3H-pyrimidin-4-one (828 g, 3.9 rr~ol) in dichloromethane (50 L) was added triethylamine (576 mL, 4.1 mol) and the resulting solution was copied to 5 °C. A
solution of trifluoromethanesulfonic anhydride (729 mL, 4.3 mol) in dichloromethane (6 L) was added slowly such that the internal temperature was maintained at <10 °C.
After the addition was complete, the reaction was judged complete by TLC and quenched by the addition of water (5.3 L). The organic layer was separated, washed with water (20 L) and saturated aqueous sodium bicarbonate (20 L), and'dried over sodium sulfate. This solution was then slowly added to a solution of 1 R-[4-(2R,fiS-dimethyl-piperazin-1-yl)-pyrimidin-2-ylj-ethyl butyrate dibenzoyl-L-tartrate salt (prepared according to the method of Preparation Fifteen, 2.49 kg, 3.75 mdl) and triethylamine (1.6 L, 11.6 mol) in dimethylacetamide (18 L) such that the internal temperature was maintained at <10 °C. The resulting solution was allowed to stir for 12 h at 10 °C and then diluted with ethyl acetate (40 L) and water (27 L).' The aqueous layer was removed and the organic layer was washed twice with water (40 L) and once with brine (20 L), and dried over sodium sulfate. The resulting solution was partially concentrated (8 L) and then hexanes (23 L) was added. The resulting suspension was allowed to granulate for 12 h and then filtered over cotton.
The solids were dried under vacuum (40 °C) to provide 1178 gm (63%) of the title compound of Example 26, Method 2, Step A as a white solid. The'H NMR and MS data for this compound are in agreement with that of Example 266.
Method 2, Step B: 1 R~4-t4-f2-l1 R-Hvdroxy-ethyl~pyrimidin~-v(1-2R.6S-dimethvl-piperazin-1-vll-pvrimidin-2-v()-ethanol. To a solution of 1 R-(4-(4-[2-(1 R-butyryloxy-ethylrpyrimidin-4-ylj-2R,6S-dimethyl-piperazin-1-yI)-pyrimidin-2-yl~ethyl butyrate (prepared according to the method of Example 26, Method 2, Step A, 1140 g, 2.28 mol) in isopropanol (11.4 L) was added 40% aqueous potassium hydroxide (800 mL) at room temperature. The resulting solution was allowed to stir for 16 h and then diluted with water (5 L) and dichloromethane (4 L). The organic layer was separated and the aqueous layer was extracted with dichloromethane (4 L). The combined organic layers were washed twice with 1 M aqueous sodium hydroxide (10 L) and twice with water {5 L), partially concentrated {5 L), diluted with ethyl acetate (4 L), and again partially concentrated (6 L). Hexanes (10 L) was added and the resulting slurry was allowed to stir at reflux for 12 h, cooled to room temperature, and filtered. The resulting solid was dried under vacuum to provide 758 g (93%) of the title compound pC'f/IB00/00296 as a white solid. The mp, 'H NMR, MS, and optical rotation data for this compound are in agreement with that of Example 26. Method 1.
Examples 27 to 62 Examples 27 to 62 were prepared from the appropriate, starting materials in a manner analogous to the method of Example 26.
Example 27 1 R-f4-f4-(4.6-Dimethyl-avrimidin-2-yll-2R.6S-dimethvl-oioerazin-1-yIl-pvrimidin-2 yll-ethanol.
Me Me N- ., N~N --~~
\ N N
Me~~w Me Me OH
mp: 150.5-152 °C;'H NMR (CD,OD, 300 MHz) S 8.14 (d, 1H), 6.62 (d, 1H), 6.46 (d, 1 H), 6.40 (s, 1 H), 4.83 (d, 2 H), 4.72-4.52 (c, 3H), 3.30 (dd, 2H), 2.28 (s, 6H), 1.46 (d, 3H), 1.23 (d, 6H); MS (APCi} 343 (MH'); [a]p +12.0 (c 1.3, MeOH).
Example 28 1 R-f4-12R.6S-Dimethv!-4-oxazolof5.4-clayridin-2-yl-pioerazin-1-vl)-ovrimidin-2-vl~
ethanol.
Me N
N~N N--<~
N ~ O ~N
Me~~~~ Me OH
'H NMR (CD,OD, 300 MHz) S 8.53 (d, 1 H), 8.28 (d, 1 H), 8.20 (d, 1 H), 7.34 (dd,1 H), fi.68 (d, 1 H), 4.90-4.72 (c, 2H), 4.69 (q, 1 H), 4.32 (d, 2H), 3.56 (dd, 2H), 1.47 (d, 3H), 1.33 (d, 6H); MS (APCf) 343 (MH'); [aj~ +8.1 (c 1.3, MeOH).
Example 29 i R-f4-f4-(4-Hvdroxymethyl-6-methyl-ovrimidin-2-yl~-2R.6S-dimethyl-oinerazin-1-vft-gyrimidin-2=vtl-ethanol.
pCT/IB00/00296 Me Me , N~N N~~
N~ ~ , . ~N
Me".. Me' OH OH
mp: 139-141 °C;'H NMR (CD,OD, 300 MHz) b 8.24 (d, 1H), 6.51 (d, 1H), 6.38 (s 1 H), 4.90 (m, 1 H), 4.84 (d, 2H), 4.77-4.53 (c, 2H), 4.55 (s, 2H), 3.24 (dd, 2H), 2.37 (s, 3H), 1.61 (d, 3H), 1.32 (d, 6H); MS (APCt) 359 (MH'); [a]p +14.8 (c 1.0, MeOH).
Example 30 1 R-(4-14-(2.6-Dimethyl-ovrimidin-4-yl1-2R.6S-dimethyl-oiperazin-1-yl1-oyrimidin-2-vll-ethanol.
Me~
'H NMR (CDCI,, 300 MHz) b 8.22 (d, 1 H), 6.36 {d,1 H), 626 (s, 1 H), 4.71 (m, 1 H), 4.65-4.50 (c, 2H), 4.42-4.28 (c, 3H), 3.24 (dd, 2H), 2.49 (s, 3H), 2.35 (s, 3H), 1.52 (d, 3H), 1.26 (d, 6H); MS (APCI) 343 (MH'); [a]o +11.4 (c 0.8, MeOH).
Example 31 1 R-f4-(2R.6S-Dimethvl~-oxazolof4.5-blovridin-2-vl-oinerazin-1 vl~-pvdmidin-2-vIl-ethanol.
Me N
N~N N
~ N ~ O /
Me~~~~ Me ~ OH
mp: 231-233 °C;_'H NMR (CDCI3, 400 MHz) 8 8.26-8.23 (c, 2H), 7.47 (d, 1 H), 6.94 (dd, 1 H), 6.39 (d, 1 H), 4.75-4.53 (c, 2H), 4.72 (q, 1 H), 4.35 {d, 1 H), 4.28 (m, 1 H), 3.44 (dd, 2H), 1.51 (d, 3H), 1.34 (d, 6H); MS (APCI) 355 (MH'); [a]p +8.0 (c 0.8, MeOH).
Exam~ie 32 , 1 R-(4-f4-(2-Hvd~oxvmethvl-6-methyl-ovrimidin-4-yl~2R.6S-dimethyi-ainerazin-1-vil-p~rrimidin-2-vii-ethanol.
-N ~ ~~N N~~ / N , N/ ~ ~N
Me""' Me OH OH
'H NMR (CD30D, 300 MHz) b 8.16 (d, 1 H), 6.66 (s, 1 H), 6:63 (d, 1 H), 4.85-4.63 (c, 2H), 4.67 (q, 1 H), 4.58 (d, 2H), 4.50 (s, 2H), 3.26 (dd, 2H), 2.35 (s, 3H), 1.46 (d, 3H), 1.24 (d, 6H); MS (APCI) 359 (MH'); [a]D +11.8 (c 0.9. MeOH).
Example 33 1 R-f4-(2R.6S-Dimethvl-4-oxazolof5.4-blpyridin-2-vl-pi~erazin-1-vl)-pvrimidin-2-vtl-ethanol.
Me~
OH
Me N
N~N N--<~
\ N ~ O N
Me mp: 204-207 °C; 'H NMR (CDCI,, 400 MHz) b 8.25 (d, 1 H), 7.95 (dd, 1 H), 7.59 (dd, 1 H), 7.15 (dd, 1 H), 6.39 (d, 1 H), 4.80-4.57 (c, 2H), 4.73 (q, 1 H), 4.30 (d, 2H), 3.42 (dd, 2H), 1.51 (d, 3H), 1.35 (d, 6H); MS (APCI) 355 (MH'); [a]o +7.5 (c 0.7, MeOH).
Example 34 2-(4-~4-f2-(1 R-Hvdroxv-ethvll-ovrimidin-4-vf1-3R.5S-dimethvl-piperazin-1-vfl-cvrimidin-2-vi~roaan-2-ol.
~N
~N /
Me Me~~
OH OH Me pC"f/IB00/00296 mp: 138-140 °C;'H NMR (CDCI,, 400 MHz) S 8.23 (d, 2H). 6.45 (d; 1H), 6.36 (d,1H), "
4.86 (s, 1 H), 4.70 (m, 1 H), 4.67-4.33 (c, 4H), 4.30 (d, 1 H), 3.31 (dd, 2H), 1.53 (s, 6H), 1.51 (d, 3H), 1.25 (d, 6H); MS (APCI) 373 (MH'); [a]~ +15.5 (c 1.2, MeOH).
Example 35 , 1 R-I4-f4-f4-Hvdroxvmethvl-6-methyl-oyrimidin-2-yl~2S-methv!-ni~erazin-1-v(1-pvrimidin-2-vll-ethanol.
Me .~ N-N~N N~~
\ N ~ ~N
Me~~~~ Me OH OH
' H NMR (CDCI,, 400 MHz) b 8.18 (d,1 H), 6.36. (d,1 H), 6.32 (s,1 H), 4.69 (q,1 H), .
4.60-4.53 (c, 3H), 4.52 (s, 2H), 4.38-4.18 (c, 2H), 3.63 (m,1 H), 3.40-3.29 (c, 2H), 324 (m, 1H), 2.32 (s, 3H), 1.49 (d, 3H), 1.20 (d, 3H); MS (APCI) 345 (MH'); [a]o +66.5 (c 1.0, MeOH).
Example 36 1 R-f4-f4-f4-Hvdroxvmethyl-6-methv!-ovrimidin-2-yl)-2R-methyl-nit~erazin-1 y~-pvrimidin-2-vl~-ethanol.
Me~~~
'H NMR (CDCI,, 400 MHz) b 8.21 (d, 1 H), 6.37 (d, 1 H), 6.33 (s, 1 H), 4.72 (m,1 H), 4.fi7-4.54 (c, 3H), 4.54 (s, 2H), 4.34 (d, 1 H), 4.20 (d, 1 H), 3.58 (b~ s,1 H), 3.42-3.32 (c, 2H), 3.26 (td, 1 H), 2.34 (s, 3H), 1.51 (d, 3H),121 (d, 3H); MS (APCI) 345 (MH'); [a]o -35.0 (c 1.1, MeOH).
pGT/IB00ro0296 Example 37 , , 1 R-~4-f4-l2-Hydrox~methvfrpvrimidin-4-vl~3S-methyl-oiaerazin-1 v(1-avrimidin-2-vl~-ethanol.
N -I ~ .\.~ N
N ~ N , Me",. Me OH OH
mp: 178-181 °C;'H NMR (CDCI$, 400 MHz) & 8.23 (d, 2H), 6.38 (d, 2H), 4.60 (q,1H), 4.60 (s, 2H), 4.56 (m, 1 H), 4.28-4.15 (c, 4H), 3.72 (br s, 1 H), 3.58 (dd, 1 H),~ 3.48 (m, 1 H), 3.33 (td,1 H), 1.51 (d, 3H),1.23 (d, 3H); MS. (APCI) 331 (MH'); [a]Q
+88.9 (c 1.1, MeOH). ,, Example 38 1 R-l4-~4-f2-l1 R-Hvdroxv-ethvll-ovrimidin-4 v1l-2S-methyl-oioerazin-1-yl)..pyrimidin-2-I thanol.
N I ~ ~N
I
N ~ N
Me~,~. Me~ ~ Me OH OH
mp:158-160 °C; 'H NMR (CDC1,, 400 MHz) 8 8.24 (d, 2H), 6.39 (d,1 H), 6.38 (d, 1 H), 4.71 (m, 2H), 4.55 (br s, 1 H), 4.32-4.16 (c, 5H), 3.60 (dd, 1 H), 3.48 (td, 1 H), 3.38 (td, 1 H), 1.52 (d, 6H), 1.24 (d, 3H); MS (APCi) 345 (MH'); [a]p +82.5 (c 1.0, MeOH).
Exam~ie 39 1 R-(4-~4-f2-(1 R-Hvdroxy~thyl~ovrimidin.-4-vt1-2R-methyl-niDerazin-1-vl~-ovrimidin-2-thanol.
Me~~.
WO 00159510 PCTIIB00l00296 -1~
mp: 155-157 °C;'H NMR (CDCI3, 400 MHz) 8 8.24 (d, 2H), 6.39 (d, 1H), 6.38 (d, 1H), 4.73 (m, 2H), 4.58 (br s, 1 H), 4.32-4.16 (c, 5H), 3.59 (dd, 1 H), 3.50 (m, 1 H), 3:38 (m, 1 H), 1.52 (d, 6H), 1.25 (d, 3H); MS (APCI) 345 (MH'); [a]~ -30.4 (c 0.9, MeOH).
Example 40 1 R-(4-t'3-f2-(1 R-Hydroxy~thyl)-oyrimidin-4-yll-3.9-diaza-bicyclof3.3.1)non-9-yt)-pyrimidin-2-vi)-ethanol.
N ~ N N~N
N N
Me Me~
OH OH
mp: 151-158 °C; 'H NMR (CDC13, 400 MHz) 8 8.24 (d, 2H), 6.42 (d, 1 H), 6.41 (d, 1 H), 4.72 (m, 2H), 4.48.18 (c, 2H), 4.29 (dd, 2H), 3.28 (d, 2H), 2.03 (m, 1 H),11.98-1.82. (c, 4 H), 1.58 (m, 1 H), 1.51 (d, 3H), 1.50 (d, 3H); MS (APCI) 371 (MH'); [a]o +27.6 (c 0.9, MeOH).
Examote 41 1 R-l4-f4-f2-l1 S-Hvdroxv-ethvl~pvrimidin-4-v(1-2R.6S~Jimethvt-pioerazin-1-yt~
pyrimidin-2-yl)-ethanol.
Me N~N N~N
N~ ~ \N
Me~~~~~ Me ~~~ Me OH OH
mp: 222-223.5 °C; 'H NMR (CDCI,, 400 MHz) 8 8.24 (d, 1 H), 8.23 (d, 1 H), 6.46 (d, 1 H), 6.36 (d, 1 H), 4.75-4.51 (c, 4H), 4.50-4.30 (c, 4H), 3.31 (dt, 2H), 1.51 (d, 6H), 1.26 (d, 6H); MS (APCI) 359 (MH'); [a]o -3.4 (c 0.5, CHCI3).
Example 42 "
1 S-(4-~4-f2-l1 R-Hvdroxv-ethvll-oyrimidin-d-vfl-2R fiS-dimethvl-piperazin-1-vll-hyrimidin-2-vll-ethanol.
N~ ~ ~N
N ~ ~N
Me Me Me OH OH
mp: 224-226 °C; 'H NMR (CDCI,, 400 MHz) b 8.24 (d, 1 H), 8.23 (d, 1 H), 6.46 (d, 1 H), 6.36 (d, 1 H), 4.76-4.51 (c, 4H), 4.50-4.23 (c, 4H), 3.33 (dt, 2H), 1.51 (d, 6H), 1.25 (d, 6H); MS (APCI) 359 (MH'); [aJo +64.2 (c 0.5, CHCl,).
Example 43 1 S-(4-(4-f2-(1 S-Hydroxy-ethyl)-oyrimidin-4-vfl-2R 6S~imethyl-piaerazin-1 vl~-pvrimidin-2-vl)-ethanol.
Me N /rN N~N
\ N/ ~ ~ ~N
Me Me w~~ Me OH OH
mp: 164-165.5 °C; 'H NMR (CDC13, 400 MHz) b 8.24 (d, 1 H), 8.23 (d, 1 H), 6.46 (d, 1 H), 6.36 (d, 1 H), 4.75-4.51 (c, 4H), 4.50-4.23 (c, 4H), 3.47-3.28 (c, 2H), 1.51 (d, 6H), 1.25 (d, 6H); MS (APCI) 359 (MH'); [a]p -43.8 (c 1.0, MeOH).
Example 4.4 1RS-l4-t4-f2-IIRS-Hvdroxv-ethvl~cvrimidin-4-y(1-2R'6S'~imethv! nioerazin 1 vlf-nyrimidin-2-vll-ethanol.
Me N~N N-~(\ N
~ N~ Y \N
Me Me Me OH OH
mp: 180-186 °C;'H NMR (CDCI9, 400 MHz) s 8.24 (d, 1 H), 8.23 (d, 1 H}, 6.46 (d, 1 H), 6.36 (d, 1H), 4.75-4.51 (c, 4H), 4.50-423 (c, 4H), 3.47,-,3.28 (c, 2H), 1.51 (d, 6H), 1.25 (d, 6H); MS (APCI) 359 (MH').
Example 45..
1-(4-~4-f2-(1 R-Hvdroxv-ethyl~pvrimidin-4-y(1-2R.6S-dimethvl-piaerazin-1-vll-ovrimidin-211-ethanone.
Me N~N N~N
\ N~ ~ ~N
Me Me Me O OH
mp: 123-i27 °C;'H NMR (CDCI,, 400 MHz) 8.8.41 (d, 1H), 8.24 (d, 1H), 6.56 (d, 1H), 6.47 (d, 1 H), 4.75-4.53 (c, 3H), 4.52-4.28 (c, 2H), 4.26 (m, 1 H), 3.36-3.29 (c, 2H), 2.68 (s, 3H), 1.51 (d, 3H), 128 (d, 6H); MS (APCt) 357 (MH'); [ajo+19.4 (c 1.0, MeOH).
Example 46 1-l4-~4-f2-l1 R-Hvdroxv-ethyl)-ovrimidin-4-vfl-3R 5S-dimethvl-oioerazin-1-vl~-ayrimidin-2-vl~ethanone.
Me N~N N~N
\ N~ ~ ~N
Me~~~~ Me Me OH O
mp: 150-164 °C; 'H NMR (CDCI,, 400 MHz) 8 8.40 (d, 1 H), 8.24 (d,1 H), 6.66 (d, 1 H), 6.37 (d, 1H), 4.74-4.52 (c, 3H), 4.51-4.31 (c, 2H), 4.29 (m, 1H), 3.36 (dd, 2H), 2.69 (s, 3H), 1.51 (d, 3H), 1.27 (d, 6H); MS (APCI) 357 (MH'); [ajo+21.8 (c 1.1, MeOH).
pC'f/IB00/00296 Example 47 "
1 R-l4-~4-f2-f1 R-Hvdroxv-ethyl)-pvdmidin-4-vll-2R.6R~dimethvl-piaerazin-1-vll-pyrimidin-2-vi)-ethanol.
Me N ~ N N~N
\ N ~ N
Me~.,.. Me Me OH OH
mp: 168-171 °C; 'H NMR (CDCI,, 400 MHz) 8 8.27 (d, 1 H), 823 (d, 1 H), 6:33 (d, 1 H), 6.30 (d, 1 H), 4.78-4.69 (c, 2H), 4.68-4.28 (c, 5H), 3.83-3.69 (c, 2H), 3.54 (m, 1 H), 1.53 (d, 3H), 1.52 (d, 3H), 1.43-1.22 (c, 6H); MS (APCI) 359 (MH'); [acJD+92.2 (c 0.5, MeOH).
Example 48 1 R-(4-~4-f2-l1 R-Hvdroxv-ethyl)-oyrimidin-4-yll-2S.6S-dimethyl-pioeraZin-1-vf~-vvrimidin-2-vl)-ethanol.
Me N ~ N N '~N
N ~ N
Me~~w Me Me OH OH
mp: 168-178 °C;'H NMR (CDC1,, 400 MHz) 8 8.26 (d, 1H), 8.23 (d, 1H), 6.32 (d, 1H), 6.29 (d, 1 H), 4.78-4.68 {c, 2H), 4.65.27 (c, 5H), 3.82-3.71 (c, 2H), 3.55 (m, 1 H), 1.52 (d, 3H), 1.51 {d, 3H); 7 .43-1.20 {c, 6H); MS (APCI) 359 (MH'); [aJo- 32.4 (c 0.7, MeOH).
' WO 00!59510 PGTIIB00100Z96 ~~~~Me Ar'--X
Example X-Ar' R R' mp (C) MS (MH'~
49 benzoxazol-2-yl (R)-Me (S}-Me 354 50 ~ benzothiazol-2-yl(R}-Me (S}-Me ~ 370 51 oxazofa[4,5-c]pyridin-2-yl(R)-Me (SrMe 355 52 quinoxafin-2-yl (R?-Me H 351 53 quinoxaiin-2-yl (S~Me H ~ 351 54 quinoxalin-2-yl (RrMe (S~Me 365 55 (4.6-dimethyl)- H H 132-133 315 pyrimidin-2-yl 56 (4,6-dimethyl)- (S}-Me H 329 pyrimidin=2-yl 57 (2,6-dimethyl~ H H 125.5-127314 pyrimidin-4-yl 58 (2-hydroxymethyl~ (S~Me H 146-148 331 pyrimidin-4-yl 59 (2-hydroxymethyl}- (R~Me (S~Me 168-171 345 pyrimidin-4-yl 60 (2-hydroxymethyl~- (S)-Me H 345 methyl)-pyrimidin-4-yl HO
~~~~Me N_ Ar'-X-N~N ~ / N
~5 Example X A~' mp (°C) MS (MHO
61 ~ ~ (4-hydroxymethyl-6-methy)- 357 Ipyrimidin-2-yl 62 (R ~[2-(1-hydroxy-ethyl)]- 357 pyrimidin-4-yl Fxamole 63 1-f4-f4-!2-Acety-avrimidin-4-vl)-2R'.6S'-dimethyl-oiaerazin-1-vll-nvrimidin-2-vl1-ethanone. , , , .
Me N ~ N N~N
\ N ~ N
Me Me Me ' O O ,.
A mixture of 1 S-(4-{4-[2-(1 R-hydrooy-ethyl)-pyrimidin-4-yfJ-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol (prepared according to the method of Example 42, 1.05 g, 2.93 mmol) and manganese(t~ oxide (5.15 g; 59.3 mmol) in dichloroethane (28 mL) was heated at reflux for 7 h, and filtered through Celite (hot). The filtrate was concentrated and purified by flash column chromatography (Flash 40M~, 5%
methanoUchlorofonn) to give 0.67 g (64%) of the title compound as a white solid. mp:
>235 °C (dec); 'H NMR (CDCI,, 400 MHz) 8 8.42 (d, 1 H), 8.41 (d, 1 H), 6.68 (d, 1 H), 6.57 (d, 1 H), 4.81.36 (c, 4H), 3.39 (dd, 2H), 2.69, (s, 3H), 2.68 (s, 3H),1.29 (d, 6H);
MS (APC1) 355 (MH').
Examflle 64 1 R-(4-f4-(4-Hydroxymethyf-6-methyl=pyrimidin-2-y1)-3R.5S-dimethyl-pinerazin-1 y1 pyrimidin-2-vl~-ethanol.
Me N \ ,~N N-N/
Me~~~~ Me OH
Step A: 1 R-f4-!4-ltart-Butoxvcarbonvlamino-tert-butoxvcarbonvlimino-methyl)-dimethvl-oiperazin-1 v(1-o3nimidin-2-yl~-ethyl butyrrate. To a mixture of 1 R-[4-(3R,5S-dimethyl-pipera~in-1-yl~pyrimidin-2-yQ-ethyl butyrate (prepared according to the method of~Preparation Three, 10 g, 32.7 mmol), N,N'-bis(tert butoxyc~rbonyt~hiourea (8.6 g, 32.7 mmol; Synth: Commun. 1993, 23, 1443), and triethytamine (9.0 mL, 65.4 pCT/IB00100296 mmol) in dimethylfonnamide (1 i 0 mL) at 0 °C was added mercury(II) chloride (9.8 g, 36.0 mmol). This mixture was stirred overnight with wat~ming to room temperature, diluted with ethyl acetate, and washed with water (3x) and brine (1x). The organic phase was dried over sodium sulfate, filtered, and evaporated to give 17.9 g (100%) of the title compound of Example 64, Step A as a yellow foam. 'H NMR (CDCI3, MHz) S 9.61 (s,1 H), 8.19 (d,1 H), 6.37 (d,1 H), 5.66 (q,1 H), 4.51-4.14 (c,, 4H), 3.36-3.23 (c, 2H), 2.37 (t, 2H), 1.75-1.60 (c, 2H), 1.55 (d, 3H),1.49 (s, 9H), 1.46 (s, 9H), 1.28 (d, 3H), 1.26 (d, 3H), 0.94 (t, 3H); MS (APCI) 549 (MH').
Step B: 1 R-14-l4-Carbamimidovl-3R.5S-dimethvl-piaerazin-1-vl~-ovrimidin.2-vi1-ethyl butyrate trifluoroacetic acid salt. A mixture of fR-{4-(4-(tent-butoxycarbonylamino~ert-butoxycarbonylimino-methyl}-3R,5S-dimethyl-piperazin-1-yI]-pyrimidin-2-YI}-ethyl butyrate (prepared according to the method of Example 64, Step A,17.9~ g, 32.7 mmol) in a 3:1 rt>ixture of dichloromethaneltriflUoroacetic add (300 mL) was stirred at room temperature overnight and concentrated to provide ~36 g of the tifle compound of Example 64, Step B as an oil that was used as is. 'H NMR (CD,OD, 400 MHz) 8 8.24 (d, 1 H), 7.25 (d, 1 H), 5.69 (q, 1 H), 4.19-4.10 (c, 4H), 3.79-3.42 (c, 2H), 2.45 (t, 2H), 1.67-1.45 (c, 2H), 1.63 (d, 3H),1.32-1.25 (c, 6H), 0.95 (t, 3H); MS
(APCI) 349 (MH').
Step C: 1 R-f4-f4-f4-Methoxvmethvl-6-methyl-ovrimidin-2-vl1-3R 5S~imethvl-pioerazin-1-vl1-pvrimidin-2y11-ethanol. A solution of 1 M sodium isopropoxide in isopropanol was prepared by adding sodium metal (3.8 g, 160 mmol) to isopropanol (160 mL) and heating at reflux until all the metal was consumed. 1 R-[4-(4-Carbamimidoyl-3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yij-ethyl butyrate t~ifluoroa~tic add salt (prepared according to the method of Example 64, Step B, 32.7 mmol theory) was added to the refluxing sodium isopropoxidefisopropanof solution followed, after 1 h, by 1-methoxy-pentane-2,4-dione (212 8,163 mmol;
J.
Am. Chem. Soc 1944, 22, 2092). After 12 h, another aliquot of sodium fsopropoxide (1 M in isopropanol, 65 mL, 65 mmol) was added. After refluxing overnight, the reaction mixture was cooled to room temperature and diluted with water (100 mL).
lithium hydroxide hydrate (6.9 g, 163 mmol) was added and this mixture was stirred for 3 h, concentrated, and extracted with 10% isopropanoUchloroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purfied by flash column chromatography (1-X2.5% methanoUchlorofonn) to give 10.5 g (87%, 2 steps) of the title compound of Example 64: Step C as a yellow solid. 'H
NMR {CDCI,, 400 MHz) 8 8.18 (d, 1H), 6.54 (s, 1H), 6.43 (d, 1H), 5_00.94 (c, 2H), 4.69 (m, 1 H), 4.37-4.34 (c, 2H), 4.33 (s, 2H), 3.45 (s, 3H), 3.29-3.23 (c, 2H), 2.33 (s, 3H), 1.51 (d, 3H),1.20 (s, 6H); MS (APCI) 373 (MH').
Step D: 1 R-f4-t4-(4..Hvdroxvmethvl-6-methyl-bvrimidin-2y11-3R.SS-dimethvl-piperazin-1-vll-oyrimidin-2-vll-ethanol. To a solution of 1R-{4-[4-(4-methoxymethyi-6-methyl-pyrimidin-2-yl~3R,5S-dimethyl-piperazin-1 ylj-pyrimidin-2 yt)~thanol (prepared according to the method of Example 64, Step C, 8.0 g, 21.5 mmol) in dichloromethane (150 mL) at 0 °C was added boron tribromide (1 M in i 0 dichloromethane, 64.3 mL, 64.3 mmol). This mixture was stirred overnight with warming to room temperature and quenched by careful addition of saturated aqueous sodium bicart~onate. The layers were separated and the aqueous phase was extracted with 10% isopropanoUchloroform (3x). The combined organic extracts were washed with brine (ix), dried over sodium sulfate, filtered, and evaporated.
The resulting solid was refluxed in ethyl acetate and filtered (hot). This procedure was repeated and the combined filtrates were concentrated to a minimal volume.
After standing at room temperature overnight, a tan solid was collected by filtration. The resulting filtrate was again allowed to stand at room temperature overnight to yield an additional crop of the desired product to give all together 6.0 g (78%) of the frtie compound as a tan solid. mp: 149-151 °C;'H NMR (CDCI,, 400 MHz) b 8.19 (d, 1H), 6.45 (d, 1 H), 6.32 (s, 1 H), 5.02-4.96 (c, 2H), 4.71 (q, 1 H), 4.53 (s, 2H), 4.50r4.23 (c, 2H), 3.31-3.25 (c, 2H), 2.33 (s, 3H), 1.51 (d, 3H), 1.23 (s, 6H); MS (APCI) 359 (MH');
[ocj~+18.9 (c 1.1, MeOH).
Examples 65 to 74 Examples 65 to 74 were prepared from the appropriate starting materials in a manner analogous to the method of Example 64.
~~DD~Z96 , -172-Exarrroie 65 lR?-1-~4-f4-(4-Hvdroxvmethvl-6-methyl-pvrimidin-2-vl)-cioerazin-1-vI1-pvrimidin-2-vl~-ethanol.
Me N-N
Me~~~
OH
mp: 139-140 °C; 'H NMR (CDCi,, 300 MHz) 8 8:21 (d, 1 H), 6.41 (d, 7 H), 6.37 (s, 1 H), 4.71 (m, 1 H), 4.54 (s, 2H), 4.32 (d, 1 H), 4.02-3.93 (c, 4H), 3.7&3.68 (c, 4H), 3.65 (b~
s, t H), 2.34 (s, 3H), 1.19 (d, 3H); MS (TS) 331 (MH'); [aj~ +21.6 (c 2.0, M,eOH).
Example 66 1R-(4-f4-14.6-Dimethvl-pvrimidin-2-vil-3R.5S-dimethvl-ninerazin-1-vll-avtimidin-2 v!1 ethanol.
Me~~~
mp: 141.5-142.5 °C; 'H NMR (CDCI,, 400 MHz) b 8.17 (d, 1 H), 6.43 (d, 1 H), 6.28 (s, 1 H), 5.03.97 (c, 2H), 4.70 (q,1 H), 4,44.18 (c, 2H), 3.32-3.20 (c, 2H), 2.27 (s, 6H), 1.50 (d, 3H), 1.20 (d, 6H); MS (APCI) 343 (MH'); jaJ~ +19.2 (c 1.1, MeOH).
18 Example 67 1 R-14-t4-l4-Methoxvmethvl-6-methyl-amimidin-2-vl~3R.5S-dimethyl-nioerazin-1 vt1-ovn'~idin-2-v11-ethanol.
Me~~~
OH
'H NMR (CDCl3, 400 MHz) b 8.18.(d, 1H), 6.55 (s, 1H), 6:43 (d, 1,H), 5.02-4.9~
(c, 2H), 4.69 (m, 1 H), 4.43-4:20 (c, 2H), 4.36 (d,1 H), 4.33 (s, 2H). 3.46 (s, 3H), 3.30-3.21 (c, 2H), 2.34 (s, 3H), 1.51 (d; 3H), 1.20 (d, 6H); MS (APCI) 373 (MH'); (a]o +16.0 (c 0.9, MeOH). , ~~ , Example 68 1 R-~4-f4-l4-Hvdroxvmethvl-6-methyl-avrimidin-2-yl)-3R-meth~rl-oinerazin-1 vll-.
p~rrimidin-2-vl~-ethanol.
Me~~~
' H NMR (CDCl3, 400 MHz) S 8. ~ 7 (d,1 H), 6.36 (d, 1 H), 6.32 (s, 1 H), 4.98 (m, 1 H), 4.69 (q, 1 H), 4.58 (dt, 1 H), 4.51 (s, 2H), 4.37-4.11 (c, 3H), 3.62 (br s, 1 H), 3.48-3.36 (c, 2H), 3.18 (td, 1 H), 2.31 (s, 3H), 1.49 (d, 3H),1.17 (s, 3H); MS (APC!) 359 (MH');
[a]o -40.6 (c 1.0, MeOH).
Examole~9 1R-f4-f4-(4-Hvdroxvmethyl-6-meth~midin-2-v(1-3S-methyl-oioerazin-1 Dyrimidin-2,rll-ethanol.
Me""
'H NMR (CDC13, 400 MHz) 8 8.17 (d,1 H), 6.36 (d,1 H), 6.33 (s,1 H), 4.99 (m,1 H), 4.69 (q, 1 H), 4.58 (m,1 H), 4.52 (s, 2H), 4.40-4.i 1 (c, 3H), 3.60 (br s, 1 H), 3.45-3.34 (c, 2H), 3.19 (td;1 H), 2.32 (s, 3H),1.49 (d, 3H),1.16 (s, 3H); MS (APCI) 359 (MH');
[a]Q +68.1 (c 0.7; MeOH).
R'2 ~ ..,. Me R' i N~N~N~ ~
R" R6 Example R" R'~ R' R mp (C) MS (MH') 70 H OH 3R-Me SS-Me 331 71 Me OH 3R-Me 5S-Me 231-232 ~ 345 72 Ph OH 3R-Me 5S-Me 407 73 Me ethoxymethyl3R-Me 5S-Me 387 74 Me ethoxymethyl2R-Me 6S-Me 106-108 ~ 387 Example 75 fR)-5-f2-(1-Hvdroxv~thvll-ovrimidin~-vtl-1-methyl-2-giuinoxafin-2-vl-1 2 4 5 6 hexah~rdro-nvrazolof4.3-clovddin-3-one.
N
N
Me~~~
OH
Step A: 3-Oxo-2-ouinoxalin-2 vl-1.2.3.4.6,7fiexat~,ydro-pvrazolof4 3-c]pmidine-carboxylic aad tert-b ester. To a solution of 4-oxo-piperidine-1,3-dicartioxylic acid 1-tert-butyl ester 3-ethyl ester (500 mg,1.84 mmol; Tebahedron 1994, 50, 515) in toluene (i0 mL) was added quinoxalin-2-ylfiydrazine (295 mg, 1.85 mmol;
Hefenxycles 9985, 23, 2603). This mixture was stirred at refiux overnight, cooled to room temperature, concentrated, and purified by flash column chromatography (25-X75% ethyl acetatelhexanes) to give 600 mg (89°~) of the title compound of Example 75, Step A as a tight orange solid. 'H NMR (CDCI,, 250 MHz, 5:1 mixture of tautomers) b 11:94 (br s, 0.83H), 10.16 (s, 0.17H), 9.57 (s, 0.83H), 8.13 (dd, 1 H), 7.91-7.69 (c, 3H), 4.45 (s, 1.66H), 4.33 (s, 0.34H), 3.79-3.72 (c, 2H), 282-2.72 (c, 2H), 1.52 (s, 9H); MS (APCI) 368 (MH').
WO 00159510 P~~0~2~
Step B: 1-Methyl-3-oxo-2-auinoxalin-2~t-1.2.3.4.6.7-hexahvdro-nyrazolof4.3- , , clovridine-5-carboxylic acid tert-b~yt I ester. To a solution of 3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (prepared according to the method of Example 75; Step.A, 250 mg, 0.68 mmol) in dimethylfom~amide (2 mL) at 0 °C with stirring under nitrogen was added sodium hydride (60% dispersion in mineral oil, 41 mg,1.02 mmol). After 10 min, ipdomethane (51 NL, 0.82 mmol) was added. This mixture was allowed to stir at 0 °C
for 2 h, quenched by addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (4x). The combined organic extracts were dried over sodium sulfate, t0 filtered, evaporated, and purified by flash column chromatography (40%
ethyl acetatelhexanes) to give 164 mg (63%) of the title compound of Example 75, Step B
as a yellow foam. 'H NMR (CDCI,, 250 MHz) 8 9.71 (s, 1 H), 8.15 (dd, 1 H),.8.02 (m, 1 H), 7.80-7.70 (c, 2H), 4.29 (s, 2H), 4.74 (t, 2H), 3.79 (s, 3H), 2.72-2.67 (c, 2H),1.50 (s, 9H); MS (APCI) 382 (MH').
Step C: 1-Methvt-2-auinoxalin-2 yl-1.2.4.5.6.7-hexahvdro-ovrazolot4 3-clovridin-3-one hydrochloride. To a solution of 1-methyl-3-oxo-2-quinoxalin-2-yh1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic aad tart butyl ester (prepared according to the method of Example 75, Step B, 27, 9 mg, 0.73 mmol) in methanol (6 mL) was added hydrogen chloride (5.85 M in methanol, 1.25 mL, 7.3 mmol). This mixture was heated at 60 °C for 30 min, cooled to room temperature, and concentrated to give 249 mg (>100%) of the title compound of Example 75, Step C as a dark red solid. 'H NMR (CD,OD, 250 MHz) S 9.45 (s, 1 H), 8.13 (dd, 1 H), 8.05 (m, 1 H), T.9i-7.83 (c, 2H), 4.05 (s, 2H), 3.64 (t, 2H), 3.56 (s, 3H), 3.12 (t, 2H); MS (APCI) 282 (MH').
Step O: (Rl-1-f4-l1-Methyl-3-oxo-2-auinoxalin-2-vl-1.2.3.4.6.7-hexa~dro-oyrazolof4.3-clovridin-5-vl~ovrimidin-2-v(I~thvl butyrate. To a stirred solution of 1-methyl-2-quinoxalin-2-yl-1,2,4,5,6,7fiexahydro-pyrazolo[4,3-cjpyridin-3-one hydrochloride (prepared according to the method of Example 75, Step C,175 mg, 0.55 nunol) and (R~1-(4-chloro-pyrimidin-2-ylj-ethyl butyrate (prepared aooording to the method of Preparation Seven,126 mg, 0.55 mmol) in isopropanol (6 mL) was added triethylamine (230 NL, 1.66 mmol). This mixture was heated to reflux overnight, cooled to room temperature, and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3x). The dined -17&
organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5% methanoUchloroform) to give 248 mg (95%) of the title compound of Example 75, Step D as a yellow oil.'H NMR (CDCI3, 250 MHz) b 9.70 (s, 1 H), 8.29 (d,1 H), 8.15 (dd, 1 H), 8.03 (m, '! H), 7.82-7.70 (c, 2H), 6.48 (d, 1 H) 5.72 (q, 1 H), 4.36 (s, 2H), 4.35-4.15 (c, 2H), 3.42 (s, 3H), 2.77-2.82 (c, 2H), 2.43 (t, 2H), 1.79-1.60 (c, 2H),1.61 (d, 3H)', 0.99 (t, 3H); MS (APCI) 474 (MH'). ' Step E: (R1-5-l2-l1-Hydroxv-ethyl)-dvrimidin-4-v11-1-meth~~l-2-auinoxalin-2-vl-1.2.4.5.6.7-hexahydro-ovrazolpJ4.3-clgyridin-3-one. To a solution of (R)-1-[4-(1-methyl-3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl}-pyrimidin-2-y~-ethyl butyrate (prepan:d according to the method of Example 75, Step D, 248 mg, 0.52 mmot) in a 52 mixture of methanoUtetrahydrofucan (7 mL) was added potassium carbonate (218 mg,1.57 mmol). This mixture was stirred at 'room temperature overnight and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5-.~3% methanol/chloroform) to give 150 mg (71%) of the title compound as a white solid. mp: 217-219 °C (dec);'H NMR
(CDCI,, 250 MHz) b 9.66 (s,1 H), 825 (d,1 H), 8.12 (dd,1 H), 7.99 (m,1 H), 7.68-7.78 (c, 2H), 6.47 (d, 1H), 4.72 (q, 12H), 4.32 (s, 2H), 4.19-4.14 (c, 3H), 3.4.1 (s, 3H), 2.80 (t, 2H), 1.51 (d, 3H); MS (APCt) 404 (MH'); [a]o +13.4 (c 1.5, CHCI3).
Examoies 76 and 77 Examples 76 and 77 were prepared from the approprtate starting n-iaterials in a manner analogous to the method of Example 75.
HO
R ~N~B ....Me N-A
~N
Example A R" B mp (C) MS (MH') 76 ~ N-Me benzothiazol-2-ylCO 176-778 4pg 77 . CO quinoxalin-2-ylN-Me 201-204 (dec)404 -177_ ~xamole 78 ' LRl-6-Chloro-1'-12-l1-hvdroxy-ettwl)-flvrimidin-4-v(1-sairofchroman-2.4'-pioeridinl-4-one.
Me~
Step A: 6-Chloro-soiro[chroman-2.4'-pperidin)~-one hvdrochforide. To a solution of 1'-benzyl-6-chloro-spiro[chroman-2,4'-piperidinJ-4-one (300 mg, 0.88 mmol, Chem.
Pharm. Bull. 1981, 29, 3494) in acetone (5 mL) at 0 °C was added 1-chtoroethyl chloroformate (0.29 mL, 2.64 mmol). This mixture was warmed to room temperature, stirred overnight, and concentrated. The residue was purified by flash column chromatography {10-X20% ethyl acetatelhexanes) to give the intermediate carbamate which was refluxed in methanol (3 mL) for 1 h. Evaporation of the reaction mbchne provided 149 mg (59%) of the tifle compound of Example 78, Step A as a colorless solid. 'H NMR (CD,OD, 250 MHz) S 7.77 (d,1 H), 7.58 (dd,1 H), 7.15 (d,1 H), 3.33 (buried, 4H), 2.90 (s, 2H), 2.46-2.20 (c, 2H), 2.04-1.81 (c, 2H); MS (APCI) 252, 254 (MH').
Step B:1Rl-1'-(2-l1-Butvrvloxv-ethvl~ovrtmidin-4-v11-6-chloro-sDirolchroman-2 4'-oioeridinl~-one. To a solution of 6-chforo-spiro[chroman-2,4'-piperidin]-4-one hydrochloride (prepared according to the method of Example 78, Step A, 175 mg, .
0.61 mmol) in isopropanol (5 mL) was added {R~1-(4-chloro-pyrimidin-2-ytrethyl butyrate (prepared according to the method of Preparation Seven, 160 mg, 0.70 mmol) followed by triethylamine (029 mL, 2.1 mmot). This mixture was stirred at reflex for 1.5 h, concentrated, and purified by flash column chromatography (1 methanoUchlorofonn) to give 270 mg (100%) of the title compound of Example 78, Step 8 as a yeElow oil. 'H NMR (CDCI,, 400 MHz) S 8.19 (d, 1 H), 7.83 (d, 1 H), T.44 (dd,1 H), 6.97 (d, ~ H), 6.37 (d,1 H), 5.64 (q,1 H), 4.18 (app s, 2H), 3.34 (t, 2H), 272 (s, 2H), 2.37 (t, 2H), 2.10 (d, 2H),1.71-1.60 (c, 4H),1.55 (d, 3H), 0.94 (t, 3H); MS
(APCI) 444, 446 (MH').
. PCT/IBOOI00296 Step C: LR~-6-Chioro-1'-f2-(1-hvdroxv-ethv(~vvrimidin-4-v!1-svirofchroman-2.4'-', pper?dinl-4-one. A mixture of (R)-1'-[2-(1-butyryloxy-ethyl)-pyrimidin-4-yi}-6-chloro-spiro[chroman-2,4'-piperidin]-4-one (prepared according to the method of F~cample 78, Step B, 270 mg, 0.61 mmol) and lithium hydroxide hydrate (80 mg, 1.83 mmol) in a 3:1:1 mixture of tetrahydrofuraNmetharioUwater (5 mL) was stirred at room temperature for 1.5 h. The organic solvents were evaporated and the residue was extracted with chloroform (4x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (ethyl acetate) to give 41 mg (18%) of the title compound as a reddish foam.
'H NMR
(CDCt,, 300 MHz) 8 8.19 (d, 1 H), 7.82 (d, 1 H), 7.44 (dd, 1 H), 6.96 (d, t H), 6.40 (d, 1 H), 4.65 (q, 1 H), 4.20 (app s, 2H), 3.42-3.32 (c,,2H), 2.73 (s, 2H), 2.14 (d; 2H),1.67 (td, 2H), 1.48 (d, 3H); MS (APCI) 374, 376 (MH'); [a]p +12.6 (c 0.5, MeQH).
Exam~~les 79 to 85 Examples 79 to 85 were prepared from the appropriate starting materials in a manner analogous to the method of Example 78.
HO
~~~~Me s N._ Rs~
IN
Example R'~ R" D mp (C) MS (MH') 79 6-Ph H CH2 402 80 6-Ph H CHOH 418 81 6-Ph H CO 416 82 6-0Me H CO 156.5-157.5 370 83 7-Br H CO 418,420 84 5-CI 6-Ct CO 408,410 85 6-OMe 7-OMe CO 400 Examn~, 86 ~Rl-1-f4-l2-Methyl-4-phenyl-5.8-dihvdro-6H-ovridof3.4-dlovrimidin-7-yl)-oyrimidin-2-I -eth ol.
N
Me~~~~~
Step A: 7-Benzvl-2-methyl-5.6.7.8-tetrahvdro-3H-ovridof3.4-dloyrimidin-4-one.
A
solution of sodium ethoxide in ethanol was prepared by addition of sodium metal (5.7 g, 247 mmol) to absolute ethanol (141 mL). After the sodium metal had all dissolved, ethyl 1-benzy!-3-oxo-4-piperidine carboxytate hydrochloride (21 g, 70.5 mmol) was added followed by acetamidine hydrochloride (13.3 g, 141 mmol). This mixture was stirred at reflex for 1 h, cooled to room temperature, and concentrated. The residue was dissolved in a minimum amount of water and the pH was adjusted to about 7 with glaaal acetic aad. The resulting yellow preapitate was filtered, washed with water (3x), air-dried for 2 h, then vacuum-dried overnight to provide 17.1 g (95%) of the tifle compound of F~cample 86, Step A as a yellow solid. 'H NMR (CDCI,, 250 MHz) 8 7.35-7.25 (c, SH), 3.70 (s, 2H), 3.42 (s, 2H), 2.73-2.64 (c, 2H), 2.64-2.60 (c, 2H), 2.41 (s, 3H); MS (APCI) 256 (MH').
Step B: 7-Benzvl~-chloro-2-methyl-5.8-dihvdro-6H-pvrfdof3.4-dlovrimidine. 7-Benzyl-2-methyl-5,6,7.8-tetrahydro-3H-pyrido[3,4-djpyrimidin-4-one (prepared according to the method of Example 86, Step A,17.1 g, 67.0 mmol) was suspended in phosphorus oxychloride (66 mL, 335 mmol). This mixture was stirred at reflex for 1 h, pooled to room temperature, evaporated, then chased with toluene. The residue was carefully diluted with ice/wateNchloroform and the layers were separated. The aqueous phase was extracted with chloroform (3x) and the combined organic extracts were washed with saturated aqueous sodium bicarbonate (1x) and water (1x), dried over sodium sulfate, filtered, and evaporated to give the title compound of Example 86, Step B as a brown oil that was used without purfication in the next step.:
'H NMR
pGT/IB00/00296 (CDCI,, 250 MHz) S 7.36-7.23 (c, 5H), 3.73 (s, 2H), 3.63 (s, 2H), 2.63 (app s, 4H), 2.36 (s, 3H); MS (APCI) 274, 276 (MH').
Step C: 7-Benzvl-2-methyl-4-phenyl-5.8-dihydro-6H-oyrid~3.4-dlovrimidine. To a suspension of 1,4-diphenylphosphinobutane (1.43, g, 3.35 mmol) in toluene (50 mL) was added bis(benzonitrile)palladium(II) chloride (1.28 g, 3.35 mmol). This mixture was stirred for 25 min at room temperature, then was added to a suspension of benzyl-4-chioro-2-methyl-5,8-dihydro-6H-pyrido[3,4-djpyrimidine (prepared according to the method of Example 86, Step B, 67.0 mmol, assumed) and phenylboronic acid (10.6 g, 87.1 mmol) in a mixture of absolute ethanol (40 mL), toluene (175, mL), and 2 N aqueous sodium carbonate (33.5 mL). This mixture was stirred at reflux for 6.5 h, cooled to room temperature and stirred for --2.5 d, then filtered through a.
pad of Celite. The filtrate was concentrated and the residue was diluted with water and extracted with chloroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (4550% ethyl acetate/hexanes) to give 16.5 g (78%, two steps) of the title compound of Example 86, Step C as a yellow oil. 'H NMR (CDCI,, 250 MHz) 8 7.57-7.54 (c, 2H), 7.48-7.24 (c, 8H), 3.71 (app s, 4H), 2.85 (t, 2H), 2.71-2.67 (c, 2H), 2.69 (s, 3H); MS (APCI) 316 (MH').
Step D: 2-Methyl-4-ohenvl-5.8-dihvdnr6H-oyridof3.4-dlovrimidine. 7-Benzyl-2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-djpyrimidine hydrochloride was fom~ed in situ by addition of hydrogen chloride (1.9 M in methanol, 31.1 mL, 51.1 mmol) to a solution of 7-benzyl-2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine (prepared according to the method of Example 86, Step C, 16.5 g, 522 mmol) in methanol (75 mL). After sorting 10 min at room temperature; a preapitate fom~ed, and another aliquot of methanol (100 mL) was added to obtain a homogeneous solution. To this mixture was added a siuny of 10% palladium on carbon (3.3 g, wl%) in methanol followed by ammonium fomiate (16.5 g, 261 mmol). This mixture was stirred at retlux for 5 h, cooled to room temperature, and filtered through Celite.
The filtrate was evaporated, diluted with saturated aqueous sodium bicarbonate, and extracted with chloroform (3x). The combined organic extracts wen: dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (3%
methanoUchloroform + 1 % ammonium hydroxide) to give 6.7 g (57%) o~ the Frtle compound of Example 86, Step D as an off~nrhite solid and 2.4 g (19%) of 7-fomryl-2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine as a yellow gum.
Treatment of the 7-formyl byproduct with methanalic hydrogen chloride at room temperature overnight followed by aqueous workup and column chromatography provided an additional 1.4 g (12%) of the title compound of Example 86, Step D. 'H NMR
(CDCt,, 250 Mtiz) b 7.55-7.40 (c, 5H), 4.09 (s, 2H), 3.05 (t, 2H); 2.75 (t, 2H), 2.79 (s, 3H); MS
(APCt) 226 (MH').
Step E: fR)-1-1'4-(2-Methyl-4-phenyl-5.8-dihvdro-6H-avrido(3.4-dlpvrimidin-7 vl~
eyrimidin-2-yll-ethyl butt irate. To a solution of 2-methyl-4-phenyl-5,8~iihydn~..6H-pyrido[3,4-djpyrimidine (prepared according to the method of Example 86, Step D, 6.8 g, 30.0 mmol) in isopropanol (125 mL) was added (R~1-(4-chioro-pyrimidin-2-yl~thyl butyrate (prepared according to the method of Preparation Seven. 6.8 g, 30 mmoi) followed by triethylamine (12.5 mL, 89.9 mmol). This mixture was stirred at reflux for 8 h, cooled to room temperature overnight, and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3x).
The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2% methanoUethyl acetate) to give 11.0 g (88%) of the title compound of Example 86, Step E, as a yellow oil. 'N
NMR
(CDCI,, 250 MHz) 8 8.28 (d, 1 H), 7.62-7.40 (c, 5H), 6.45 (d,1 H), 5.69 (q,1 H), 4.78 (s, 2H), 3.93 (app s, 2H), 2.95 (t, 2H), 2.77 (s, 3H), 2.40 (t, 2H),1.?7-1.63 (c, 2H), 1.60 (d, 3H), 0.98 (t, 3H); MS (APCI) 418 (MH').
Step !_: ~Rl-1~t4-!2-Methyl-4-r~henvl 5 8-dihvdro-6H-oyridoL3 4-d~ovrimidin-7 yll~
py~imidin-2-vtl-ethanol. To a solution of (R~1-[4-(2-methyl-phenyl-5,8-dihydro-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yt]-ethyl butyrate (prepared according to the method of Example 86, Step E. 11.0 g, 26.4 mmol) in dioxane (13 mL) was added concentrated hydrochloric aad (22 mL, 264 mmol). This rriodure was stirred at room temperature overnight, cooled to 0 °C, neutralized via slow addition of 6 N aqueous sodium hydroxide, and extracted with ethyl acetate (4x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2-~5% methanoUethyl acetate) to give an oil which after filtration with hexanes provided 8.0 g (88%) of the title compound as a white solid.
mp:114-116 °C;~'H NMR (CD,OD, 250 MHz) 8 8.26 (d,1H), 7.62 7.47 (c, 5H), 6.52 (d,1H), 4.79 (s, 2H), 4.66 (q, 1 H), 424 (br s, 9 H), 3.90-3.80 (c, 2H), 295 (t, 2H), 270 (s, 3H),1.49 (d, 3H); MS (APCI) 348 (MH'), [ajp +15.6 (c 1.0, MeOH).
E~camnles 87 to_ 100 ' Examples 87 to 100 were prepared from the appropriate starting' materials in a manner analogous to the method of Example 86.
Me Example R~' R~' mp (C) MS (MH'~
87 H Ph 72 74 88 Ph H ~ 334 89 Ph Et ' 362 90 Ph NH2 225-228 (dec) 349 91 Ph Ph 73-?5 410 92 Ph 4-pyridy! 411 93 (4-OMe)Ph Me 62-64 378 94 (4-t7Ph Me 55-58 366 95 (4-Ct)Ph H 368, 370 96 OMe Me 302 97 OPh Me 156-158 364 98 SPh Me 103-105 380 99 N-indolinyfMe 128-131 38g 100 NMez Et 329 Example 101 ~4-f2-(1 R-Hvdroxv~thvl~ovrimidin-4-y~f -2R 6S-dimethvl oioerazin-1~r(~-(2-ohenvl-7 8-dihydro-SH-ovridot4.3-dipvrimidin~-vl~methanone.
wo oors9sio -~ s3-M
Step A: 4-0xo-oioeridine-1-carboxvlic.aad tert-butyl ester. A mixture of 4-piperidone monohydrate hydrochloride (9.22 g; 60 mmoi) and di-tert-butyl Bicarbonate, (10.9 g, 50 mmol) in a 1:1 mixture of dichloromethane/saturated aqueous sodium bicarbonate (100 mL) was stirred at room temperature for 15.5 h. The layers were separated and the aqueous layer was extracted with chloroform (3x). The combined organic extracts were washed with 1 N aqueous phosphoric acid (3x), dried over sodium sulfate, filtered, and evaporated to give 10.0 g (100%) of the title compound of Example 101, Step A as a white solid. 'H NMR (CDCl3, 400 MHz) 8 3.70 (t, 4H), 2:42 (t, 4H),1.47 (s, 9H).
Step B: 3-Dimethvlaminomethvlene~4-oxo-oioeridine-1-carboxylic add tert-by~l ester. To a solution of 4-oxo-piperidine-1-carboxylic acid tart-butyl ester (prepared acxording to the method of Example 101, Step A, 4.0 g, 20.0 mmo!) in dimethyfformamide (40 mL) was added tart-butoxybis(dimethylamino)methane (4.35 mL, 22 mmol). This rriucture was stirred at reflex for 15 h, cooled to room temperature, diluted with water, and extracted with ethyl acetate (Sx). The combined organic extracts were washed with water (3x) and brine (1 x), drted over sodium sulfate, filtered, and evaporated to give 3.64 g (72%) of the title compound of Example 101, Step B as a brown oil that was suffiaentfy pure to carry on to the next step.
'H NMR
(CDCI,, 400 MHz) S 7.47 (s,1 H), 4.53 (s, 2H), 3.58 (t, 2H), 3.09 (s, 6H), 2.43 (t, 2H), 1.46 (s, 9H); MS (APCI) 255 (MH').
Step C: 2-Phenyl-7 8~iihvdro-SH-ovrido(4 3-dlpvrimidine-6-carboxylic acid tart-buhrl ester. A rriucture of 3~imethylaminomethylene-4~xo-piperidine-1-carboxylic aad tert-butyl ester (preRared according to the method of Example 101, Step B, 509 mg, 2.0 mmol), benzamidine hydrochloride hydrate (470 mg, 3.0 mmol), and sodium ethoxide (1 M in ethanol, 6.0 mL, 6.0 mmol) in,absolute ethanol (4 mL) was heated to reflex for about 3 d, cooled to room temperature, and concentrated. The residue was diluted ' WO OOI59510 PCTIIBOOI0029G
with saturated aqueous sodium bicarbonate and extracted with chloroform (3x).
The combined organic extracts were dried over sodium suffate, filtered, evaporated, and purified by flash column chromatography (Biotage Flash 40S"', 1015% ethyl acetatelhexanes) to give 304 mg (49%) of the title compound of Example 101, Step C
as a yellow oil. 'H NMR {CDCI3, 400 MHzj S $.52 (s, 1 H), 8.40-8.38 (c, 2H), 7.50-7.44 (c, 3H), 4.62 (s, 2H), 3.78 (t, 2H) 3.02 (t, 2H),1.50 (s, 9H); MS (APCt) 312 (MH').
Step D: 2-Phenv(-7.8-dihvdro-SH-ovridof4.3-d~pvrimidine hydrochloride. To a sotution of 2-phenyl-7,8-dihydro-SH-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester (prepared according to the method of Example 101, Step C, 304 mg, 0.98, mmol) in ethyl acetate (2 mL) was added hydrogen chloride (2.5 M in ethyl acetate, 3.9 mL, 9.76 mmol). This mixture was stirred at room temperature far 16 h and concentrated to give 256 mg (>100%) of the title compound of Example 101, Step D es a pale yellow solid. 'H NMR (CD,OD, 400 MHz) 8 8.75 (s, 1 H), 8.42-8.38 (c, 2H), 7.57-7.45 (c, 3H), 4.48 (s, 2H), 3.68 (t, 2H) 3.35-3.25 (buried, 2H); MS (APCI) 212 (MH').
Step E: 1 R-f4-(4-Chlorocarbonvt-3R.5S-dimethvl_piperazin-1 vt)-ovrimidin-2-vll-ethv!
butyrate. To a solution of 1 R-[4-(3R,5S-dimethyl-piperazin-1 yl)-pyrimidin-2-yI]~thyl butyrate (prepared according to the method of Preparation Three, 1.36 g, 4.44 mmol) in dichloromethane (22 mL) at 0°C under nitrogen was added pyridine (0.36 mL, 4.44 nunol) followed by triphosgene (883 mg, 2.97 mmol). This mixture was stirred with wamung to room temperature for 1.5 h and quenched with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous phase was extracted with chloroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.-~2°~
methanoUchloroform) to give 1.59 g (97%) of the title compound of Example 101, Step E as a brown oil. 'H NMR (CDCI,, 400 MHz) 8 8.23 (d,1 H), 6.39 (d,1 H), 5.66 (q, 1 H), 4.54-4.47 (c, 2H), 4.35 (m,1 H), 4.25 (m,1 H), 3.20 (dt, 2H), 2.38 (t, 2H),1.72-1.62 (c, 2H),1.5fi (d, 3H),1.31 (d, 3H),1.30 (d, 3H), 0.95 (t, 3H); MS (APCI) 369, 371 (MH').
Step I=: f4-f2-(1 R-Hvdroxv-ethvl~vrimidin~yl~-2R 6S~iimethvl oioer~rn 1 v11~2 phenyl-7.8-dihvdro-SH-ovridof4.3~ilovrimidin-6 vl~methanone. A mixture of 2-phenyl-7,8-dihydro-SH=pyrido[4,3-djpyrimidine hydrochloride (prepared according to the method of Example 101, Step D,160 mg, 0.65 mmol),1 R-[4-(4-chlorocarbonyl-3R,5S-dimethyl-p'~perazin-1-ylj-pyrimidin-2-yl~ethyl butyrate (prepared according to the method of Example 101, Step E, 200 mg, 0.54 mmol), and triethylamine (0.19 mL, - WO 00!59510 1.36 mmol) in tetrahydrofuran (5 mL) was stirred at reflux for 3 h; cooled to room temperature overnight, and concentrated. The residue'was diluted with a 4:1 mixture of methanoUwater (5 mL) and lithium hydroxide hydrate (114 mg, 2.71 mmol) was added. This mixture was stirred for 2.5 h, .concentrated; and partitioned between saturated aqueous sodium bicarbonate and chtorofortn. The layers were separated and the aqueous phase was extracted with 20% isopropanoUchioroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2-.>5% methanollchloroform) to give mg (71%) the title compound as a white foam.'H NMR (CDCI9, 400 MHz) 88.56 (s, 1 H), 8.41-8.39 (c, 2H), 8.20 (d,1 H), 7.50-7.46 (c, 3H), 6.38 (d, 1 H), 4.71 (s, 2H), 4.69 (m, 1 H), 4.28 (d, 1 H), 3.89 (t, 2H) 3.83 (d, 2H), 3.60-3.56 (c, 2H), 3.46-3.39 (c, 2H), 3.09 (t, 2H), 1.50 (d, 3H), 1.18 (d, 6H); MS (APCI) 212 (MH'); [cz]p +6.i (c"1.8, CHCh).
Exam~fes 102 to 110 Examples 102 to 110 were prepared from the appropriate starting materials in a manner analogous to the method of Example 101.
NO
R,e .,... Mg O z $ N-~N " N ~ / N
zz R N
Rz,. R,a , Example R~ Rz' R" R'° mp (°C) MS (MH') i02 quinolin-2-yl H 3R-Me 5S-Me 772-174:5 407 103 quinolin-3-yl H 2R-Me 6S-Me . 4p7 104 quinolin-4-yl H 3R-Me 5S-Me 407 105 quinolin-6-yl H 3R-Me 5S-Me 4p7 106 pyridin-3-yl- pyridin-3-2R-Me 6S-Me . ' 462 methyl y!-methyl Example NR='R~ R" R" mp (C) MS (MHO
107 2-amino-7,8-dihydro-SH-2R-Me 6S-Me 225=228 413 pyrido[4,3-dJpyrimidin-6-yl 108 2-(1-hydroxy-1-methyl-2R-Me 6S-Me 4~
ethyl}-7.8~ihydro-5H-pyiid~[4,3-dJpyrimidin-6-yl 109 5,7-dihydro- 2R-Me 6S-Me 458 dibenzo[c.e]azepin-6-yl 110 4-[2-{1 R-hydroxy-ethyl)-3R-Me 5S-Me 499 pyrimidin-4-ylJ-3R,5S-dimethyl-piperazin-1-yl Example 111 (E?-1 R-f4-f4-l2-Phenvl-ethenesulfonvl~-oit~erazin-1-vfl-nyrirnidin-2-vl~-ethanol.
HO
....Me N-~ si, ~ N
II ~ ~ /
WO 00/59510 rcr~BOOiooi~
Step A: (E)-1 R-f4-t4-f2-Phenyl-ethenesulfonvl)-oiperazin-1-vtlwrimidin-2-vlf-ethyl acetate. To a solution of (R~1-[4-piperazin-1-ytrpyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Two, 0.25 g, 1.0 mmol) and triethylamine (0.10 g, 1.0 mmol) in tetrahydrofuran~ (5 mL) was added (~
styrenesulfonyl chloride (0.21 g, 1.0 mmol)~at ambient temperature and stirred for 1 h.
The mixture was diluted with water and extracted twice with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and the filtrate was concentrated to an oil, which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound of Example 111, Step A as an oil, 0.15 g (34%). 'H NMR
(CDCI,, 300 MHz) 81.48' (d, 3H), 2.15 (s, 3H), 323 (m, 4H), 3.84 (m, 4H), 5.67 (q,1H), 6.40 (d,1 H), 6.65 (d,1 H), 7.39-7.52 (m, 6H), 821 (d,1 H); MS (TS) 417 (MH'). ;
Step B: (El-1R-f4-f4-(2-Phenv!-ethenesulfonyl~oiaerazin-1-vll-ovtimidin-2-vll-ethanol, To a solution (E)-1 R-{4-[4-(2-phenyl-ethenesuifonyl~piperazin-1-yl]-pyrimidin-2 yI}=
ethyl acetate (prepared according the method of Example 111, Step A, 0.14 g, 0.33 mmol) in methanol (1 mL) was added at ambient temperature 6 N aqueous potassium hydroxide (0.25 mL). After stirring for 3 h, the solution was diluted with ethyl acetate and washed twice with water. The organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound as a white solid, 0.09 g (69%).'H NMR (CDCI', 300 MHz) 81.48 (d, 3H), 3.23 (m, 4H), 3:84 (m, 4H), 4.20 (br s,1 H), 4.71 (q, 1 H), 6.40 (d, 1 H), 6.65 (d, 1 N), 7.39-7.52 (m, 6H), 8.21 (d, 1 H); mp: 68-70 °C; MS (TS) 375 (MH'); [a]p +20.9 (c 1.0, MeOH).
Examples 112 and 113 Examples 112 and 11.3 were prepared from the appropriate starting materials in a manner analogous to the method of Example 111.
HO
R~° :.,.Me N-R"-N N, ~ / N
R
Example .R' R" R" mp (C) '. MS
(MH') 112 (RrMe (S~Me isopropylsulfonyl 7 52-154 343 113 (R~Me (S)-Me 1-methyl-1 H-imidazol-4-157-158 381 yl-sulfonyl Example 114 1 R-f4-f5-(4-Bromobenzenesulfonvl~2R.5S-diaza-bievclo[2.2.11heat-2-y(1-ovrimidin-2-vl~-ethanol.
HO
~~~~Me O N-CI ~ ~ SI-N N N
II ~ /
Step A: 1~4-(2R.5S-Diaza-biwclof2.2.11hept-2-yl~ovrimidin-2-y(1-ethyl butyrate. To a suspension of 2,5-diaza-bicyGo[2.2.1)heptane dihydrobromide (7.57 g, 88.0 mmot;
Synthesis 1990, 10, 925) in dichloromethane (90 mL) was added 1,8-diazabicyGo[5.4.0]undec-7-ene (13.7 g, 90 mmol) and stirred until homogeneous.
A
solution of (R~1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 10.2 g, 45 mmol) in dichioromethane (10 mL) was added and stirred at reflux for 14 h. The mixture was filtered and washed with saturated aqueous sodium bicarbonate. The organic tayer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a aude product which was purified b~ flash chromatography (9:1->5:1 dichloromethane:methanoll to give the title compound of Example 114, Step A as an oil, 6.75 g (51 %). 'H NMR (CDCI,, 300 MHz) b 0.92 (t, 3H), 1.54 (d, 3H), 1.68-1.78 (m, 5H), 2.68 (t, 2H), 3:38 (m, 1 H), 3.76 (m, 3H), 4.42 (m, 1 H), 5.35 (q, 1 H), 6.16 (d, 1 H), 8:12 (d, 1 H); MS (CI) 291 (MH').
Step B: 1 R-f4-f5-l4-Bromobenzenesulfonvl)-2R.5S-diaza-bicvclof2.2.11hent-2-y(1-Qvrimidin-2-vl)-eth~tyrate. To a solution of 1R~,4~2R,5S-diaza-bicydoj2.2.1]hept-2-yl~pyrimidin-2-ylj-ethyl butyrate (prepared according to the method of Example 114, Step A, 0.58 g, 2.0 mmol) and triethylamine (0.22 g, 2.2 mmol) in chloroform (10 mL) was added 4-bromobenzenesulfonyl chloride (0.56 g, 2.2 mmol) and stirred at ambient temperature for 16 h. The mixture was washed once with water, once with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound of Example 114, Step B as a dear oil, 0.92 g (90%). 'H NMR
(CDCl3, 300 MHz) S 0.92 (t, 3H), 1.54 (d, 3H), 7.68-1.78 (m, 5H), 2.68 (t, 2H), 325 (m, 1 H), 3.46 (m, 3H), 4.28 (m, 1 H), 5.25 (q, 1 H), 6.16 (d, 1 H), 7.58 -7.64 (m, 4H), 8.12 (d, 1 H); MS (CI) 510 (MH').
Step C: 1 R-(4-f5-l4-Bromobenzenesulfonvl)-2R.5S-diaza-bicvclof2.2.11hent-2-v(1-evrimidin-2-vl)-ethanol. To a solution of 1 R-{4-[5-(4-bromobenzenesulfonylr2R,5S-diaza-bicydo[2.2.1]hept-2-yl]-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 114, Step 8, 0.85 g,1.6 mmol) in a 2:1 mixture of tetrahydrofuran:methanol (10 mL) was added at ambient temperature 6 N aqueous potassium hydroxide (1 mL). After stirting for 6 h the solution was diluted with dichioromethane and washed twice with water. The organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to a viscous oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound as a white foam, 0.49 g (66%). 'H NMR (CDCI,, 300 MHz) 1.54 (d, 3H), 1.68 (m,,2H), 1.78 (m, 1H), 3.25 (m, 1H), 3.46 (m, 3H), 4.28 (m, 1H), 4.78 (q, 1 H), 6.16 (d, 1 H), 7.64 (m, 4H), 8.12 (d, 1 H); mp: 83-88 °C; MS (C!) 440 (MH'); [a]D -49.2 (c 1.0, MeOH).
Examples 115 to 120 Examples 115 to 120 were prepared from the appropriate starting materials in a manner analogous to the method of Example 114.
WO 00!59510 PCTIIB00/00296 HO
w~~Me N-R"-N' \ -N , ~ /N'_ Example R" mp (C) MS (MH') 115 4-chlorophenylsulfonyl 83-88 395, 397 116 2-~ienylsulfonyl 84-86 '~ 367 117 2-(5-chlorothienyl)-sulfonyl62-64 401, 403 118 4-carboxamidoylphenyl-sulfonyl148-151 404 H
119 4-(tart-butylphenyl~sulfonyl72-75 417 120 N,N-dimethylsutfamoyl 110-111 328 Example 121 {4-(4-(Pvrrolidine-1-sulfonvl)-piperazin-1-vll-ovrimidin-2-vl1-methanol.
HO
N-\NIIN~ ~~N
O
Step A: 2-Methoxvmethvl-4-t4-(QVrrofidine-1-suffonv()-oioerazin-1-vf!-ovrimidine. To a solution of 2-methoxymethyl-4-piperazin-1-yl-pyrimidine (prepared according to the method of Preparation One, 2.08 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in tetrahydrofuran (20 mL) was added N-pyrrolidinesulfonyl chloride {1.69 g, 10 mmol) at 0 °C and stirred for 3 h at ambient temperature. The mixture was diluted with ethyl acetate and washed twice with water. The organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to an oil which was purified by flash chromatography (95:5 dichloromethane:methanol) to give the title compound of Example 121, Step A as a dear oil, 3.24 g (93%). 'H NMR (CDCl3, MHz) 81.81-1.85 (m, 4H), 3.12-3.18 (m, 8H), 3.59 (s, 3H), 3.81 (m, 4H~ 4.43 (s, 2H), 6.71 (d, 1 H), 8.18 (d, 1 H); MS (TS) 342 (MH').
Step B: f4-f4-lPvrrolidine-1-sulfonvll-oiDerazin-1-vll-ovrimidin-2-~rt~-methanol. To a solution of 2-methoxymethyl~-[4-(pyrrolidine-1-sulfonyL~piperazin-1-yl]-pyrimidine I 1 , , (prepared according to the method of Example 121, Step A, 3.1 g, 9.4 mmol) in dichlorornethane (47 mL) was added boron tribromide (1 M in dichioromethane, mL, 18.7 mmol) at 0 °C then stirred at ambient temperature for 2 h. The mixture was washed twice with saturated aqueous sodium bicarbonate; and the organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give an oil which was crystallized from isopropyl ether to give the title compound as a white solid, 2.43 g (7790). 'H NMR (CDCI3, 300 MHz) b 1.82 (m, 4H), 3.15 (m, 8H), 3.81 (m, 4H), 4.35 (d, 2H), 4.83 (t,1H), 6.71 (d;1H), 8.18 (d, 1H); mp:128-131 °C;
MS (Cl) 328 (MH').
Examples g22 to 125 "
Examples 122 to 125 were prepared from the appropriate starting materials in a manner analogous to the method of Example 121.
R' N
R" ~ ~ ~\N
Example R' R" mp (C) MS (MHO
122 CHZOH 2,5-dimethyipymolidin-1-128-131 356 ytsulfonyl 123 CHZOH piperidin-1-ylsulfonyl141-142 342 124 (R)-CH(Me)OH aza-bicydo[3.21]octan-8-11 i-112 382 ylsulfonyl 125 (R~CH(Me)OH aza-bicydo(32.1]octan-3-113-114 396 one-8-yl-sulfonyl Examote 126 (E?-1-f4-f2-f 1 R-Hvdroxv-ethvl~-ovrimidin~.-vll-oinerazin-1-vl~-2-methyl-3-ohernrl-pro~enone.
~~~~ Me ., pCTIIB00/00296 Step A: ~E>-1 R-(4-~4-(2-Methvl-3-phenyl-acrvlovl~cioera~in-1-vll-avrimidin-2-vl~-ethyl acetate. To a solution of (R}-1-(4-piperazin-1-y!-pyrimidin-2-yl~ethyl acetate (prepared according to the method of Preparation Two, 0.54 g, 2.1 mmol) and a-methylcinnamic acid (0.34 g, 2.1 mmol) in diG~loromethane (10 mL) was added 1-hydroxybenzotriazole (0.50 g, 3.6 mmol) followed by 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (0.45 g, 2.4 mmot) at ambient temperature and stirred for 48 h. The mixture was washed once with water, once with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and the ftltrate was concentrated to an oil which was purified by flash chromatography (9:1 dichloromethane:methanot) to give the title compound of Example 126, Step A as a Gear viscous oil, 0.53 g (63%). 'H NMR (CDCI,, 300 MHz) S 1.51 (d. 3H), 2.14 (s, 3H), 2.18 (s, 3H), 3.75 (m, 8H), 5.fi8 (q,1 H), 6.41 (d,1 H), 6.59 (s,1 H), 725-7.43 (m, 5H), 8.23 (d, 1 H); MS (CI) 395 (MH'); ja]~ +38.6 (c 1.0, MeOH).
Step B: ~E?-1-f4-T2-(1R-Hydroxv-ethvl~-ovrimidin-4-vll-flioerazin-1-vl~-2-methyl-3-phenvl-aropenone. To a sotution of (E}-1 R-{4-[4-(2-methyl-3-phenyl-acryfoyl~
piperazin-1-yl}-pyrimidin-2-yl}-ethyl acetate (prepared according to the method of Example 126, Step A, 0.51 g, 1.3mmo1) in methanol (5 mL) was added at ambient temperature 6 N aqueous potassium hydroxide (1 mL). Afterstining for 1 h the solution was diluted with ethyl acetate and washed twice with water. The organic layer was separated, dried over magnesium sulfate, ftltered, and the ftltrate was concentrated to give the title compound as a white solid, 0.25 g (55%). 'H NMR
(CDC1,, 300 MHz) 51.51 (d, 3H), 2.14 (s, 3H), 3.75 (m, 8H), 4.22 (br s, 1 H), 4.71 (q, 1 H), 6.41 (d, 1 H), 6.59 (s, 1 H), 7.25-7.43 (m, 5H), 8.23 (d,1 H); mp: 119-121 °C; MS
(CI) 353 (MH'); [c~J~ +16.0 (c 1.0, MeOH).
Examples 127 to 129 Examples 127 to 129 were prepared from the appropriate starting materials in a manner analogous to the method of Example 126.
WO 00/59510 PC'TIIBOOf00296 ,."Me R' Example ~ A~' R° R' mp (°C) ~ ~ MS (MH') 127 thien-2-yl H H 104-106 345 128 thien-2-yl (R}-Me . (S~Me 69-73 373 Ho ~~~~Me An~ ~ N-Jr--N N N
O
Example A~ mp (°C) MS (MH') 129 . 4-(o-tolylcarbamoyly-phenyl 9&103 446 Example 130 (E~3-Benzofuran-2-vl-1-(4-f2-(1 R-hvdroxv-ethyl)-ovrimidin-4-vf1-2R,6S-dimethvi-piperazin-1-vl~-oropenone.
HO
1Ae w~~Me N-Me Step A: (E)-1 R-(4-f4-(3-Benzofuran-2-vl-acrvIovIJ-3R.5S-dimethvl-oioerazin-1-vll-p, r~rimidin-2-vf)-ethyl butyrate. To a solution of 1 R-(4-(3R,5S-dimethyl-piperazin-1-yl~
pyrimidin-2-yfJ-ethyl butyrate (prepared according to the method of Preparation Three, 0.79 g, 2.6 mmol) and triethylamine (0.26 g, 2.6 mmol) in dichloromethane (90 mL) was added (E)-3-benzofuran-2-yl-acryloyl chloride (0.54 g, 2.6 mmol) and stirred at ambient temperature for 16 h, then at reflux for 2.5 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product, which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound of Example 130, Step A as a viscous oil, 0.79 g (54%). 'H NMR (CDCI,, 300 MHz) i; 0.95 (t, 3H), 1.40 (d, 6H), 1.56 (d, 3H), 1.67 (q, 2H), 2.38 (t, 2H), 3.25 (d, 2H), 4.33 (m, 2H), 4.75 (m, 2H), 5.66 (q, 1 H), 5.95 (d, 1 H), 6.40 (d, 1 H), 7.14-7.37, (m, 5H), 8.06 (d, 1 H), 8.22 (d, 1 H); MS (Ci) 477 (MH'); [a]o +49.1 (c 1Ø MeOH).
Step B: (El-3-Benzofuran-2-vl-1-(4-f2-(1R-hvdroxy~thvl)-pvrimidin-4-vfl-2R 6S-dimethvl-piperazin-1-vl)-orooenone. To a solution of (E~-1 R-(4-[4-(3-benzofuran-2-yt-acryloyl)-3R,5S-dimethyl-piperazin-1-yt]-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 130, Step A, 0.51 g, 1.1 mmol) in methanol (5 mL) was added at ambient temperature 6 N aqueous potassium hydroxide (1 mL).
After stirring for 1 h the solution was diluted with ethyl acetate and washed twice with water. The organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound as a white soiid, 0.49 g (75%).
'H NMR (CDC13, 300 MHz) 8 1.40 (d, 6H), 1.56 (d, 3H); 325 (d, 2H), 4.33 (m, 2H), WO 00159510 PC'f/IB00/00296 4.75 (m, 2H), 4.68 (q, 1 H), 5.95 (d; 1 H), 6.40 (d, 1 H), 7.14-7.37, (m, 5H), 8.06 (d, 1 H), "
8.22 (d, t H); mp: 80-82 °C; MS (CI) 407 (MH'); [a]~ +17.7 (c t.0, MeOH).
Examflle 131 Cvclohexvl-f4-f2-(1 R-hvdroxv-ethyl)-pvrimidin~l-vtl-2R.6S-dimethvt-oioerazin-1-vl)-methanone.
HO
Me ~~~~Me N-N. N ~ /N
O
Me Step A: 1 R-f4-(4-Cvclohexaneca~onvf-3R.5S-dimethvl-aioerazin-1-vl~oyrimidin-2-vll-ethyl butyrate. To a solution of 1R-j4-(3R,5S-dimethyl-piperazin-1-yl)-pynmidin-2-yfJ-ethyl butyrate (prepared according to the method of Preparation Three, 306 mg, 1.0 mmol) and triethylamine (230 mg, 1.2 mmol) in dichloromethane (10 mL) was added at ambient temperature cydohexanecarbonyl chloride (161 mg,1.1 mmoi).
After 1 h the mixture was washed with water, and the dichloromethane layer was dried over magnesium sulfate and filtered. The filtrate was oonoentrated to give the tine compound of Example 131, Step A as an oil, 388 mg (94%). 'H NMR (CDCI,, 300 MHz) 8 0.94 (t, 3H), 1.2-1.4 (m, 6H), 1.54 (d, 3H), 1.5-1.83 (m, t2H), 2.44 (m, 3H), 3.2-3.3 (m, 2Hj, 4.4-4.6 (m, 4H), 5.52 (q, 1 H), 6.44 (d; 1 H), 8.22 (d, 1 H);
MS (CI) 417 (MH').
Step B: Cvdohexvl-(4-f2-f 1 R-hvdroxv-ethyll-ovrimidin-4-vt1-2R.6S-dimethvl-oioerazin-1-v(1-methanone. Ta a solution of 1 R-j4-(4-cydohexanecarbonyl-3R.5S-dimethyl-piperazn-1-yl)-pyrimidin-2-yt]-ethyl butyrate (prepared according to the method of Example 131, Step A, 375 mg, 9.0 mmol) in methanol (5 mL) was added 6 N
aqueous potassium hydroxide (0.5 mL) and stirred at ambient temperature for 4 h. The reaction mixture was concentrated, diluted with water, and extracted into dichloromethane. The extract was washed twice with water, dried over magnesium sulfate, and evaporated to an oil. The cxude product was crystallized from ethyl ether to give the title compound as a white soiid,106 mg (34%). 'H NMR (CDCI,, 300 MHz) 81.2-1.4 (m, 6H),1.55 (d, 3H),1.6-1.8 (m,10H), 2.46 (m,1 H), 3.2-3.3 (m, 2H), 4.6 (m, 4H), 4.78 (q, 1H), 6.43 (d, 1H), 8.22 (d, 1H); mp: 174-175 °C;
MS (CI) 347(MH'); [a]p +18:4 (c 1.0, MeOH).
Example 132 Furof3.2-clovridin-2-vl-f4-f2-( 1 R-hvdroxv-ethyl)-pyrimidin-4-yl]-2R.6S-dimethvt-eiperazin-1-vl)-methanone.
~~~~Me Me Step A: 7-Chloro-furoL.2-clpvridine-2-cart~oxvlic acid. To a solution of,n-butyllithium (2.5 M in hexanes, 17 mt_, g, 42.6 mmol) in anhydrous ethyl ether (90 mL) was added dropwise a solution of 4-chloro-furo[3,2-c]pyridine (5.81 g, 37.8 mmot; J.
Heterocycl.
Chem. 1975, 12, 705) in ethyl ether (85 mt-) at 78 °C under nitrogen atmosphere.
This mixture was stirred for 1.5 h at--65 °C, poured onto dry ice (100 cx) and warmed to ambient temperature and quenched into water. The separated organic layer was extracted once with water and the combined aqueous layers were aadified to pH
with concentrated hydrochloric aad to give the title compound of Example 132, Step A
as a white solid, 3.33 g (45%). 'H NMR (CDCI,, 300 MHz) 8 7.69 (s, 1H), 7.85 (d, 1H), 8.42 (d, 1 H); mp: 233-235 °C (dec); MS (CI) 153 (MH' - CO= ).
Step B: 7-Chloro-furo(3 2-clovridine-2-cart~oxvlic aad chloride. 7-Chloro-faro[3,2-c]pyridine-2-carboxylic aad (prepared according to the method of Example 132, Step A, 8.94 g, 45.2 mmol) was combined with thionyl chloride (30 ml-) and sodium carbonate (9.59 g, 90.5 mmol) and heated to reflux for 16 h under nitrogen atmosphere. The cooled mixture was diluted with dichloromethane and filtered.
The filtrate was evaporated to give the title compound of Example 132, Step B as an orange oil, 9.19 g (94%). The aad chloride was used directly without further purificafjon.
Step C:1 R-(4=f4-(4-Chloro-faro(3.2-clayridine-2-carbonyl)-3R 5S-dimethyl-o,perazin-1-vtl-ovrimidin-2-vl~thyl butyrate. To a soluflon of 1 R-[4-(3R,5S-dimethyl-piperatin-1-yl~pyrimidin-2-y~-ethyl butyrate (prepared according to the method of Preparation Three, 13.04 g, 42.5 mmot) and triethytamine (8.61 g, 85.1 mmol) in dichlorbmethane (90 mL) was added 7-chloro-furo[3,2-c]pyridine-2-carboxylic acid chloride (prepared according to the method of Example 132, Step B, 9.1 g; 84.0 mmol) and stirred at ambient temperature for 2 h. The mixture was washed-successively with saturated aqueous sodium bicarbonate and water, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound of Example 132. Step C as. a viscous oil,18.9 g (91 %). 'H NMR
(CDCI,, 300 MHZ) 8 0.95 (t, 3H),1.40 (d, 6H),1.56 (d, 3H),1.67 (m, 2H), 2.38 (t, 2H), 3.25 (d, 2H), 4.33 (m, 2H), 4.75 (m, 2H), 5.66 (q,1 H), 6.40 (d, 1 H), 7.33 (s. 1 H), 7.41 (d, 1 H), 8.23 (d, 1 H), 8.35 (d, 1 H); MS (CI) 487 (MH'); [ot]p +33.3 (c 1.0, MeOH).
Step D: 1 R-l4-f4-(Furof3.2-clovridine-2-carbonyl)-3R.5S-dimethvt-nioerazin-1-vl1-pvrimidin-2-vll-ethyl butyrate. To a solution of 1 R-{4-[4-(4-chloro-furo(3,2-c]pyridine-2-carbonyl)-3R,5S-dimethyl-piperazin-1-yfj-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 132, Step C, 18.6 g, 38.4 mmol) in ethanol (1f0 mL) was added sodium carbonate (4.07 g, 38.4 mmol) and 10% palladium on carbon (6.10 g, 33 wt%). This mixture was hydrogenated at 50 psi hydn~gen for 6 h using a Parr apparatus. The catalyst was filtered and the filtrate was evaporated to an oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to gi~re the title compound of Example 132, Step D as a yellow oil, 14.2 g (82°~). 'H NMR
(CDCI,, 300 MHz) S 0.95 (t, 3H),1.40 (d. 6H),1.56 (d, 3H),1.67 (q, 2H), 2.38 (t, 2H), 3.25 (d, 2H), 4.33 (m, 2H), 4.75 (m, 2H), 5.68 (q, 1 H), 6.40 (d, 1 H), 7.37 (s, 1 H), 7.48 (d, 1 H), 8.22 (d,1 H), 9.04 (s,1 H); MS (CI) 452 (MH'); [ac]o +36.7 (c 1.0, MeOH).
Step E: Furoj3.2-clpyridin-2-v!-f4~-(1R-hvdroxv~thvll-ovrtmidin-.4-v(1-2R.6S-øimethyl-oioerazin-1-vtl~-methanone. 1 R-{4-{4-(Furo[3,2-c]pyridine-2-ca~onyl)-3R,5S-dimethyl-piperazin-1-yIj-pyrimidin-2-yl}-ethyl butyrate (prepared aooording to the method of Example 132, Step D, 5.48 8,12.1 mmol) was combined with concentrated hydrochloric aad (15 mL) and stirred at ambient temperature for 6 h. The mixture was poured into cold 6 M aqueous sodium hydroxide and extracted twice with ethyl acetate. The organic extract was washed once with water, dried over sodium sulfate and evaporated to a foam which crystallized from isopropyl ether to give the tibe compound as a white solid, 3.33 g (72%). 'H NMR (CDCl,, 300 MHz) S 1.43 (d, 6H).
1.52 (d, 3H), 3.37 (m; 2H), 4.38 (m, 2H), 4.71 (q,1 H), 4.83 (m, 2H), 6.43 (d,1 H), 7.38 (s, 1 H), 7.47 (m, 1 H), 8.22 (m, 1 H), 8.54 (d, 1 H), 8.58 (d, 1 H), 9.04 (s, 1 H); inp: 142-,, 143 °C; MS (CI) 382 (MH'); [aJ~ +15.9 (c 1.0, MeOH). , , Example 133 f4-f2-f1R-Hvdroxv-ethyll-pvrimidin-4-yll-2R 6S-dimethyl-piDerazin-1-vl}-(4-ovrrolidin-1-yl-furof3.2-cipvridin-2-vl)-methanone.
~~~~Me Me A solution of 1 R-{4-[4-(4-chloro-furo[3,2-c]pyridine-2-carbonyl~3R,5S-dirrtethyf-piperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 132, Step C, 0.046 g, 0.11 mmol) in pyrrolidine (0.037 mL, 0.44 mmol) was heated to reflux for 14 h and evaporated to give the title compound as a tan solid, 0.04 g (80%). 'H NMR (CDCI,, 300 MHz) 81.43 (d, 6H), 1.53 (d, 3H), 2.08 (m, 4H), 3.43 (m; 2H), 3.77 (m, 4H), 4.43 (m, 2H), 4.71 (q, 1 H), 4.92 (m, 2H), 6.43 (d, 1 H), 6.70 (d, 1 H), 7.60 (s, 1 H), 8.08 (d, 1 H), 8.23 (d, 1 H); MS (CI) 451 (MH').
Examples 134 to 158 I ' Examples 140 and 142 to 158 were prepared from the appropriate starting materials in a manner analogous to the method of Example 131. Example 141 was prepared from the appropriate starting materials in a manner analogous to the method of Example 133.
HO
R,e. "" Me N-R"N N ~ / N
Example R" R' R" mp (C) MS (MH') 134 cyclopropylcarbonyl2R-Me 6S-Me 110-111 305 135 cyclobutylcarbonyl2R-Me 6S-Me 134-135 319 136 cyclopentylcarbonyl2R-Me 6S-Me 199-200 333 137 tert-butylcart~onyl2R-Me 6S-Me 168-169 321 WO 00/59510 PGTlIB00l00296 'Me O
z~
Ar R.- ', Exampl Ars R" R" mp (°C) MS (MH') a 138 benzofuran-2 yl 2R-Me 6S-Me 124-126 381 139 furo[3,2-cjpyridin-2-ylH H 55-65 354 140 faro[3,2-cjpyridin-2-yl3R-Me 5S-Me , 382 141 morphofin-4 y!-furoj3,2-2R-Me 6S-Me ~ 467 cjpyridin-2-yl 142 faro[2,3-c]pyridine-2-yl2R-Me 6S-Me 129-131 382 143 5-chtorobenzofuran-2 H H 387, 389 yl 144 5-chlorobenzofuran-2-yl3R-Me 5S-Me 114-116 415, 417 145 5.7-dichtorobenzofuran-2-yl2R-Me 6S-Me 136-137 450, 452 146 5,7-dichtorobenzofuran-2-yl3R-Me 5S-Me 152-153 450, 452 ~
147 5-nitrobenzofuran-2-yl2R-Me 6S-Me 153-154 426 148 5,7-dimethyibenzofuran-2-yl3R-Me 5S-Me 134-136 409 149 5-methoxybenzofuran-2-yl3R-Me 5S-Me 137-138 411 150 5-methoxybenzofuran-2-yl2R-Me 6S-Me 118-119 411 151 imidazo[1.2-a]pyridin-2H H 149-150 353 yl 152 imidazo[1.2-a]pytidin-23R-Me 5S-Me 171-173 381 yl 153 imidazo[1.2-a]py~idin-2-yl2R Me 6S-Me 147-149 381 154 6-chtoroimidazo[1,2- 2R-Me 6S-Me 76-84 416, 418 b]pytidazin-2-yl 155 6-methylimidazo[1,2- 3R-Me 5S-Me 164-165 395 ajpyridin-2-yl ' 156 benzoxazol-2-yl 2R-Me 6S-Me i26-127 382 157 4-cyanophenyl 2R-Me 6S-Me 90-a00 366 158 6-hydroxy-pyridazin-3-yl2R-Me 6S-Me 359 Example 159 1-f4-f2-l1 R-Hvdroxv-ethyl)-ovrimidin-4-vll-2R.6S-dimethvl-oioerazin-1-vl~-2-(6-methvl-pvridin-3 yloxv)-ethanone.
N \~--N
Me ~~"
~H Me Step A: 1 R-f4-(4-Chloroacetvl-3R.5S-dimethvl-~i~erazin-1-yl?-ovrirnidin-2-vll-ethyl bu te. To a solution of 1 R-(4-(3R,5S-dimethyf-piperazin-1-yt~pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Preparation Three, 9.69 g, 31.3 mmol) and fiethylamine (4.74 g, 46.9 mmol) in chloroform (150 mL) was added dropwise chloroacetyl chloride (3.00 mL, 37.6 mmol) at 0 °C then stirred at ambient temperature for 12 h under nitrogen atmosphere. The mixture was washed success'rvefy with saturated aqueous sodium bicarbonate and water, and the organic layer was dried over sodium sulfate, treated with activated carbon, and filtered. The filtrate was concentrated to obtain an oil which was purfied by flash chromatography (9:1 dichloromethane:methanol) to give the title compound of Example 159, Step A as an oil, 8.98 g (75%). 'H NMR (CDCI,, 300 MHz) 8 0.96 (d, 3H), 1.32 (d, 6H), 1.59 (d, 3H), 1.71 (m, 2H), 2.40 (t, 2H), 3.28 (m, 2H), 4.28 (s, 2H), 4.35 (m, 4H), 5.68.(q, 1 H), 6.41 (d, 1 H), 8.23 (d, 1 H); MS (CI) 383, 385 (MH').
Step B: 1 R-l4-f3R.5S-Dimethvl-4-fl6-methyl-pvridin-3-vloxv~-acetvll-pioerazin-pvrimidin-2-v1)-ethyl butyrate. To a suspension of sodium hydride (60%
dispersion in oil, 0.05 g, 1.3 mmol) in tetrahydrofuran (2 mL) was added a solution of 6-methyl-3-pyridinol (0.14 g, 1.3 mmol) in tetrahydrofuran (3 mL) at 0 °C under nitrogen atmosphere and stirred for 0.5 h warming to ambient temperature. Next, a solution of 1R-[4-(4-chloroaoetyl-3R,5R~iimethyl-piperazin-1-yl)-pyrimidin-2-yQ-ethyl butyrate (prepared according to the method of Example 159, Step A, 0.40 g, 1.1 mmol) in tetrahydrofuran (2 mL) was added and fefluxed for 1 h. The mixture was diluted with dichloromethane.and washed with saturated aqueous sodium bicarbonate; dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash chromatography (91 dichloromethane:methanol) to give the title compound of Example 159, Step B as an oil, 0.31 g (66%). 'H NMR (CDCI,, 300 MHz) b 0.96 (d, 3H), 1.32 (d, 6H), 1.59 {d, 3H), 1.71 (m, 2H), 2.40 (t. 2H), 2.46 (s, 3H), 3.28 (m, 2H), 3,78 (s, 2H), 4.35 (m, 4H), 5.68 (q, 1 H), 6.41 (d, 1 H), 6.83 (m, 1 H). 7.14 (m, 1 H), 8.08, (d, 1 H), 8.23 (d, 1 H); MS (CI) 456 (MH').
Step C: 1~4-f2-l1R-Hvdroxy-ethvl~oyrimidin-4-vll-2R.6S-dimethvl-oiDerazin-1-v(1-2-(6-methyl-pyridin-3-vloxv~ethanone. 1 R-(4-{3R,5S-Dimethyl-4-[(6-methyl-pyridin-3-yioxy)-acetylj-piperazin-1-yl}-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Example 159, Step B, 0.30. g, 0.65 mmol) was combined with concentrated hydrochloric aad (3 mL) and stirred at ambient temperature for 6 h. The mixture was neutralized with 6 N aqueous sodium hydroxide to pH 9 and extracted twice with ethyl acetate. The organic extract was washed once with water, dried over sodium sulfate and filtered. The filtrate was concentrated to an oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound as a white foam, 0.14 g (55%). 'H NMR (CDCI,, 300 MHz) 8 1.38 (d, 6H), 1.55 (d, 3H), 2.46 (s, 3H), 3.28 (m, 2H), 3.76 (s, 2H), 4.35-4.65 (m, 4H), 4.67 (q, 1 H), 6.38 (d, 1 H), 6.83 (m, 1 H), 7.11 (m, 1 H), 8.08, (d, 1 H), 8.21 (d, 1 H); mp: 55-65 °C; MS
(CI) 330 (MH'); [ajD
+16.0 (c 1.0, MeOH).
Example 160 1-(4-(2-(1R-Hydroxy-ethvl~oyrimidin-4-yft-2R 6S-dimethyt-oioerazin-1-vll-2-(ovrimidin 2-vlsulfanvll-ethanone.
Me S
N~ ~ N
\ N ~ ~\
~ O N
Me "' ~ tulea OH
Example 160 was prepared from the appropriate starting materials in a manner analogous to example 159. 'H NMR (CDCI3, 300 MHz) 81.38 (m, 6H),1.48 (d, 3H), 3.28 (m, 2H), 3.96 (s, 2H), 4.35 (m, 4H), 4.65-4.97 (m, 3H), 6.28 (d, 1 H), 6.93 (m,1 H), 7.11 (m,1 H), 8.21 (d,1 H), 8.45, (m, 2H); mp: 60-70 °C; MS (CI) 389 (MH'); [aJ~ +16.8 (c 1.0, MeOH).
pCTIIB00f00296 lExamole i 61 4-[2-f 1 R=Hvdroxv-ethyl)-ovrimidin-4-v(1-2R.6S-dimeth~l-pioerazine-1-carboxylic acid , , phenW ester.
~~~~Me Me Step A: 4-I2-f 1 R-Butyrvloxy-ethvll~avrimidin-4-vll-2R.6S-dimethyf-oioerazine-carboxvlic acid ohenvl ester. To a solution of 1 R-[4-(3R,5S-dimethyl-piperazin-1 yl~
pyrimidin-2-ylj-ethyl butyrate (prepared according to the method of Preparation Three, 0.30 g, 0.98 mmol) and triethytamine (0.20 g, 1.9 mmof) in dichloromethane (5 m~) was added phenyl chloroformate (0.76 g, 4.8 mmot) and stirred at ambient temperature for 2 h under nitrogen atmosphere. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain an oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound of Example 161, Step A as an oil, 0.35 g (84%). 'H NMR (CDCh, 300 MHz) S 0.96 (d, 3H), 1.32 (d, 6H), 1:59 (d, 3H), 1.71 (q, 2H), 2.40 (t, 2H), 3.28 (m, 2H), 4.35 (m, 4H), 5.68 (q, iH), 6.41 (d,1H), 7.12 (d, 2H), 7.22 (m,1 H), 7.35 (m, 2H), 8.23 (d,1 H); MS (CI) 427 (MH');
[a]~ +39.6 (c 1.0, MeOH).
Step 8: 4-f2-(1 R-Hydroxy-ethvl~-oYrimidin-4-vll-2R.6S-dimeth~l-nioerazine-'~
carboxylic aad ohenvl ester: 4-[2-(1 R-Butyryloxy~thyl)-pyrimidin-4-y(}-2R,6S-dimethyt-piperazine-1-carboxylic add phenyl ester (prepared according to the method of Example 161, Step A, 0.31 g, 0.70 mmol) was combined with concentrated hydrochloric add (5 mL) and stirred at ambient temperature for 6 h. The macbune was neutralized with 6 N aqueous sodium hydroxide to pH 9 and extracted twice with etfiyl acetate: The organic extract was washed once with water, dried over sodium sulfate and filtered. The filtrate was concentrated to an oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound as a white solid, 0.12 g (81 %). 'H NMR (CDC13, 300 MHz) 81.41 (d, 6H),1.51 (d, 3H), 3.34 (m, WO 00/59510 PCT/IB00~0296 2H), 4.43 (m, 2H), 4.52 (m, 2H), 4.71 (q, 1 H), 6.46 (d, 1 H), 7.12 (m; 2H), 7.23 (m, 1 H), 7.35 (m, 2H), 8.23 (d, 1 H); MS (CI) 357 (MH'); [aJp +16,9 (c 1Ø MeOH).
Example 162 4-f2-l1 R-H~droxv-ethyl)-avrimidin-4-vll-2R.6S-dimethyl-oioerazine-1-carboxylic acid g~ridin-3-yl ester.
HO
Me ~~~~Me / \ o ~ N_ N- h--N N \ / N
Me Step A: 4:I2-l1 R-Hvdroxv-ethyl)-QVrimidin-4-vll-2R.6S-dimethvl-fli~erazine-1-carbonyl chloride. To a solution of 1 R-[4-(3R,5S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Preparation Three, 3.61, 11.8 mmol) and pyridine (0.93 g, 11.8 mmol) in dichioromethane (50 mL) was added triphosgene (1.17 g, 3.9 mmol) and stirred at ambient temperature for 16 h under ri~trngen atmosphere. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain an oil which was purified by flash chromatography (ethyl acetate) to give the title compound of Example 162, Step A as a yellow oil, 2.12 g, (51 %). 'H NMR (CDCI,, 300 MHz) 8 0.90 (t, 3H),1.31 (d, 6H), 1.56 (d, 3H), 1.68 (m, 2H), 2.38 (t, 2H), 3.21 (m, 2H), 3.88-4.40 (m, 4H), 5.66 (q, 1H), 6.43 (d, 1 H), 8.22 (.d, 1 H); MS (CI) 369, 371 (MH').
Step B: f4-I2-(1R-Butvrvloxv-ethyl?-DVrimidin-4-vl1-2R.6S-dimeth~r!-oiDerazine~-1-carboxylic add oyridin-3-v! ester. To a suspension of sodium hydride (60%
dispersion in oil, 0.046 g, 1.15 mmol) in anhydrous tetrahydrofuran (8 mL) was added 3-hydroxypyridine (0.11 g,1.15 mmol) at 0 °C. After a homogeneous solution was obtained, a solution of 4-[2-(1 R-hydroxy-ethyl)-pyrimidin.~-ytj-2R,6S-dimethyl-piperazine-1-cariaonyl chloride (prepared according to the method of Example 162, Step A, 0.36 g, 0.96 mmol) in tetrahydrofuran (3 mL) was added at 0 °C
and this mixture was warmed to ambient temperature, then heated to reflux far 6 h. The mixture was quenched in water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated to obtain an oil, which was purified by flash chromatography (ethyl acetate) to give the title compound of Example 162, Step B as a semi-solid, 0.31 g (78%). 'H NMR (CDCI,, 300 MHz) 8 0.90 (t, 3H), 1.35 (m, 6H), 1.61 (d, 3H), 1.69 (m, 2H), 2.41 (t, 2H), 3.30 (m, 2H), 4.11-4.38 (m, 4H), 5.69 (q, 1 H), 6.41 (d, 1 H), 7.32 (m;
1 H), 7.52 (m, 1 H), 8.22 (d, 1 H), 8.46 (s, 1 H), 8.48, (d, 1 H); MS (CI) 428 (MH').
Step C: 412-f 1 R-Hvdroxv-ethvl~ovrimidin-4-yt1-2R.6S-dimethv!-nioerazine-1-carboxylic acid ovridin-3-of ester. {4-[2-(1R-Butyryloxy-ethyl~pyrimidin-4-yl]-2R,6S-dimethyi-piperazine}-1-carboxylic acid pycidin-3-yl ester (prepared according to the method of Example 162, Step B, 0.31 g, 0.T0 mmol) was combined with concentrated hydrochloric acid (5 mL) and stirred at ambient temperature for 6 h. The mixture was neutralized with 6 N aqueous sodium hydroxide,to pH 9 and extracted twice with ethyl acetate. The extract was washed once with water, dried over sodium sulfate and filtered. The filtrate was concentrated to an oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to give. the title compound as a white solid, 0.12 g (81 %). 'H NMR (CDCI,, 300 MHz) b 1.41 (d, 6H), 1.51 (d, 3H), 3.33 (m, 2H), 4.25-4..45 (m, 4H), 4.71 (q, 1 H), 6.43 (d, 1 H), 7.33 (m, 1 H), 7.56 (m, 1 H), 8.23 (d, 1H), 8.25 (d, 1H), 8.48 (d, 1H); MS (CI) 358 (MH'); [a]o +18.5 (c 1.0, MeOH).
Example 163 4-(2-f1 R-Hvdroxv-ethvl~ovrimidin-4-vIl-2R-phenyl-pioerazine-1-carboxylic aad p~rridin-3-vl ester.
HO
~~~~Me Step A: 1 R-f4-l3R-Phenyl-o oerazin-1-vll-ovrimidin-2-v>t-ethyl butyrate. To a solution of (R~2-phenylpiperazine (0.48 g, 3.0 mmol, Indian J. Chem. Sect B 1994, 33.
285) and triethylamine (1.21 g, 12.0 mmol) in tetrahydrofuran (10 mL) was added (R}-1-(4-chloropyrimidin-2-ylrethyl butyrate (prepared according to the method of Preparation Seven, 0.68 g, 3.0 mmot) and stirred at ambient temperature for 18 h. The mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl ' WO 00/59510 PGT/IB00/00296 acetate. The combined organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product which was purified by flash chromatography (95:5 dichloromethane:methanol) to give the title compound of F~cample 163, Step A as a viscous oil, 0.70 g (67%). 'H NMR (CDCI,, 300 MHz) 8 0.95 (t, 3H), 1.56 (d, 3H), 1.67 (m, 2H), 2.40 (t, 2H), 3.55 (m, 2H), 4.0 (m, 2H), 4.32 (m, 2H), 4.70 (m, 1 H), 5.69 (q, 1 H), 6.49 (d, 1 H), 7.40 (m, 5H), 8.21 (d, 1 H); MS (CI) 355 (MH').
Step B: 4-f2-(1 R-Butvrvloxv-ethvl~pvrimidin-4-vfl-2R-phenyl-piperazine-1-carboxylic acid pvridin-3-vl ester. To a solution 1R-[4-(3R-phenyl-piperazin-1-yl)-pyrimidin-2-yi3 ethyl butyrate (prepared according to the method of Example 163, Step A,~~0.22 g, 0.6 mmol) and triethylamine (0.31 g, 3.1 mmol) in toluene (5 mL) was added dipyridin-3-yl carbonate (0.67 g, 3.1 mmol) and.heated to reflex for 3 h. The mixture was poured into saturated aqueous sodium bicarbonate, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound of Example 163, Step B as a yellow oil, 0.22 g (73%). MS
(CI) 476 (MH').
Step C: 4-f'2-l1R-Hvdroxv-ethvf~ovrimidin-4-vf1-2R=ohenvl niperazine 1-carboxylic add pvridin-3-vl ester. 4-[2-(1 R-Butyryfoxy-ethyl)-pyrimidin-4-yt]-2R-phenyt-piperazine-1-carboxylic aad pyridin-3-yl ester (prepared according to the method of Example 163, Step B, 0.21 g, 0.4.4 mmol) was combined with concentrated hydrochloric aad (2 mL) and stirred at ambient temperature for 6 h. The mixture was neutralized with 6 N aqueous sodium hydroxide to pH 9 and extracted twice with ethyl acetate. The combined extracts were washed once with water; dried over sodium sulfate and filtered. The ftltrate was concentrated to an oil which was purifted by flash chromatography (9:1 dichloromethane:methanol) to give the title compound as a white solid, 0.13 g (73%). 'H NMR (CDCI,, 300 MHz) 81.55 (d, 3H), 3.55 (m, 2H), 4.0 (m, 2H), 4.32 (m, 2H), 4.71 (m, 1 H), 4.75 (q, 1 H), 6.40 (d, 1 H), 7.18-7.41 (m, 7H), 824 (d, 1 H), 8.35 (br s, 1 H), 8.45 (d, 1 H); MS (Ct) 408 (MH').
Examples 164 to 173 Examples 164 to 173 were prepared from the appropriate starting materials in a manner analogous to the method of Example 163.
wo oo~s9sio rc~rnBOOioo2~
HO
Ar' , Rs . ..., Me O ~ N-~N N ~ / N
O
R' Example , R' R Ar' mp (C) MS (MH') 164 3R-Me 5S-Me phenyl 357 165 3R-Me 5S-Me 2-methyl-pyridin-3-yl65-75 372 166 H H ~ pyridin-3-yl 107-110 330 167 3R-Me 5S-Me 2-d~ioro-pyridin-3-yl60-70 392, 394 168 3R-Me 5S-Me 5-chloro-pyridirr3-yl65-69 392, 394 169 3R-Me 5S-Me isoquinolin-5-yl60-70 407 170 3R-Me 5S-Me 4-chloro-pyridin-3-yl60-70 392, 394 171 3R-Me 5S-Me 6-methyl-pyridin-3-yl60-70 372 172 2RS- H pyridin-3-yl 388 CHZOMe 173 2RS-COzEt H' pyridirr3-yl 4p2 Example 174 (Rl~-Benzvl-1-f2-( 1-hvd roxv~thvtl-ovrtmidin-4-vt1-oioeridin-4-ot.
~~»Me Step A: (R>-1.-(4-(4-Benzvl-4-hvdroxv-oic~eridin-1 vll-ovrimidin-2-vll-ethv) acetate. To a solution of 4-tienzy!-4-hydroxypiperidine (0.95 g, 5.0 mma<) and triethytamine (0.51 g, 5.0 mmol) in dichioromethane (10 mL) was added (R)-1-(4-methanesulfonyloxy-pyrimidin-2-yly-ethyl butyrate (prepared according to the method of Preparation Eight, 1.23 g, 4.0 mmol) and stirred at ambient temperature for 18 h. The mixture was WO 00/59510 pCT/IB00100296 washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filten:d. The filtrate was evaporated to an oil which was purified by flash chromatography (95:5 dichloromethane:methanol) to give the title compound,of Example 174, Step A as a viscous oil, 0.99 g (52%). 'H NMR (CDCIS, 300 MHz) s 0.95 (t, 3H),1.53 (d, 3H), 1.65-1.78 (m, 4H), 1.88 (m, 2H), 2.08 (m, 2H), 2.48 (t, 2H), 3.45 (m, ZH), 4.42 (tar s, 1 H), 5.68 (q, 1 H), 6.41 (d, 1 H), 7.30-7.48 (m, 5H), 8.18 (d, 1 H); MS (Cl) 384 (MH').
Step B: (R~4-Benzvl-1-f2-(1-hvdroxv-ethvl~-ovrimidin-4-vIl-oioeridin~-ol. To a solution of (R~1-[4-(4-benzyl-4-hydroxy-piperidin-1-y(~pyrimidin-2-ytJ-ethyl butyrate (prepared accordEng to the method of Example 174, Step A, 0.20 g, 0.52 mmol) in methanol (5 mL) was added 1 N aqueous sodium hydroxide (1 mL) and timed for 4 h at ambient temperature. The mixture was diluted with dichloromethanq and washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate v~ras evaporated to give the title compound as a foam, 0.12 g (68%). 'H NMR (CDCI', 300 MHz) s 1.49 (d, 3H),1.74 (br s, 2H),1.82 (m, 2H), 2.08 (m, 2H), 3.42 (m, 2H), 4.42 (br s, 1 H), 4.7i (q, i H), 6.43 (d, 1 H), 7.33-7.48 (m, 5H), 8.21 (d, 1 H); MS (Cl) 314 (MH').
Example 175 fR?-4-Phenv!-1-f2-( 1-hvdroxv~thvl~-ovrimidin-4-yp-nineridin-4-ol.
Me Example 175 was prepared from the appropriate starting materials in a manner analogous to the method of Example 174. mp: 114 °C; MS (CI) 300 (MH*).
Example 176 (R~1-f4-f4-(3-Chlorobenzvtidene?-niperidin-1- ~rr~midin-2 vll-Methanol.
HO
CI ~ / ....Me N
N ~ 'N
Step A: 1-f4-~3-Chlorobenzvlidene)-oioeridine-1-v(1-1~-carboxylic acid tert-butyl ester.
To a suspension of 4-chlorobenryltriphenylphosphonium chloride (4.23 g, 10.0 mmol) in tetrahydrofuran (40 mL) was added n-butyllithium in hexanes (2.5 M in hexanes, 4.4 mL, 11.0 mmol) at 0 °C under nitrogen atmosphere and stirred 0.5 h. A
solution of 4-oxo-piperidine-1-carboxylic aad tert-butyl ester (prepared according to the method of Example 101, Step A, 1.99 g, 10.0 mmol) in tetrahydrofuran {10 mL) was added at 10-°C and warmed to ambient temperature. The mixture was evaporated to an oil which was purified by flash chromatography (9:1 hexanes:ethyl acetate) to give the title compound of Example 176, Step A as an oil, 2.63 g (85%). 'H NMR (CDCI,, 10 MHz) 8 1.39 (s, 9H), 2.48 (m, 2H), 2.57 (m, 2H), 3.68-3.82 (m, 4H), 6.36 (s, 1H), 7.08 (m, 1 H), 7.12-7.28 (m, 3 H); MS (CI) 308 (MH').
Step 8: 4-l3-Chloro-benzviidene>-piperidine hydrochloride. To a solution of 1-[4-(3-chlorobenzylidene)-piperidine-1-y(j-1-carboxylic aad tert-butyl ester (prepared according to the method of Example 176, Step A, 2.5 g, 8.1 mmol) in dichloromethane 15 (20 mL) was added hydrogen chloride (4 M in dioxane, 4.0 mL, 16.0 mmol) at ambient temperature and stirred for 4 h. The mixture was evaporated to dryness, suspended in ethyl ether and filtered to give the title compound of Example 176, Step B
as a white solid. 1.63 g (82%). 'H NMR (CDCh/D20, 300 MHz) b 2.48 (m, 2H), 2.57 (m, 2H), 3.63 (m, 2H), 3.77 (m, 2H), 6.36 (s,1 H), 7.10 (m, 1 H), 7.12-728 (m, 3H);
rr~: u~-~s~ ~c.
Step C: IR?-1-f4-f4-l3-Chloro-benzvlidenel-piperidin-1-vl1-ovrimidin-2-vll-ethyl butyrate. To a solution of 4-(3-chlorobenzylidene~piperidine hydrochloride (prepared according to the method of Example 176, Step B, 0.46 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) in dichloromethane (10 mL) was added (R}-1-(4-chloropyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Five, 0.54 g, 22 mmol) and stirred at ambient temperature for 12 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product which was purified by flash chromatography (95:5 dichforomethane:methanol) to give the title compound of Example 176, Step C as a viscous oil, 0.64 g (80%). 'H NMR (CDCI,, 300 MHz) 8 0.95 (d, 6H),1.51 (d, 3H), 1.68 (m, 2H) 2.35 (m, 2H), 2.47-2.64 (m, 4H), 3.67-3.75 (m, 4H), 5.68 (q, 1 H), 6.36 (s, 1 H), 6.40 (d, 1 H), 6.98 (m, 1 H), 7.12-7.28 (m, 3H), 8.18 (m,1 H); MS (CI) 400 (MH').
WO 00/59510 PCTIIBOOf00Z96 Step D: lR)-1-~-[4-(3-Chloro~enzYtid~,ne~viperidin-1=3~(-vvrimidin-2-vl~-ethanol. To a ,"
solution of (R}-1-{4-[4-(3-chforo-benzylidene~piperidin-1 yfJ-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 176, Step C, 0.62 g, 1.55 mmol) in methanol (8 mL) was added 1 N aqueous sodium hydroxide (1 mL) then stirred for 4 h at ambient temperature. The mixture was diluted with chlorofom~ and washed once with water, once with saturated aqueous sodium chloride,and.the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product which was purified by flash chromatography (95:5 dichloromethane:methanol) to give the title compound as a white solid, 0.31 g (61 %).
'H NMR (COCI,, 300 MHz) b 1.51 (d, 3H), 2.46 (m, 2H), 2.56 (m, 2H), 3.07 (m, 2H), 3.77 (m, 2H), 4.35 (d,1 H), 4.69 (q,1 H), 6.36 (s, 1 H), 6.40 (d,1 H), 7.07 (m, 1 H), 7.12-7.28 (m, 3H), 8.18 (m, 1H); mp: 45-S5 °C; MS (CI) 330 (MH'); [a]o +16,8 (c 1.0, MeOH).
Examples 177 to 181 ' 15 Examples 177 to 781 were prepared from the appropriate starting materials in a manner analogous to the method of Example 176.
HO
~~~~Me R'z N ..
N ~ ,N
R
Example R'~ it's' mp (C) MS ~M(~
177 4-chlorophenyi H 33p, 332 178 (E}-2-phenyl-ethen-1-ylH
179 benzoyl H 44-59 324 180 phenyl phenyl 108-109 372 181 . phenyl Pyrid-2-yl98-101 373 Example 7 82 jR~,l~4-L4-P~rridin-2-vlmethvl-niflera~in-1-vl~vvrimidin-2-yg-ethanol.
N
N ~--J N
Me ~,..
OH
Step A: (R>-1-f4-l4-Pvridin-2-vlmethvl-nioerazin-1-vl)wrimidin-2-vll-ethyl acetate. To a solution of (Rj-1-[4-piperazin-1 yl~pyrimidin-2-ytj-ethyl acetate (prepared according to the method of Preparation Two, 1.55 g, 6.2 mmol) and triethyfamine (0.86 mL, 6.2 mmol) in tetrahydrofuran (20 mL) was added 2-picoylchloride hydrochloride (1.01 g, 6.2 mmol) at ambient temperature and stirred for 1 h. The mixture was diluted with water and extracted twice with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered, and the filtrate was concentrated to an oil which was purified by flash chromatography (95:5 dichtoromethane:methanol) to give the title compound of Example 182, Step A, 0.98 g (46%). 'H NMR (CDCl3, 300 MHz) 8 1.58 (d, 3H), 2.15 (s, 3H) 2.62 (t, 4H), 3.72 (t, 4H), 3.75 (s, 2H), 5.67 (q, 1 H), 6.35 (d, 1 H), 7.22 (m, 1 H), 7.46 (d, 1 H), 7.73 (m,1 H), 8.21 (d, 1 H), 8.62 (d,1 H); MS
(CI) 342 (MH').
Step B: iR)-1-f4-(4-Pvridin-2ylmethvl-pioerazin-1-vl)-ovrimidin-2-vll-ethanol.
To a solution of (R)-t-(4-(4-pyrtdin-2-ylmethyl-piperazin-1-yl}-pyrimidin-2-yQ-ethyl acetate (prepared acxording to the method of Example 182, Step A, 0.14 g, 0.33 mmot) in dioxane (6 mL) was added at ambient temperature 6 N aqueous potassium hydroxide (0.5 mL). After stirring for 3 h the solution was diluted with ethyl acetate and washed twice with water. The organic Layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound as a white solid, 0.09 g (69%). 'H NMR (CDCI,, 300 MHz) b 1.52 (d, 3H), 2.38-2.59 (m, 4H), 3.72-3.77 (m, 6H), 4.69 (q, 1 H), 6.37 (d, 1 H), 7.22 (d,1 H), 7.41 (d, 1 H), 7.69 (m, 1 H), 8.21 (d, 1 H) 8:58, (d,1 H); mp: 68-70 °C; MS (CI) 300 (MH'); [a]~ +162 (c 1.0, MeOH).
Examples 183 to 187 Examples 183 to 187 were prepared from the appropriate starting materials in a manner analogous to the method of Example 182.
HO , ~~~~Me N_ R°- ~ N
Example R' mp (C) MS (MH7 183 phenylmethyl 299 184 ' isoquinolin-2-yl-methyl' 350 185 benzothien-2-yl-methyl 355 186 benzothiazot-2-yl-methyl356 187 benzofuran 2-yl-methyl v 339 Example 188 1 R-f4-f2R.6S-Dimethvl-.4-l2-f1.2.41triazof-1-vl-ovrimidin-4-yl~oiaerazin-1-vl1-nvrimidin-2-vtl-ethanol.
~~Me Step A: 4-(3R.5S-Dimethvl-oioerazin-1-v1~2-methanesulfonvl-ovrimidine. To a solution of cis-2,6-dimethylpiperazine (10.7 g, 94.1 mmol) and triethylamine (9.52 g, 94.1 mmol) in chloroform (300 mL) was added 4-chloro-2-methanesulfonylpyrimidine (15.1 g, 78.4 mrnol; Hetemcycles 1985, 23, 611) at ambient temperdbime and stin~ed for 1 h. The mixture was partitjoned with saturated aqueous sodium bicarbonate and the separated organic layer was washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filten:d: The filtrate was evaporated to an orange solid which was slurried in ethyl ether and filtered to give the title compound of Example 188, Step A as a white solid.
15.4 g (73%). 'H NMR (CDCI,, 400 MHz) 81.01 (m, 6H), 2.35-2.78 (m, 4tfi), 2.85 (s, 3H), 3.32 (m, 2H), 6.81 (d, 1 H), 8.2 (d, 1 H); mp: 182-9 ~3 °C; MS
(CI) 301 (MH').
Step B: 4-(3R.5S-Dimethvl-oioerazin-1-vl)-2-f1.2.41triazol-1-vl-o~rimidine. To a slurry of sodium hydride (60% dispersion in oil, 0.37 g; 9.4 mmol) in dimethylfom~amide (5 mL) was added a solution of 1,2,4-triazole (0.67 g, 9.4 mmol) in dimethylformamide (4 mL) at 0 °C under nitrogen atrr~sphere. After 10 min, a solution of 4-(3R,5S-dimethyl-piperazin-1-y1~2-methanesulfonyl-pyrimidine (prepared according to the method of Example 188, Step A, 2.54 g, 9.4 mmol) in warm dimethylfom~amide (5 mL) was added dropwise and stirred at ambient temperature for 2 h then heated to 100 °C
for 0.5 h. Thelmixture was quenched in saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound of Example 188, Step B as an oil, 0.50 g (62%). 'H NMR (CDCI,, 400 MHz) S 1.01 (m, 6H), 2.35-2.88 (m, 5H), 3.32 (m,1H), 6.81 (d,1H), 8.16-823 (m, 2H), 9.25 (d, 1 H); MS (CI) 260 (MN').
Step C: 1R-f4-f2R.6S-Dimethvl-4-l2-(1.2 3]triazol-1-vl-ovrimidin-4-vi)-oioerazin-1-v(1 p~rrimidin-2-vll-ethyl butvrat~. To a solution of 4-(3R,5S-dimethyl-piperazin-1~t)-2 (1,2,4)triazol-1-yl-pyrimidine (prepared according to the method of Example 188, Step B, 0.46 g,1.8 mmol) in acetonitrile (3 mL) was added (R~1-(4-methanesulfonyloxy-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Eight, 0.57 g, 2.0 mmol) and heated to refiux for 6 h under nitrogen atmosphere. The mixture was quenched in saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound of Example 188, Step C as an oil, 0.22 g (54%). 'H NMR (CDCI,, 400 MHz) b 0.95 (t, 3H),1.51 (m; 6H), 1.54 (d, 3H), 1.63 (m, 2H), 2.38 (t, 2H), 3.38 (m, ZH), 4.33-4.64 (m, 4H), 5.68 (q,1 H), 6.28 (d, 1 H), 6.58 (d,1 H), 8.10 (s,1 H), 8.26-8.32 (m, 2H), 9.10 (d, 1 H); MS (Cl) 452 (MH'); [a]p +50.0~(c 1.0, MeOH).
' WO 00/59510 PCTIIB00/00296 Step D: 1R-l4-f2R.6S-Dimethvl-4-l2-f1.2.41triazol-1-vl-pyrimidin-4-vl)-oioerazin-1-vll-pvrimidin-2-vl)-ethanol. 1 R-{4-[2R,6S-Dimethyt-4-(2-j.1,2.3jtriazoi-1-yl-pyrimidin-4-yl)-piperazin-1-y(j-pyrimidin-2-yl}-ethyl butyrate (prepared acxording to the method of Example 188, Step C, 0.18 g, 0.40 mmol) was combined with concentrated hydrochloric acid (2 mL) and stirred at ambient temperature for 4 h. The mixture was quenched in saturated aqueous sodium bicarbonate and extracted twio~ with ethyl acetate. The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash ~
, chromatography (9:1 dichloromethane:methanol) to give the title compound as a white solid, 0.13 g (87%). 'H NMR (CDCI,, 400 MHz) 81.31 (d, 6H), 1.51 (d, 3H), 3.42 (m, 2H), 4.42-4.73 (m, 5H), 6.41 (d, 1 H), 6.56 (d, 1 H), 8.12 (s, 1 H), 8.24 {d;
1 H), 8.30 (d, 1 H), 9.10 (s, 1 H); MS (CI) 382 (MH'); [ajo +18.6 (c 1.0, MeOH).
Examples 189 to 195 Examples 189 to 195 were prepared from the appropriate starling materials in a manner analogous to the method of Example 188.
HO
R" R6 .."Me ~N N-N~ ~ N
s s R' Example R" R' R' mp (C) MS (MH') 189 2-hydroxyphenyl 2R-Me 6S-Me 60-70 407 190 imidazol-1-yl 2R-Me 6S-Me 60-70 381 191 [1,2,3]triazol-1-yl 2R-Me 6S-Me 70-80 382 192 , pyrrol-1-yl 2R-Me 6S-Me 70-80 380 193 4-methylimidazol-1-yl2R-Me 6S-Me 70-80 395 194 2-methylimidazol-1 2RMe 6S-Me 70-80~ 395 yl 195 2.4~imethylimidazol-1-yl2R-Me 6S-Me 70-80 409 Examote 196 , 1R-f4-f2R 6S-Dimethvl-4-(4-f1 2 4ltriazol-1-vl-pyrimidin-2-yll-oioerazin-1-yll-pyrimidin-2-vl?-ethanol. , N~N HO
'N Me ~~~~Me N ~ N-~~N N ~ / N
N
Me Step A: 2-Thiomethvl-4-f1.2.41triazol-1-vl-pvrimidine. To a slurry of sodium hydride (60% dispersion in oil, 24.2 g, 605 mmol) in dimethylformamide (800 mL) was added a solution of 1,2,4-triazole (0.67 g, 9.4 mmol) in dimethylfom~amide (4.0 mL) at 0 °C
under nitrogen atmosphere. After 10 min, a solution of 4-chloro-2-methylthio-pyrimidine (97.2 g, 605 mmol) in dimethyffom~amide (200 mL) was added dropwtse at 10 °C and stirred at ambient temperature for 14 h: The ni~xture was quenched in water and the solid precipitate was filtered off and'~dried under vacuum to give the title compound of t=xample 196, Step A as a white solid, 113.8 (94%). 'H NMR (CDCt,, 400 MHz) b 2.82 (s, 3H), 6.82 (d, 1 H), 8.18 (d, 1 H), 8.19 (s, 1 H), 9.35 (s, 1 H); mp:
125-126 °C; MS (CI) 194 (MH').
Step B: 2-Methanesulfonvl-4-f1.2.41triazol-1-vl-pvrimidine. To a mechanically stirred suspension of 3-chloroperoxybenzoic acid (75%, 127 g, 551 mmol) in chloroform (625 mL) was added a solution of 2-thiomethyl-4-[1,2,4)triazof-1-yl-pyrimidine (prepared according to the method of Example 196, Step A, 50.7 g, 262 mmol) in chloroform (625 mL) and stirred at ambient temperature for 16 h. The mixture was filtered and the filtrate was washed six times with saturated aqueous sodium cartxmate. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the title compound of Example 196, Step B as a white solid, 37.8 g (64%). 'H NMR (CDCI,, 400 MHz) S 3.62 (s, 3H), 6.82 (d, 1 H), 8.19 (s, 1 H), 8.24 (d, 1 H), 9.35 (s,1 H); mp:
135-136 °C; MS (CI) 226 (MH').
Step C: 2-(3R.5S-Dimethvl-oiperazin-1-vl>-4-t1.2.4],fiazol-1-vl-ovrimidine, v2-;, Methanesulfonyi-4-[1,2,4]triazot-7-yhpyrimidine (prepared according to the procedure of Example 196, Step B, 32.5 g, 144 mmol) was combined with cis-2,6-dimethylpiperazine (34.5 g, 302 mmol) and heated neat at 135 °C for i h, cooled, dissolved in 2 N aqueous hydrochloric acid and washed once with ethyl acetate.
The acidic aqueous layer was basified to pH 9 with 6 N aqueous sodium hydFoxide at 0 °C
then extracted four times with ethyl acetate. The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to pn oil which crystallized from hexanes to give the title compound of Example 196, Step C as a white solid, 31.8 g (71 %). 'H NMR (CDCI,, 400 MHz) b 0.99 (d, 6H), 2.38 (m, 4H), 3.30 (s, 2H), 6.82 (d, 1 H), 8.18 (d, 1 H), 8.19 (s, 1 H), 9.35 (s, 1 H); mp:
14~-145 °C; MS
(CI) 260 (MH').
Step D: 1R~4-f2R.6S-Dimethvl-4-(4-f1.2.41triazol-1-vl-p"~imidin-2-vl~pioerazin-1-vl1-wrimidin-2-vl1-eth~f but~rrate. To a solution of 2-(3R,5S-dimethyl-piperazin-1 ylr4~-[7,2,4jtriazol-1-yl-pyrimidine (prepared according to the method of Example 196, Step C. 8.33 g, 32.1 mmol) in acetonitrile (30 mL) was added (R}-1-(4-trifluoromethanesutfonyloxy-pyrimidin-2-yl)-ethyl butyrate (prepan:d according to the method of Preparation Nine, 5.50 g, 16.1 mmol) and heated to reflux for 3 h under nitrogen atmosphere. The tooted mixture was filtered and the solids were washed twice with ethyl acetate. The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash chromatography (99:1 dichloromethane:methanol) to give the title compound of Example 196, Step D as an oil, 3.61 g (50%). 'H NMR (COCI,, 400 MHz) b 0.91 (d.
6H), 1.26 (t, 3H), 7.59 (d, 3H), 1.69 (q, 2H), 2.40 (m, 2H), 3.40 (d, 2H), 4.60 (m, 4H), 5.70 (q,1 H), 6.39 (d, 7 H), 6.58 (d, 1 H), 8.12 (s,1 H), 8.25 (d, 1 H), 8.31 (d,1 H), 8.35 (s, 1 H); MS (CI) 452 (MH').
Step E: 1R-f4-T2R.6S-Dimethvl-4-(4-f1 2 4ltriazol-1 yl-ovrimidin-2-vl>-ninerazin-1-vt1-gyrimidin-2-vl~-ethanol. 1R-{4-[2R,6S-Dimethyl~-(4-j1,2,4]triazol-1-yl-pyrimidin-2-yl~
piperazin-1 yQ-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 196, Step D, 3.60 g, 8.0 mmol) was combined with concentrated hydrochloric aad (10 mL) and stirred at ambient temperature for 4 h. The mixture was WO 00l595I0 PCTIIBOOI00296 ~217-quenched in saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oi! which was purified by flash chromatography (99:1 dichloromethane:methanol) to give the title compound as a white solid, 2.35 g (77%). 'H NMR (CDCI,, 400 MHz) 81.31 (d, 6H), 1.51 (d, 3H), 3.34 (m, 2H), 4.42 (m, 2H), 4.68.82 (m, 3H), 6.42 (d, 1 H), 7.11 (d, 1 H), 8,11 (s, 1 H), 8.23 (d, 1 H), 8.49 (d, 1 H), 9.12 (s, 1 H); mp: ~s~-Fez ~c; MS (CI) 382 (MH').
Examples 197 to 200 Examples 197 to 200 were prepared from the appropriate starting materials in a manner analogous to the method of Example 196.
HO
Rs ..
R"
N-- ~---N N ~ / N
N s s R' Example R" R' R" mp (~C) MS (Mti~
197 imidazol-1-yl 2R-Me 6S-Me 60-70 381 198 morphQlin-4-yl 2R-Me 6S-Me 70-80 400 199 pyrrolidin-1-yl 2R-Me 6S-Me 70-80 384 200 4-methylpiperazin-1-yl3R-Me 5S-Me 168-170 413 ~xamale 201 1R-f4-t2R.fiS-0imethvl-4-!2-ovridin-3-y!-ovrimidin~l-vl>~oiperazin-1-vl~-ovrimidin 2 vll' ethanol.
wo oors9s><o rcrr><aoorooZ9s -21 &
,, ~~~~Me ' Step A: 2-Pvridin-3-vl-pvrimidin~-vl fifluoromethanesulfonate. To a solution of 2-pyridin-3-yi-3H-pyrimidin-4-one (150 mg, 0.87 mmol; J. Med. Chem. 1990, 33, 1230) and triethytamine (Q.13 mL, 0.95 mmol) in dichloromethane (3 mL) was added dropwise a solution of trifiuoromethanesulfonic anhydride (0.22 mL, 0.91 mmol) in dichloromethane (2 mL) at 0 °C under nitrogen atmosphere. The mixture was allowed to stir for 30 min at 0 °C then diluted with dichloromethane and washed qnce with water and the aqueous layer was extracted twice with dichloromethane. The organic extracts were combined, washed sequentially with saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over sodium sulfate and filtered. The filtrate was evaporated to give the tifle compound of Example 201, Step A as an orange oil, 0.22 g (95%), that was used without further purifrcation.
Step B: 1 R-f4-f2R.6S-Dimethvl-4-!2-ovridin-3-vt-pvrimid'm-4-vl~oioerazin-1 v11-eyrimidin-2-yll-ethanol. A solution of 2-pyridin-3-yl-pyrimidin-4-yl trifiuoromethanesulfonate (prepared according to the mett~d of Example 201, Step A, 0.15 g, 0.5 mmol) in tetrahydrofuran (3 mL) at 0 °C was added dropwise to a solution of 1R-[4-(2R,6S-dimethyl-piperazin-1yl)-pyrmidin-2-ytJ~thyl butyrate (prepared according to the method of Preparation Four, 0.15 g, 0.45 mmol) in tetrahydrofuran (2 mL) and stirred for 1 h at ambient temperature. The mixture was quend~ed in saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate.
The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil and dissolved in concentrated hydrochloric aad (3 mL) and stirred at ambient temperature for 4 h. The mixture was quendied in saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate.
The combined Extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to give the title compound as a white foam; 0.091 g (48%). 'H
NMR (CDCI,, 400 MHz) 81.31 (d, 6H), 1.51 (d, 3H), 3;,34 (m, 2H), 4.42-4.70 (m, 4H), 4.71 (q, 1 H), 6.40 (d, 1 H), 6.56 (d,1 H), 7.37 (m, 1 H), 8.22 (d, 1 H), 8.36 (d, 1 t;), 8.62-8.68 (m, 2H), 9.53 (m, 1H); mp: 61-70 °C; MS (Ct) 392,(MH').
Examcle 202 1 R-(4-f2R.6S-Dimethvl-4-f2-l4-methyl-oiaerazin-1-vil-avrimidin-4-v11-oioerazin-1-vlf-pvrimtdin-2-vll-ethanol.
Me HO
Me ~~~~Me N
N~ N ~ ~ N
Me Step A: 1 R-f4-f4-(2-Methanesulfonvl-ovrimidin~-vll-2R 6S-dimethvl-oioerazin-1 v11=
pvrimidin-2-vf!-ethyl butyrate. To a solution of 4-(3R,5S-dimethyl-piperazin-1-yl}-2-methanesulfonyl-pyrimidine (prepared according to the method of Example 188, Step A, 7.70 g, 14.3 mmol) in aoetonitrile (30 mL) was added 1 R-(4-trifluoromethanesulfonyloxy-pyrimidin-2-yl~thyl butyrate, (prepan:d according to the method of Preparation Nine, 5.50 g, 16.1 mmol) and heated to reflux for 3 h under nitrogen atmosphere. The cooled mixture was filtered and the solids were washed twice with ethyl acetate. The combined extracts were washed once with water;
once with saturated aqueous sodium chloride and the organic tayer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash chromatography (98:2 dichloromethane:methanot) to give the tifle compound of Example 202, Step A as an oil, 4.01 g (62%). 'H NMR (CDCI,, 400 MHz) 8 0.93 (t, 3H},1.21 (d, 6H),1.55 (d, 3H),1.64 (q, 2H), 2.36 (t, 2H), 3.25 (s, 3H), 3.37 (m, 2H), 4.5-4.7 (m, 4H), 5.65 (q, 1 H), 6.33 (d,1 H), 6.68 (d,1 H), 8.22 (d,1 H), 8.28 (d,1 H); MS
(Cl} 463 (MH').
Step B: 1 R-f4-f4-(2-Methanesulfonvl-pvrimidin-4-yl~2R 6S-dimethyl-o~~erazin-1 vtl-pvrimidin-2-vIt-ethanol. 1 R-(4-[4-(2-Methanesulfonyl-pyrimidin-4-yIr2R,6S~imethyl-piperazin-1 y(]-pyrimidin-2-yI}-ethyl butyrate (prepared according to the method of W~ 00/5951 ~~~~Z~
Example 202. Step A, 0.42 g, 0.9 mmol) was combined with concentrated ~' hydrochloric acid (3 mL) and stirred at ambient temperature for 4 h. The mixture was '' quenched in saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic' layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash .
chromatography (99:1 dichloromethane:methano!) to give the title compound of Example 202, Step B as a white foam, 0.25 g (71 %). 'H NMR (CDCI,, 400 MHz) 8 1.26 (d, 6H).1.50 (d, 3H), 325 (s, 3H), 3.41 (m, 2H), 4.5-4.7 (m, 5H), 6.37 (d, 1 H), 6.71 (d, 1 H), 8:24 (d, 1 H), 8.30 (d, 1 H); MS (CI) 393 (MH').
Step C: 1 R-l4-f2R.6S-Dimethvl-4-f2-!4-methyl-oioerazin-1 of ~nvrimidin-4-vl1-pic~erazin-1-yl?-wrimidin-2-vl>-ethanol. 1 R-{4-(4-(2-Methanesulfonyf-pyimidin-4-yt}-2.6-dimethyl-piperazin-1-yQ-pyrimidin-2-yf}-ethanol (prepared according to the method of Example 202, Step B, 0.25 g, 6.4 mmol) was combined with N-methylpiperazine (2.0 mL) and heated at 80 °C for 1 h under nitrogen atmosphere. The mixture was quenched in water and extracted twice with ethyl acetate. The combined extracts were washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash chromatography (96:4 chlorofortn:methanol) to give the title compound as a white foam, 0.11 g (41%). 'H NMR (CDCI,, 400 MHz) 1.31 (d, 6H),1:51 (d, 3H), 2.47 (s, 3H), 2.63 (m, 4H), 323 (m, 2H), 3.94 (m, 4H), 4.33 (m, 2H), 4.57 (m, 2H), 4.71 (q, 1 H), 5.96 (d, 1 H), 6.46 (d, 1 H), 7.98 (d, 1 H), 823 (d, 1H); mp: 60-70 °C; MS (CI) 413 (MH').
Examples 203 to 207 Examples 203 to 207 were prepared from the appropriate starting materials in a manner analogous to the method of Example 202.
pCTIIB00/00296 HO
R6 I ' ..., Me // N ~ ~ N-N~N N ~ / N
s ' s .
R' Example R" R' R° mp (°C) MS (MH') 203 morpholin-4-yl 2R-Me fiS-Me 70-80 400 204 pyrrolidin-1-yl 2R-Me 6S-Me 70-80 ~ 384 205 2,6-dimethylmorpholin-4-yi 2R-Me 6S-Me 42g 206 3,5-dimethylpiperidin-1-y1 2R-Me 6S-Me 426 207 5-methyl-furan-2-yl 2R-Me 6S-Me 123-128 395 Example 208 1 R-f4-f3R.5S-Dimethyl~-l2-(4-methyl-piaerazin-1-vl)-ayrimidin-4-v(i-oiperazin-1-vi>'-gvrimidin-2-vl~thanol.
~~~Me Me Step A: ~Benzyl-2R.6S-dimet~l-piperazin-1-vl~-2-methanesulfonvl-vvrimidine.
To a solution of as-1-benzyl-3,5-dimethylpiperazine (24.9 g, 122 mrnol, O~g.
Prep.
Proceed. Int 1976, 8,19) in dimethylacetamide (60 mL) was added 4-.chloro-2-methanesulfonyl pyrimidine (11.8 g, 61.3 mmol) and stirred for 16 h at 120 °C. The mixture was partitioned between water and ethyl acetate and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed three times with 1% aqueous copper sulfate, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an orange solid which was slurried in isopropyl ether (100 mL) and filtered to give the title compound of E~cample 208, Step A as an orange solid, 16.5 g PC'fIIB00/00296 (75%). 'H NMR (CDCI,, 300 MHz) b 1.35 (d, 6H), 2.25 (m, 2H); 2.76 (m, 2H), 3.23 (s, 3H), 3.53 (s, 2H), 4.35-4.65 (m, 2H), 6.51 (d, 1 H), 7.26 (m, 2H), 7.34 (m, 3H), 8.24 (d, 1 H); MS (CI) 361 (MH').
Step B: 4-(4-Benzyl-2R.6S-rJimethvl-piaerazin-1-yl~-2~4-methvlpiperazin-1-vl~
evrimidine.4-(4-Benzyl-2R,6S-dimethyipiperazin-1-y1~2-methanesulfonylpyrimidine (prepared according to the method, of Example 208, Step A, 11.5 g, 31.9,mrnol) was combined with N-methylpiperazine (15 mL, 128 mmol) and heated to 120 °C
for 2 h.
The mixture was diluted with ethyl acetate and washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filteted. The filtrate was evaporated to give the title compound of Example 208, Step 8 as an orange solid, 14.7 g (84%). 'H NMR (CDCI,, 300 MHz) 81.30 (d, 6H), 2.21 (m, 2H), 2.33 (s, 3H), 2.46 (m, 4H), 2.72 (d, 2H), 3.53 (s, 2H),~~.78 (m, 4H), 4.31 (m. 2H), 5.79 (d, 1 H), 7.24 (m, 2H), 7.31' (m, 3H), 7.90 (d, 1 H); MS
(Cl) 381 (MH').
Step C: 4-(2R.6S-Dimethvl-oiperazin-1-vl~-2-(4-methvloiaerazin-1-vl~-ovrimidine. To a solution of 4-(4-benzyl-2R,6S-dimethyipiperazin-1-yl)-2-(4-methyl-piperazin-1-ylr pyrimidine (prepared according to the method of Example 208, Step B. 9.8 g, 25.8 mmol) in methanol (200 mL) and hydrochloric acid (1 N in ethyl ether, 38.7 mL, 38.7 mmol) was added ammonium fom~ate (16.3 g, 25.8 mmol). After stirring at ambient temperature for 5 min, 10% palladium on carbon (1.96 g, 20 wt% pre-wetted with isopropanol) was added and this mixture was heated to reflux for 2 h. The cooled reaction was filtered and the filtrate was concentrated to a solid, which was diluted with ethyl acetate and washed twice with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to give the tide compound of Example 208, Step C as a dear oil, 6.01 g (81%). 'H NMR (CDCI,, 300 MHz) b 1.25 (s, 6H), 2.31 (s, 3H), 2.24-2.44 (m, 4H), 2.90 (m, 4H), 3.76 (m, 4H), 4.25 (m, 2H), 5.79 (d,1 H), 7.90 (d, 1 H); MS (C1) (MH').
Step D: 1 R~4-f3R.5S-Dimethvl-4-f2-l4-meth~rl-piperazin-1-vl~-nvrimidin-4-y,11-pioerazin-1-yll-pvrimidin-2-vl)-ethyl butyrate. To a solution of 4-(2R,6S-dimethyl-piperazin-1-yl)-2-(4-methyl-piperazin-1-yl)-pyrimidine (prepared according to the method of Example 208, Step C, 9.0 g, 31.1 mmol) and triethylamine (6.5 g, 46.5 mmol) in dimethytforrnamide (90 mL) was added (R}-1-(4-chloro-pyrimidin-2-yl)-ethyl WO 00159510 ~2~
butyrate (prepared according to the method of Preparation Seven; 7.78 g, 34.1 mmol) and heated to reflux for 3 h under nitrogen atmosphere, The cooled mixture was filtered and the solids were washed twice with ethyl acetate. The combined extracts were washed once with water; once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered: The filtrate was evaporated to an oil which was purified by flash chromatography (95:5 chlorofortn:methanol) to give the title compound of Example 208, Step D as an oil, 11.4 g {76%). 'H
NMft (CDCI,, 300 MHz) s o.95 (t, 3H), 1.18 (d, 6H), 1.54 (d, 3H), 2.23-2.35 (m, 7H), 2.51 (m, 4H), 3.21 (m, 2H), 3.81 (m, 4H), 4.32 (m, 2H), 4.52 (m, 2H), 5.65 (q, 1 H), 5.82 (d, 1 H), 6.38 (d, 1 H), 7.39 (d, 1 H), 8.18 (d, 1 H); MS (CI) 483 (MH').
Step E: 1 R-(4-f3R.5S-Dimethvl-4-12-f4-methyl-ninerazin-1 girl)-ovrimidin-4-,y11-piperazin-1-vl~-oyrimidin-2-vll-ethanol. 1 R-(4-{3R,5S-dimethy(~-[2-(4-methyl-piperazin-1-yl)-Pyimidin-4-yf)-piperazin-1-yl}-pyrimidin-2-yl)-ethyl butyrate {prepared according to the method of Example 208, Step D, 11.3 g; 23.5 mmol) was combined i 5 with concentrated hydrochloric acid (60 mL) and stirred at ambient temperature for 4 h. The mixture was quenched in saturated aqueous sodium bicarbonate and extracted five times with 10~ isopropanoUchlorofortn. The combined extracts v~re washed once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil and crystallized from isopropanol to give the title compound as a white solid, 7.34 g (76%). 'H
NMR
(CDCI,, 300 MHz) 81.21 (d, 6H), 1.51 {d, 3H), 234 (s, 3H), 2.45 (m, 4H), 3.24 (m, 4H), 3.76 (m, 2H), 4.30.53 (m, 4H), 4.68 (q, 1 H), 5.82 (d, 1 H), 6.42 (d,1 H), 7.94 (d, 1 H), 8.21 (d, 1 H); rr~: ~s~-~e2 ~c; MS (CI) 413 (MH').
Examples 209 to 211 Examples 209 to 211 were prepared from the appropriate starting materials in a manner analogous to the method of Example 208.
P~'~I00296 .."Wle .
Example R" R' R mp (Cj ~ ' MS (MH'j 209 2,6-dimethyfmorpholin-4-yf3R-Me 5S-Me 428 210 4-ethyfpiperazin-1-yl3R-Me 5S-Me 144-146 427 211 4-isopropylpiperazin-1-yl3R-Me 5S-Me 137-139 ' 441 Example 212 1 R-f4-f2R.6S-Dimethvl-4-(4-mornho(ino~-yl-f1.3.51triazin-2-yl~aioe zin-1-vt1-oyrimidin-2-yl~-ethanol.
~~~Me Me Step A: 1R~4-f4-(4-Chloro-6-morphoiino-f1.3.51triazin-2-vl~2R.6S-dimethyloioerazin-1-vt~-nvrimidin-2-vl1-~thvl butyrate. To a solution of 1R-[4-(2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yq-ethyl butyrate (prepared according to the method of Preparation Four, 0.31 g, 1.0 mmol) and sodium bicarbonate (0.17 g, 2.0 mmol) in dimethyffomiamide (3 mL) was added 2,4-dichloro-6-morpholino-[1,3,5jtriazine (0.24 g,1.0 mmol; Chem. Pharm. Bull.1997, 45, 291 ) and stirred at ambient temperature for 2 hours. The mixture was diluted with ethyl acetate and washed twice with water, once with saturated aqueous sodium chloride, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to an oil, which was purified by flash chromatography (99:1 chlorofortn:methanol) to give the title compound of Example 212, Step A as a white solid, 0.19 g (37%). 'H NMR (CDCIs, 300 MHz) b 0.93 (t, 3H), 1.23 (d, 6H), i :53 (d, 3H), ,1.66 (m, 2H), 2.37 (t, 2H), 3.16 (m, 2H), 3.72-pCTIIB00100296 WO 00!59510 3.78 (m, 10H), 4.12-4.78 (m, 2H), 5.65 (q, 1 H), 6.34 (d,-1 H). 8.1~, {m, 2H);
MS (CI) 505, 507 (MH').
Step B: 1R-~4=f2R.fiS-Dimethv!-4-(4-morahofino-4-vl-f1.3.51triazin-2-vl)-o'roerazin-1-yj]wrimidin-2-vll-ethanol. To a solution of 1 R-{4-[4-(4-chloro-6-morphotino-[1,3,5]triazin-2-yIr2R,6S-dimethyl-piperazin-1-y~-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 212, Step A, 0.15 g, 0.35 mmo() in ethanol (10 mL) was added 10% palladium on carbon (0.75 g, 500 wt %) and hydrogenated at 45-50 psi using a Parr apparatus for 12 hours. The catalyst was fettered off and the filtrate was concentrated to an oil which was added to concentrated hydrochloric acid (2 mL) and stirred at ambient temperature for 6 hours. The mixture was diluted with chloroform and washed twice with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to give the title compound as a white solid, 0.47 g (40%). 'H NMR (CDCI3, 300 MHz) b 1.23 (d, 6H), 1.53 (d, 3H), 3.16 (m, 2H), 3.72-3.78 (m, 10H), 4.12-4.78 (m, 3H), 6.34 (d,1 H), 8.19 (m, 2H); mp: 78-82 °C; MS (C1) 401 (MH'); [a]o +15.1 (c 1Ø MeOH).
Example 213 1 R~4-f4-l4-Methoxv-6-methyl-f 1.3.51triazin-2-yl)-3R.5S-dimethyloioerazin-1~~
pyrimidin-2-vff-ethanol.
HO
Me0 Me ~~~~Me N-N ~N N ~ / N
~N
Met Me Step A: 1 R-(4-f4-(4-Chlpro-6-methyl-f1.3.51tciazin-2-vl~3R.5S-dimethylninerazin-1-vfi-pvrimidin-2-vl)-ethyl butyrate. To a solution of 1R-[4-(3R,5S-dimethyl-piperazin-1 ylr pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Preparation Three, 1.47 g, 6.43 mmol) and sodium bicarbonate (2.25 g, 26.8 mmol) in dimethylfomiamide (10 mL) was added 2,4-dishloco-6-methyl-[1,3,5]triazine (0.88 g, 5.3 mmol; Monatsh. Chem.1970, 101, 724) and stirred at ambient temperature for h. The mixture was diluted with ethyl acetate (150 mL) and washed twice with water, once with 10% aqueous CuSO,, once with saturated aqueous sodium chloride, and pGTIIB00100296 the organic layer was dried over sodium sulfate and filtered. The filtrate was ;
concentrated to give the title compound of Example 213, Step A as a tan soi'~d, 2.12 g (91%). 'H NMR (CDCI,, 300 MHz) b 0.93 (t, 3H), 1.23 (m, 6H), 1.54 (d, 2H), 1.fi6 (m, 2H), 2.31 (s, 3H), 2.37 (m, 2H), 2.41 (s, 1H), 3.19 (m, 2H); 4.22-4.55 (m, 2H), 4.91 (m, 2H), 5.65 (q, 1 H), fi.40 (d, 1 H), 820 (d,1 H); MS (CI) 434, 436 (MH').
Step B: 1 R-14-f4-(4-Methoxv-6-methyl-f1.3.5ltrtazin-2-yl)-3R.5S~iimethvtoiDerazin-1-vll-ovrimidin-2-vl)-ethanol. A solution of sodium methoxide in methanol was freshly prepared by allowing sodium metal (0.4 g, 17.3 mmol) to dissolve in methanol (40 mL). To this mixture was added 1R-{4-[4-(4-chloro-6-methyl-[1,3,5)triazin-2-yf}-3R,5S-dimethyl-piperazin-1-ylj-pyrimidin-2-yl}~thyl butyrate (prepared according to the method of Exarnpie 213, Step A, 1.5 g, 3.46 mmol) which was stirred at ambient temperature for 76 h. The reaction mixture was evaporated to an oil, diftrted with chloroform and washed twice with water, once with saturated aqueous sodium chloride, and the organic layer was dried over sodium sulfate and filtered.
The filtrate was concentrated to a dear oil which was crystallized ft~om isopropyl ether to give the title compound as a white solid, 0.85 g (72%). 'H NMR (CDCI,, 300 MHz) 81.23 (d, 6H), 1.48 (d, 3H), 2.36 (s, 3H), 3.20-3.26 (m, 2H), 3.90 (s, 3H), 4.18.43 (m, 2H), 4.63 (m, 2H), 4.68 (q, 1 H), 4.85 (d, 1 H), 6.42 (d, 1 H), 8.18 (d, 1 H); mp:
161-162 °C;
MS (CI) 360 (MH'); [ajo +16.8 (c 1.0, MeOH).
Example 214 1 R-f4-f4-14.6-Dimethoxv-f1.3.51triazin-2-vI)-3R.5S-dimethyl-oiDerazin-1-vI1-9vrimidin-2-vl)-ethanol.
Me0 ~~Me r--N
N~~
~N
Me0' Me Step A: 1 R-f4-f4-f4.6-Dichloro-f 1.3.51triazin-2-v1)-3R.5S-dimethvl-Dioerazin-1-vIt-p~rrimidin-2-vll-ethyl butyrate. To a solution of 1R-[4-(3R,5S-Dimethyl-piperazin-1-yl)-pyrimidin-2-yf)-ethyl butyrate (prepared according to the method of Preparation Three, 3.25 g, 10.5 mmol) and sodium bicarbonate (1.01 8,19.2 mmol)~ in dimethylfomlamide (8 mL) was added cyanuric chloride (1.76 g, 9.6 mmol) and stirred -227_ at ambient temperature for 2 h. The mixture was diluted with ethyl acetate and washed twice with water, onoe with saturated aqueous~,sodium diloride, and the organic layer was dried over sodium sulfate and flitered. The filtrate was concentrated to give the title compound of F~cample 214, Step A,as a white semi-solid, 1.42 g (68%). 'H NMR (CDCl3, 300 MHz) 8 0.93 (i, 3H), 1.23 (m, 6H), 1.54 (d, 3H), 1.66 (m, 2H), 2.37 (m, 2H), 3.19 (m, 2H), 4.42-4.55 (m, 2H), 4.91 (m, 2H), 5.65 (q,1 H), 6.40 (d, 1 H), 820 (d, 1 H); MS (Ci) 446, '448 (MH').
Step B: 1R-f4-f4-(4 6-Dimethoxv-f1 3 5ltriazin-2-vll-3R 5S-dimethvl-oinerazin 1 vi1 wrimidin-2-vlf-ethanol. A solution of sodium methoxide in methanol was freshly prepared by allowing sodium metal (0.18 g, 8.0 mmol) to dissolve in methanol (16 mL). To this mixture was added 1R-{4-(4-(4,6-dichloro-[1,3,5)triazin-2-yl}-3R,5S-dimethyt-piperazin-1-ylj-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 214, Step A, 0.91 g, 2.0 minoi) at 0 °C, then wam~ed to ambient temperature for 1 h. The mixture was evaporated to an oil, diluted with chloroform and washed once with water, once with saturated aqueous sodium chloride, dried over sodium sulfate and filtered. The filtrate was concentrated to a dear oil which crystallized from isopropyl ether to give the title compound as a white solid, 0.54 g (72%). 'H NMR (CDCl3, 300 MHz) b 1.23 (d, 6H), 1.50 (d, 3H), 3.20 (m, 2H), 3.95 (s, 6H), 4.32 (m,1 H), 4.67-4.86 (m, 4H), 6.34 (d, 1 H), 8.22 (d,1 H); mp:187-188 °C; MS
(CI) 376 (MH').
Example 215 1R-f2R 6S-Dimethvl-4-(4-phenyl-f1 3 5ltriazin-2vl~oiDerazin-1-vl1-nvrimidin 2 vt>~-ethanol.
HO
Me ~~~~Me N----N N
N
Me Step A: 1 R-f4-f4-l4-Chloro-6-phenyl-f1 3 5ltriazin-2-vl~-2R 6S-dimethvl-oin~erazin-1 ~~pyrimidin-2y11~-ethyl butyrate. To a solution of 1 R-(4-(2R,6S-dimethyl-piperazin-1yl}-pyrmidin-2yf}~thyl butyrate (Prepared according to the method of Preparatron WO 00!59510 PCTIIB00/00296 Four, 2.35 g, 7.67 mmol) and sodium bicarbonate (1.29.8,15.3 mmol) in ~ ,, dimethylformamide (25 mL) at 0 °C was added 2,4-dichloro-6-phenyl[1,3,5)trtazine (1.73 g, 7.67 mmol; Helv. Chim. Ada 9950, 33, 1365) portionwise. The reaction mixture was allowed to warm to room temperature and stir under nitrogen for 4 h, poured into water then filtered to give the title compound of F~cample 215, Step A as a light tan solid, 1.99 g (51 %). 1 H NMR (CDCI,, 400 MHz) S 0.94 (t, 3H),1.25 (d, 6H), 1.57 (d, 3H), 1.68 (m, 2H), 2.40 (t, 2H), 327 (d, 2H), 4.65 (m, 2H), 4.82 (d, 1H), 5.00 (d,1 H), 5.68 (q,1 H), 6.34 (d,1 H), 7.46 im, 3H), 821 (d,1 H), 8.40 (d, 2H);
MS (CI) 496, 498 (MH'). ,, Step B: 1 R-f4-f4-(6-Phenyl-f1.3.51trtazin-2-vIJ-2R.6S-dimethyt-cioerazin-1 yl1-pvrimidin-2-vll-ethyl buivrate. To a solution of 1 R-{4-[4-(4-chloro-6-phenyl-[1,3,5]triazin-2-yl~2R,6S-dimethyl-piperazin-1-yQ-pyrimidin-2-yI}-ethyl butyrate (prepared according to the method of Example 2i 5, Step A, 4.81 g, 9.7 mmol) in methanol (50 mL) was added 10% palladium on carbon (940 mg, 20 wt%), ammonium fom~ate (5.98 g, 97 mmol), and hydrochloric aad (2 M in ethyl ether, 7.1 mL,14.2 mmol) and refluxed for 1.5 h. The mixture was allowed to cool, then filtered.
The filtrate was concentrated and partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered, and the filtrate was evaporated to an oil which was purified by flash chromatography (99:1 chlorofortn:methanol) to give the tithe compound of Example 215, Step B as a dear oil, 2.69 g (59%). 1 H NMR (CDCI3, 400 MHz) b 0.95 (t, 3H), 125 (d, 6H), 1.57 (d, 3H),1.68 (m, 2H), 2.40 (t, 2H), 3.2? (d, 2H), 4.65 (m, 2H), 4.82 (d, 1 H), 5.00 (d, 1 H), 5.68 (q, 1 H), fi.34 (d, 1 H), 7.46 (m, 3H), 821 (d, 1 H), 8.40 (d, 2H), 8.66 (s, 1 H); MS (CI) 462 (MH').
Step C: 1 R--f2R 6S-Dimethvl-4-(4-ohenvl-f1 3 5ltriazin-2vlMioerazin-1 v(1-ovrimidin 2 thanol. Concentrated hydrochloric add (10 mL) was added to 9 R-{4-[4-(6-phenyl-[1.3.5]triazin-2-Y1~2R.6S~limethyl-piperazin-1 y(j-pyrimidin-2y(j-ethyl butyrate (prepared according to the method of Example 215, Step B, 2.69 g, 5.8 mrnol) and alla~nred to stir for 5 h at ambient temperature. The reaction mixture was cooled to 0 °C, diluted with chloroform, and 6 M aqueous sodium hydroxide was added slowly until basic (pH 9). The layers were separated and the aqueous layer was extracted lwioe with chloroform. The combined organic extracts were washed once with saturated aqueous sodium chloride, dried over sodium sulfate, filtered; and the filtrate WO 00!59510 was concentrated to an oil which was purified by flash chromatography (97:3 chloroform:methanol) to give a white foam that crystallized from isopropyl ether to give the title compound as a white solid, 1.55 g (68%). 1 H NMR (CDCI,, 400 MHz) a 1.28 (d, 6H), 1.54 (d, 3H), 3.31 (d; 2H), 4.63 (m, 2H), 4'.77 (q, 1 H), 4.85 (d, 1 H), 5.50 (d, 1 H), 6.42 (d, 1 H), 7.50 (m, 3H), 8.25 (d,1 H), 8.41 (d, 2H), 8.68 (s, 1 H);
mp: 133-134 °C; MS (CI) 392 (MH'); [aJo +18.7 (c 1.07, MeOH).
Examples 216 to 235 Examples 216 to 235 were prepared from the appropriate starting materials in a manner analogous to the method of Example 215.
~~~~Me R
WO 00!59510 PCT/IB00/00296 ExampleR" R'= R6 R' , mp (C) MS (MHO
~ , , 216 C7 morpholin-4-yl 2R-Me 6S-Me 138-141435; 437 217 H morpholin-4-yl 3R-Me 5S-Me 152 401 218 OMe morpholin-4-yl 2R-Me, 6S-Me 176-178431 219 Me 4-methyl-piperazin-3R-Me 5S-Me 428 1-yl " . , 220 Me H 2R-Me 6S-Me 91-94 330 221 OMe OMe ~ 2R-Me 6S-Me 128-129376 222 OEt Me 3R-Me 5S-Me 141-1~2374 223 OiPr Me 3R-Me 5S-Me 87-91 388 224 phenyl H 3R-Me 5S-Me 154-1<55392 225 phenyl OMe 3R-Me 5S-Me , , 4~
226 phenyl OMe ~ 2R-Me6S-Me 135-138'422 227 iPr H 2R-Me 6S-Me 122-124358 228 iPr OMe 3R-Me 5S-Me 75-80 388 229 phenyl H H H 115-117364 230 OMe Me H H 173-175332 231 o-tolyl H 3R-Me 5S-Me 123-125406 232 o-tolyl OMe 3R-Me 5S-Me 143-145436 233 cydopropylH 3R-Me 5S-Me 134-135356 234 cydopropylH 2R-Me 6S-Me 133-134356 235 OMe CH=OMe 3R-Me 5S-Me 104-105390 Example 236 1R-f4-f4-(4-Hvdroxvm ethvl~-methoxv-f1.3.5itriazin-2-yl)-3R
erazin-1-5S-dimeth io vIl-avrimidin-2-vll-ethanol.
~Me _ Step A: 1 R-f4-t4-(4-Chloro-6-diazomethvl-I1.3.51triazin-2-vi~3R.5S-dimethvt-oiaerazin-1-vll-ovrimidin-2-vll-ethyl butyrate. To a solution of 1R-[4-(3R.5S-dimethyl-piperazin-1-yl)-pyrimidin-2-y~-ethyl butyrate (prepared according to the method of Preparation Three, 3.06 g, 10.0 mmol) and sodium bicarbonate (1.68 g, 20.0 mmol) in dimethylformamide (10 mL) was added 2,4-dichloro-6-diazomethyl-[1,3,5jtriazine (1.90 g, 10.0 mmol; J. Am. Chem. Soc. 1957, 79, 94.4) and stirred at ambient temperature for 2 h. The mixture was diluted with ethyl acetate, washed twice with water, once with saturated aqueous sodium chloride, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated and purified by flash 1fl chromatography (ethyl acetate) to give the title impound of Example 236, Step A as a foam, 1.84 g (4i °~). 'H NMR {CDCh, 300 MHz) 8 0.94 (t, 3H), 1.23 {m, 6H), 1.55 (d, 3H), 1.66 (m, 2H), 2.38 (m, 2H), 3.19 (m, 2H), 4.22-4.45 (m, 2H), 4.86 (m, 2H), 5.10 (s, 1 H), 5.65 (q, 1 H), 6.40 (d, 1 H), 8.20 (d, 1 Hj; ~mp: 106-108 °C;
MS (CI) 461, 463 (MH').
Step B: 1R-f4-f4-l4-Hvdroxvmethvl-6-methoxv-f1.3.51triazin-2-vllr3R 5S-dimethvl-vioerazin-1-vl1-ovrtmidin-2-vl1-ethanol. 1 R-{4-[4-(4-Chtoro-6-diazomethyl-[1,3,5]triazin-2 yl)-3R,5S-dimethylpiperazin-1 ylJ-Pyrimidin-2-yt}-ethyl butyrate (prepared according to the method of Example 23fa, Step A,1.5 g, 3.2 mmoi) was dissolved in ethyl acetate (20 mL) and 10% aqueous sulfuric acid {5 mL) was added slowly at ambient temperature, stirred 5 min then basfied to pH 9 with 6 N
aqueous sodium hydroxide. The separated ethyl acetate layer was washed once with brine, dried over magnesium sulfate, and conoenVated to a semi-solid. To a freshly prepared solution of sodium methoxide, generated by dissolving sodium metal (0.92 g, 4.0 mmol) in methanol (6 mL), was added the crude solid (0.89 g, 2.0 mmol).
This mixture was stirred for 4 h at ambient temperature then evaporated to dryness.
The residue was purified by flash chromatography (95:5 dichiorornethane:methanoi) to give the title compound as a white solid, 0.084 g (13%). 'H NMR (CDCI,, 300 MHz) 8 1.23 (d, 6H),1.49 (d, 3H), 3.14-3.21 (m, 2H), 3.96 (m, 2N), 3.90 (s, 3H), 4.18-4.38 (m, 2H), 4.69 (q, 1 H), 4.97 (m, 2H), 6.44 (d,1 H), 820 {d, 1 H); mp:170-171 °C; MS (CI) 376 (MH'); [a]o +16.6 (c 1.0, MeOH).
~amDle 237 1 R-t4-(4-(4-Methoxvmethvl-f 1 3 5ltriazin-2-vl1-3R 5S-dimethvl-niaerazin 1 v0-pyrimidin=2-vll~-ethanol.
pCTIIB00100296 ' HO '.
Me w~~~Me ' ~ ~ , N-N ~N N ~ / N
~N , MeO~ Me Step A: 1 R-(4-f4-(4-Chloro-6-methoxvmethvl-f1.3.51triazin-2-vl)-3R.5S-dime pperazin-1-vll-ovrimidin-2-vl~-ethyl butyrate. 1R-(4-[4-(4-Chloro-6-diazomethyl-(1,3,5]triazin-2-yl}-3R,5S-dimethylpiperazin-1-yl]-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 236, Step A, 1.5 g, 3.2 mmol) was dissolved in methanol (10 mL) and 10% aqueous sulfuric acid (3 mL) was added.
This mixture was stirred at ambient temperature for 1 h then diluted with ethyl acetate.
The separated ethyl acetate layer was washed once with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated to an oil which was purified by flash chromatography (99:1 dichloromethane:methanol) to give the title compound of Example 237, Step A as an oil, 1.02 (60%). 'H NMR (CDCI,, 300 MHz) 8 0.95 (t, 3H), 1.26 (d, 6H), 1.58 (d, 3H), 1.67 (q, 2H), 2.41 (t, 2H), 3.24 (m, 2H), 3.51 (s, 3H), 4.18-4.38 (m, 4H), 4.69 (q, 1 H), 4.92 (m, 2H), 6.47 (d, 1 H), 8.24 (d, 1 H);
MS (CI) 464, 466 (MH').
Step B: 1 R-f4-f4-(4-Methoxvmethyl-f1.3.51triazin-2-vl)-3R,.5S-dimethvl-oinerazin-1-v(1-pvrimidin-2-vl''-ethanol. To a solution of 1 R-{4-(4-(4-chloro-6-methoxymethyl-[1,3,5]triazin-2-yIr3R.5S-dimethpiperazin-1-yi]-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 237, Step A, 0.43 g, 0.92 mmol) in methanol (8 mL) and hydrochloric acid (2 M in ethyl ether, 0.7 mL, 1.37 mmol) was added ammonium formate (0.58 g, 9.2 mmol) and 10% palladium on carbon (0.085 g, 20 wt%) and heated to reflux for 3 h. The solvents were removed and concentrated hydrochloric aad (2 mL) was added and stirred at ambient temperature for 16 h, based to pH 9 with 6 N aqueous sodium hydroxide and diluted with ethyl acetate.
The separated ethyl acetate layer was washed once with saturated aqueous sodium chloride; dried over magnesium sulfate, and concentrated to an oil which was purified by flash chromatography (9:1 dichloromethane:methanol) to give the title compound as a whitesolid, 0.12 g (36%). 'H NMR (CDCI,, 300 MHz) 81.25 (d, 6H),1.49 (d, 3H), 3.24 (m, 2H), 3.51 (s, 3H), 4.18-4.38 (m, 4H), 4.72 (q, 1 H), 4.97 (m, 2W), 6.47 (d, , 1 H), 8.22 (d, 1 H), 8.57 (s, 1 H); MS (CI) 3fi0 (MH'). ,, , Exarrroles 238 to 240 Examples 238 to 240 were prepared from the appropriate starting materials in a manner analogous to the method of Exariiple 237.
~~~~Me Example R" Ru R' R mp (C) MS (MHO
238 CHZOH H 3R-Me 5S-Me 173=175 346 239 OMe CHZOMe 3R-Me 5S-Me 143-145 390 240 CHZOH phenyl 2R-Me 6S-Me 173-175 422 ' Example 241 1R-(4-f4-(4 6-Dimethvl-f1 3 5ltriazin-2-vtl-2R 6S~iimethvic~ioerazin-1 yl]-nvrimidin-2-th nol.
'Me Step A: 1R-(4-L4-l4-Methyl-6-trichloromethyl-f1 3 5ltriazin-2-vl1-2R 6S-dimethyl-eoerazin-1-vf1-pyrimidin-2-vl>~-ethyl butyrate. To a solution of 1R-[4-(2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl]-ethyl butyrate dibenzoyl-L-tartrate salt (prepared according to the method of Preparation Fifteen,1.33 g, Z.0 mmol) and sodium bicarbonate (0.34 g, 4.0 mmol) in dimethylfomiamide (S mL) was added 2-methyl-4,6-R
pCT/IB00100296 bis-trichloromethyt-[1,3,5jtriazine (1.00 g, 3.0 mmol; Butl. Chem. Soc., Jpn.
"1969, 42, 2924) and stirred at ambient temperature for 14 h. The mixture was diluted with ethyl 1I
acetate and washed twice with water and the organic layer was dried over magnesium sulfate and concentrated. The crude oil was purified by flash chromatography (95:5 dichloromethane:methanoi) to give the title compound of Example 241, Step A as a foam, 0.71 g (69%). 'H NMR (CDC13, 300 MHz) 8 p.95 (t, 3H), 1.22 (m, 6H), 1.56 (d, 3H), 1.66 (m, 2H), 2.37 (m, 2H), 2.55 (s,1 H), 3.27 (m, 2H), 4.48-4.78 (m, 2H), 4.84 (m, 2H), 5.fi7 (q, 1 H), 6.32 (d, 1 H), 8.22 (d,1 H);
MS (CI) 517, 519 (MH').
Step B: 1R-f4-f4-(4:6-Dimethvhf1.3.51triazin-2-vl~-2R.6S-dimeth~~lnioerazin-1-vI)-ovrimidin-2-vI>'-ethanol. A suspension of 1 R-{4-[4-(4-methyl-6-trichloromethyl-[1,3,5jtriazin-2-yl~2R.6S dimethyl piperazin-1-yfj-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 241, Step A, 0.65 g, 1.2 mmol) and 10°~ palladium on carbon (0.2 g) in triethylamine (1 mL) and methanol (20 mL) was hydrogenated at 40 psi for 0.5 hours using a Parr apparatus. The catalyst was filtered and the filtrate was concentrated to a solid which was dissolved in concentrated hydrochloric aad (2 mL) and stirred for 6 hours. This mixture was diluted with water, basified to pH 9 with 6 N aqueous sodium hydroxide, and extracted into dichloromethane. The extract was washed twice with water, once with saturated.
aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to a dear oil which crystallized from isopropyl ether to give the title compound as a white solid, 0.25 g (58%). 'H NMR
(CDCI,, 300 MHz) 8 1.21 (d, 6H), 1.49 (d, 3H), 2.40 (s, 6H), 3.16 (m, 2H), 4.45-4.68 (m;
2H), 4.71 (q, 1 H), 4.84 (m, 2H), 6.42 (d, 1 H), 8.20 (d, 1 H); mp: 172-173 °C;
MS (CI) 344 (MH');
[a)o +17.2 (c 1.0, MeOH).
Example 242 1R-f4-f4-14.6-Dimethvl-f1.3.51triazin-2 vf~3R.5S~iimethvl-oioerazin-1-vil~rimidin-2-thano .
HO
Me Me , ~~~~Me ~N ~ N-N'/ ~~N N ,,~ '/N
~N
Me/ Me pCT/IB00/00296 Step A: 4-Methyl-6-trichloromethvl-f1.3.51triazin-2-vl methanesuffonate. To a solution of 2-hydroxyl-methyl-6-trichloromethyi-[1,3,5]triazine (1.74 g, 5.0 mmol; J.
Amer. Chem. Soc. 1956, 78, 2447) and triethylamine (0.51 g, 5.5 rnmol) in dichloromethane was added methanesulfonyl chloride (0.57 g, 5.0 mmol) at 0 °C and stirred for 1 h then quenched in saturated aqueous sodium bicarbonate. The separated organic layer was washed once with saturated sodium chloride, dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound of Example 242, Step A as an orange oil, 0.98 g (65%) which was used directly without any further purification. MS (CI) 291,293 (MH').
Step B: 1R-(4-f3R.5S-Dimethvt-4-f4-methyl-6-trichloromethvl-f1.3.51triazin-2-vll-yiperazin-1-vfl-ovrfmidin-2-vl~thvl butyrate. To a solution of 1R-[4-(3R,5S-dimethyl-piperazin-1-yl~-pyrimidin-2-y(j-ethyl butyrate (prepared according to the method of Preparation Three; 0.62 g, 2.0 mmol) and sodium~bicarbonate (0.34 g, 4.0 mmol) in dimethylfomiamide (5 mL) was added 4-methyl-6-trichloromethyl-[1,3,5]triazin-2-yl methanesuifonate (prepared according to the method of Example 242, Step A, 1.00 g, 3.0 mmol) and stirred at ambient temperature for 14 h. The mixture was diluted with ethyl acetate and washed twice with water and the organic layer was dried over magnesium sulfate and concentrated. The crude oil was purified by flash chromatography (ethyl acetate) to give the title compound of Example 242, Step B as a dear oil, 0.41 mg (96%). 'H NMR (CDCI,, 300 MHz) b 0.95 (t, 3H), 7.22 (m, 6H), 1.56 (d, 3H), 1.66 (m, 2H), 2.37 (m, 2H), 2.55 (s, 3H), 327 (m, 2H), 4.48-4.78 (m, 2H), 4.84 (m, 2H), 5.67 (q, 1 H), 6.32 (d, 1 H), 8.22 (d, 1 H); MS (CI) 517, 519 (MH').
Step C: 1R-f4-f4-~4.6-Dimethvl-f1.3.51triazin-2-vl1-3R.5S-dimethvl-oinerazin-1-yfl-pyrimidin-2-vll-ethanol. A suspension of 1 R-{4-[3R,5S~irr~thyt-4-(4-methyl-6-trichloromethyl-[1;3,5jtriazin-2-yl)-piperazin-1-y(j-pyrimidin-2-yt}-ethyl butyrate (prepared according to the method of Example 242, Step B, 0.65 g, l2.mmol) and 10% palladium on carbon (0.2 g, 30 wt%) in triethylamine (1 mL) and methanol (20 pCTIIB00/00296 mL) was hydrogenated at 40 psi for 0.5 h using a Parr apparatus. The catalyst was , , filtered off and the filtrate was concentrated to a solid which was dissolved in concentrated hydrochloric aad (3 mL) and stirred for 6 h. This mixture was diluted with water, basified to pH 9 with ~6 N aqueous sodium hydroxide, and extracted into dichloromethane. The extract was washed twice with water and once with saturated aqueous sodium chloride and the organic Payer was dried over sodium sulfate and concentrated to a Gear oil which crystallized from isopropyl ether to give the title compound as a white solid, 025 g (23%). 'H NMR (CDCt,, 300 MHz) 8121 (d, 6H), 1.49 (d, 3H), 2.40 (s, 6H), 3.16 (m, 2H), 4.45-4.68 (m, 2H), 4.71 (q, 1 H), 6.4~ (d, 1 H), 8.20 (d, 1 H); MS (CI) 344 (MH'); mp: 157-159 °C; taJ~ +17.2 (c 1.0, MeOH).
Examples 243 to 246 Examples 243 to 246 were prepared from the approprtate starting materials in a manner analogous to the method of Example 242.
~~~~Me Example R". R'= ~ R' R mp (C) MS (Mli~
243 Me phenyl 2R-Me 6S-Me 406 244 Me phenyl 3R-Me 5S-Me 132-134 _ 406 245 Me tetrahydrofuran-2-yl2R-Me 6S-Me 428 246 Me o-tolyl ZR-Me 6S-Me 14&150 436 Example 247 (Rl-2-f2-(1-Hvdro~cv-ethvl~ovrimidin-~-vt1-1.2.3 4-tetrahvdro-isoouinoline-7-sulfonic aad dimethvlamide.
R
Me= \ i0. , , o ~S HO , .."Me \ ''v ~ N-N ~ ~N
Step A: 2-Trifiuoroacetvl-1.2.3.4-tetra~dn~-isoauinoline-7-sulfonic acid dimethvlamide. A mixture of 2-fifluoroacelyl-1,2,3,4-tetrahydro-isoquinolirte-sulfonyl chloride (400 mg, 1.22 mmo(, .l. Med Chem.1980, 23, 837), dimethylamine hydrochloride (150 mg,1.83 mmol), and triethy(amine (0.50 mL, 3.66 mmol)~in dioxane (10 mL) was refluxed with stirring for 30 min, cooled to room temperature, concentrated, and purified by flash column chromatography (10-X50% ethyl acetate/hexanes) to give 337 mg (82%) of the title compound of Example~247, Step A
as a yellow oil. 'H NMR (CDC13, 300 MHz, 9:5 mixture of rotamers) 8 7.67-7.52 (c, 2H), 7.36 (t, 1 H), 4.87 (s,1.3H), 4.81 (s, 0.7H), 3.96-3.86 (c, 2H), 3.08-3.02 (c, 2H), 2.72 (s, 6H); MS (TS) 337 (MH').
Step B: 1.2.3.4-Tetrahvdnrisoauinoline-7-sulfonic aad dimethvlamide. A mixture of 2-trif(uoroacetyt-1,2,3,4-tetrahydro-isoquinotine-7-suffonic aad dimethylamide (prepared acxording to the method of Example 247; Step A, 337mg,1.0 mmol) and potassium carbonate (207 mg,1'.5 mmol) in a 3:1 mixture of methanollwater (10 mL) was stirred at room temperature for 1 h and concentrated. The remaining aqueous residue was extracted with 10% isopropanoUchloroform (7x) and the combined organic extras were dried over sodium sulfate, filtered, and evaporated to give 214 mg (89%) of the title compound of Example 247, Step B as a white solid. 'H NMR
(CD,OD, 300 MHz) b 7.52 (d, 1 H), 7.48 (s,1 H), 7.36 (d, 1 H), 4.90 (s, 2H), 3.11 (t, 2H), 2.91 (t, 2H), 2.65 (s, 6H); MS (CUNH,) 241 (MH').
Step C: fR~1-f4-t7-0imethvlsulfamovl-3.4-dihvdr~o-1 H-isoouinolin-2-vll-rnrrimidin-2-yt~-ethyl acetate. To a solution of 1,2,3,4-tetrahydro-isoquinofine-7-sulfonic aad dimethylamide (prepared according to the method of Example 247, Step B, 210 mg, 0.88 mmol) in isopropanol (5 mL) was added (R}-1-(4-chloro-pyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation five,175 mg, 0.88 mmol) followed by triethylamine (0.24 mL, 1.75 mmol). This mbchrre was stirred at room temperature for 1.75 h then heated to retlux for 1.5 h, cooled to room temperature, WO 00159510 PCTIIBOOIOOZ96 .
evaporated, and purified by flash column chromatography (1%
methanoUcHlbrofonn) to give 327 mg (92%) of the title compound of Example 247, Step C as a white solid.
'H NMR (CDCI,, 250 MHz) 8 8.28 (d,1 H), 7.68-7.58 (c, 2H), 7.47 (d, 1 H), 6.44 (d, '1 H), 5.72 (q, 1H), 4.86 (s, 2H), 3.92 (t, 2H), 3.05 (t, 2H), 2.73 (s, 6H), 2.19 (s, 3H), 1.62 (d;
3H); MS (TS) 431 (MH').
Step D: (Rl-2-T2-(1-H~droxv~thvll-ovrimidin-4-of1-1.2.3.4-tetrahvdro-isoauinoline-7-sulfonic acid dimethylamide. To a solution of (R)~1-j4-(7-dimethylsulfamoyl-3,4-dihydro-lH-isoquinolin-2-yl)-pyrimidin-2-yt]-ethyl acetate (prepared according to the method of Example 247, Step G, 326 mg, 0:81 mmol) in a 4:1 mixture of methanolMrater~(8 mL) was added t'~thium hydroxide hydrate (170 mg, 4.0 mmol).
This mixture was stirred at room temperature for 50 min, concentrated, n.-suspended in water, and extracted with 10% isopropanoUchlorofortn (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified 1by flash column chromatography (1 % methanoUchloroform) to give a white foam which was further purified by recrystallization from ether/methanol to give 90 mg (31%) of the title compound as a white solid: mp: '120.5-122 °C;'H NMR (CDCI,, 300 MHz) 8 8.24 (d, 1 H), 7.62-7.59 (c, 2H), 7.35 (d,1 H), 6.44 (d, 1 H), 4.83 (s, 2H), 4.73 (q,1 H), 4.34 (br s, 1 H), 3.93-3.85 (c, 2H), 3.03-(t, 2H), 2.71 (s, 6H), 1 X52 (d, 3H); MS (TS) 363 (MHO.
Example 248 1-f4-(6-Thioohen-3-vt-3.4-dihvdro-1 H-isoauinoGn-2-vll-dvrimidin-2-vil-ethanol.
HO
~~~~Me S ~ ~ ~ N-N ~ /N
Step A: 6-Thioohen-3-vt-3,4-dihvdro-1 H-isoauinoline-2-carbox~c acid tert-butyl gster. A mixture of bis(benzonitrile)palladium(II) chloride (30 mg, 0.079 mmof) arid 1,4-bis(diphenyiphosphino)butane (33.6 mg, 0.079 mmol) in toluene (3 mL) was stirred at room temperature for 20 min. To this mixture was added &
trifluoromethanesulfonyloxy-3,4~ihydro-1 H-isoquinoline-2-carboxylic aad tart-butyl ester (300 mg, 0.79 mmol, Synth. Common. 1995, 25, 3255), thiophene-3-boronic aad (131 mg,1.02 mmol), 1 M aqueous sodium carbonate (1.57 mL,1.57 mmol), and ethanol (2 mL). This dark mixture was heated to reflux with stirring under nitrogen pCT/IB00/00296 overnight, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (4x). The,combined organic extracts ;
were dried over sodium sulfate, filtered through Celite, evaporated, and purified by flash column chromatography (hexanes-->5% ethyl acetate/hexanes) to give 252 mg (100%) of the title compound of Example 248, Step A as a pale yellow waxy solid. 'H
NMR (CDCI,, 250 MHz) b 7.47-7.38 (c, 5H), 7.14 (d, 1 H), 4.60 (s, 2H), 3.~2-3.64 (c, 2H), 2.95-2.82 (c, 2H), 1.52 (s, 9H); MS (TS) 316 (MH'). , Step B: 6-Thioohen-3-vl-3.4-dihvdro-1 H-isoauinofine ~drochloride. A mixture' of 6-(thiophen-3-yl-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tart-butyl ester; (prepared 7 0 according to the' method of Example 248, Step A, 250 mg, 0.79 mmol) and hydrochloric aad (4 M in dioxane, 6 mL, 23.8 mmol) was stir-ed at room temperature for 1 h and concentrated to give 170 mg (86%) of the title compound of F~cample 248, Step B as a yellow solid that was used without purification in the next step.
'H NMR
(CD,OD, 250 MHz) 8 7.66 (m,1H), 7.61-7.53 (c, 2H), 7.51-7.42 (c, 2H), 7.23 (d, 2H), 4.38 (s, 2H), 3.52 (t, 2H), 3.16 (t, 2H); MS (TS) 216 (MH').
Step C: (R~-1-f4-f6-ThioDhen-3-vl-3.4-dihvdro-1 H-isoauinolin-2-vl~pvdmidin-2-y(~-ethvl acetate. To a solution.of 6-thiophen-3-yl-3,4-dihydro-lH-isoquinoline hydrochloride (prepared according to the method of Example 248, Step B, 170 mg, 0.68 mmol) in isopropanol (6 mL) was added (R~1-(4-chloro-pyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Five; 136 mg, 0.68 mmol) followed by triethylamine (0.28 mL, 2.04 mmol). This mixture was stirred at reflux for 7 h, cooled to room temperature overnight, evaporated, and purified by flash column chromatography (0.51 % methanoUchlorofoml) to give 253 mg (98%) of the title compound of Example 248, Step C as a yellow solid. 'H NMR (CDCI,, 250 MHz) E
8.26 (d, 1 H), 7:52-7.36 (c, 6H), 6.43 (d, 1 H), 5.73 (q, 1 H), 4.76 (s, 2H), 3.96 3.82 (c, 2H), 3.02 (t, 2H), 2.21 (s, 3H), 1.63.(d, 3H); MS (TS) 380 (MH').
Step D: 1~4-f6-'Thioahen-3-vl-3 4-dihydro-1 H-isoauinolin-2-vl1-ovrimidin-2-yf1-ethanol.
To a solution of (R}-1-(4-(6-thiophen-3-yl-3,4-dihydro-l H-isoquinolin-2-yl)-pyrimidin-2-y(j-ethyl acetate (prepared according to the method of Example 248, Step C, 253 mg;
0.67 mmol) in a 3:1,:1 mixture of methanoUtetrahydrofuranlwater (5 mL) was added lithium hydroxide hydrate (84 mg, 2.0 mmol). This mixture was stirred at room temperature for 1 h, concentrated, re-suspended in water, and extracted with .
chloroform (4x). The combined organic extracts were dried over sodium sulfate, pC'TIIB00/00296 filtered, evaporated, and purifed by flash column chromatography (2% ~ , methanoUchloroform) to give a yellow solid which was further purified by recrystallization from ether/methanol to give 163 mg (72%) of the title compound as a white solid. mp: 125.5-127.5 °C; 'H NM,R (CDCI,, 300 MHz) S 8.22 (d, 1 H), 7.47-7.35 (c, 5H), 7.22 (d, 1 H), 6.42 (d, 1 H), 4.78.72 (c, 2H), 4.46 (br s, 1 H), 3.93-3.84 (c, 2H), 2.99 (t, 2H), 1.54 (d, 3H); MS (APCI) 338 (MH'). , , Examples 249 to 252 Examples 249 to 252 were prepared from the appropriate starting materials in a manner analogous to the method of Example 248.
' Rza H O
..... Me N
N ~ ~N
Example . R= " mp (C) MS (MH') _ 249 6-thiophen-2-yl i 04-105 338 250 6-pyrimidin-5-yl ~ 334 251 7-pyrimidin-5-yl 135-137 334 252 6-hydroxy 272 Examples 253 to 258 Examples 253 to 258 were prepared from the appropriate starting materials in a manner analogous to the method of Example 86.
:
HO
~ ...., Me Rza~~ ,.. ~ ~- .
N N ~ ~ ~N
Example Rz' mp (C) MS (MHO
253 H _ 79-82 258 254 Me ~ 272 ~
256 NHz 20&210 273 257 Ph 128-131 334 258 pyridin-4-yl ~ Exarrrole 259 (Rl-1-f4-(3-Benzothiazot-2-vt-5 6-dihvrd~o-8H,~1 2 4Ltriazolof4 3-alo~razin-7~r1~
pvrimidin-2-vll-e~anol.
Me Step A: 5-Ethoxy 3.6-dihvdro-2H-nvrazine-1-carboxylic acid benzvi ester. To a i0 solution of 3-oxo-piperazine-1-carboxylic aad benzyl ester (2.0 g, 8.54 mmol, Maybridge) in dichioromethane (18 mL) at room temperature was added triethyloxonium tetrafluoroborate (4.1 g, 21.3 mmol). This mixture was allowed to stir for about 3 days then quenched by the addition of ice chips followed by saturated aqueous sodium bicarbonate until a neutral pH was obtained. The organic layer was separated and the aqueous layer was extracted with chloroform.(3x). The aimbined organic extracts were washed with brine (1 x), dried over sodium sulfate, and concentrated to give 2.11 g (95%~ of the title compound of .Example 259, Step A as a slightly yellow oil that was sufficiently pure,~to carryon to the next step.
'H NMR
(CDCI,, 300 MHz) b 7.43-6.97 (c, 5H), 5.17 (s, 2H), 4.i0 (q, 2H), 3.98 (s, 2H), 3.60-3.40 (c, 4H),1.27 (t, 3H); MS (APCI) 263 (MH').
Step B: 3-__Benzothiazol-2 vl-5.6-dihvdn3-8H-f1.2.41triazolot4.3-alovrazine-7-carboxylic acid benzvl ester. A mixture of 5-ethoxy-3,6-dihydro-2H-pytazine-1-carboxylic~acid benzyl ester (prepared according to the method of Example 259, Step A, 490 mg, 1.87 mmol) and benzothiazole-2-cart~oxylic aad hydrazide (360 mg, 1.87 mmot;
J.
Org. Chem.1958, 23, 134.4) in n-butanol (2 mL) was stirred at reflux overnight, cooled to room temperature, concentrated, arid purified by flash column chromatography (1 methanoUchloroform) to give 580 mg of the tibe compound of F-xample 259, Step B
(contaminated with an equimolar amount of benzothiazole-2-carboxylic aad hydrazide which was removed in the subsequent step) as a yellow solid.
Step C: 3-Benzothiazol-2-vl-5.6-dihvdn~-8HJ1.2.41triazolof4 3-alovrazine. To a solution of 3-benzotniazol-2-y!-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-carboxylic aad benzy! ester (prepared according tQ the method of Example 259, Step B, 580 mg, contaminated with bdnzothiazole-2-carboxylic aad hydrazide) in dichioromethane (10 mL) at 0 °C was added a solution of boron tribromide (1 M in dichloromethane, 4.45 mL, 4.45 mmol). This mixture was warmed to room temperature overnight, quenched by addition of water, and cflncentrated. The residual aqueous layer was washed with ether (6x), neutralized with saturated aqueous sodium bicarbonate, and extracted with 10% isopropanoUchloroform (3x).
The combined organic extracts v~re dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1-X10% metharioUchlorofom~) to give 175 mg (36%, two steps) of the title compound of Example 259, Step C as a white solid. 'H NMR (CDCh; 300 MHz) 8 8.05 (d,1 H), 7.96 (d, 1 H), 7.57-7.41 (c, 2H), 4.62 (t, 2H), 4.36 (s, 2H), 3.35 (t, 2H); MS (APCI) 258 (MH').
Step D: (Rl-1-(4-(3-Benzothiazol-2-vl-5 6-dihvdro-8H~1 2 4lhiazolol4 3-aiovra rr7 ~rt~-ovrimidin-2-yfl~thvl butyrate. A mixture of 3-benzothiazol-2-yl-5,6-dihydro-8H-[1.2.4]triazolo[4,3-a]Pyrazine (prepared according to the method of Example 259, Step C, 170 mg, 0.66 mmol), (R)-1-(4-chloro-pyrimidin-2-y1)-ethyl butyrate (prepared according to the method of Preparation Seven, 150 mg, 0.66 mmvl), and triethylamine (0.28 mL, 1.98 mmo() in n-butanol (2.2 mL) was heated to reflux overnight, cooled to room temperature, evaporated, and purified by flash column chromatography (1 %
methanol/chloroform) to give 224 mg (76%) of the title compound of Example 259, Step D as a colorless solid. 'H NMR (CDCI,, 300 MHz) s 8.37 (d, 1 H), 8.08 (d, 1 H), 7.97 (d, 1 H), 7.57-7.43 (c, 2H), 6.53:(d, 1 H), 5.71 (q,1 H), 5.09 (s, 2H), 4.82 (t; ~2H), 4.33-4.26 (c, 2H),.2.42 (t, 2H), 1.78-1.64 (c, 2H),1.61 (d, 3H), 0.99 (t, 3H);~MS (APC1) 450 (MH'). .
Step E: (R~-1-t4-f3-Benzothiazo(-2-v(-5.6-dihvdero-8H-I1.2.41trfazolo14.3-alovr'azin-7-vll-ovrimidin-2-vl1-ethanol. To a solution of (Ry-1-[4-(3-benzothiazol-2-yl-5,6-dihydro-8H-[1,2,4)triazolo[4,3-a]Pyrazin-7-YI)-Pyrimidin-2 ytj-ethyl butyrate (prepared according to the method of Example 259, Step 0, 220 mg, 0.49 mmol) in a 3:1:1 mixture of tetrahydrofuraNmethanoUwater (5 mL) was added lithium hydroxide hydrate (62 mg, 1.47 mmol). This mixture was stined at room temperature for 3 h, concentrated, and extracted with chloroform (3x). The combined organic extracts were died over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (5%
methanollchioroform) to give 192 mg (100%) of the title compound as a cotortess solid. mp: 216.5-218.5 °C;'H NMR (CDCI,; 300 MHz) S 8.37 (d, 1 H), 8.06 (d, 1 H), -7.97 (d, 1 H), 7.56-7.45 (c, 2H), 6.56 (d, 1 H), 5.11 (s, 2H), 4.83 (t, 2H), 4.77 (m, 1 H), 4.35-4.25 (c, 2H), 4.16 (s, 1 H), 1.54 (d, 3H); MS (APCI) 380 (MH-), [a]p +14,2 (c 1.0, CHCt,).
Examples 260 to 263 Examples 260 to 263 were prepared from the appropriate starting materials in a manner analogous to the method of Example 259.
WO 00!59510 HO ' ~N .,...Me j ~~ . N_ ~~N N N
\ ~
xampte R"_ mp (C) MS (MHO
260 phenyl 161-164 ~ 323 261 quinoxalin-6-yl 212-215 375 262 benzothiophen-2-yl 224-226 , 379 263 biphen-4-yl 123-i25 399 Example 264 (Rl-1-14-(Soirofbenzothiaaoline-2.4'-oioeridinel?-pyrimidin-2-v11-ethanol. ' HO
.... Me _ S N-W l N \ ~N
N
H
Step A: Soirofbenzothiazolip-2.4'-oioeridinel hydrochloride. To a solution of 1'-benzylspiro[benzothiazoline-2,4'-piperidine) (500 mg, 1.69 mmol; Indian J.
Chem.
19T6, X48, 984) in acetone (5 mL) at 0 °C was added 1-chloroethyl chlorofom~ate (0.37 mL, 3.38 mmol). This mixture was stirred at 0 °C for 2 h, warmed .to room temperature, and concentrated. The residue was purified by flash column chromatography (1025% ethyl acetatelhexanes) to give the intem~ediate carbamate which was refluxed in methanol (2 mL) for 30 min. Evaporation of the reaction mixture provided 128 mg (31 %) of the title compound of Example 264, Step A as a white solid.
'H NMR (CD30D, 400 MHz) 8 6.98 (dd,1 H), 6.88 (t,1 H), 6.68-6.64 (c, 2H), 3.48-3.34 (c, 2H), 3~5-3.11 (c, 2H), 2.39-220 (c, 4H); MS (APCI) 207 (MH').
WO 00!59510 pG"f/IB00/00296 Step B: (R~1-f4-(Soirofbenzofhiazoline-2.4 -niperidinej~nyrimidin-2-vIl-Ethyl butyrate.
To a solution of spiro[benzothiazolin-2,4'-piperidine] hydrochloride (prepared ' according to the method of ExaFnple 264, Step A, 147 mg, 0.60 mmol) in isopropanol (4 mL) was added (R~1-(4-chloro-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Preparation Seven, 140 mg, 0.60 mmol) followed by triethylamine (0.25 mL, 1.8 mmol). This mixture was stirred at reflux for 2 h, concentrated, and purified by flash column chromatography (1%-~2% methanollchforoform) to give mg (88%) the title compound of Example 264, Step B as a yellow oil. 'H NMR
(CDC13, 300 MHz) 8 8.20 (d,1 H), 7.09 (dd,1 H), 6.95 (t, 1 H), 6.78 (t, 1 H), 6.68 (d, 1 H), 6.40 (d, 1 H), 5.68 (q, 1 H), 4.32-4.18 (c, 2H), 4.02 (s, 1 H), 3.38-3.25 (c, 2H), 2.39 (t, 2 h), 2.36-2.25 (c, 2H), 1.99-1.83 (c, 2H), 1.75-1.64 (c, 2H);'1.57 (d, 3H), 0.9fi (t, 3H); MS (APCI) 399 (MH').
Step C: (Rl-1-f4-(Soirofbenzothiazoline-2.4'-piperidinel~nyrimidin-2-yfl-ethanol. A
mixture of (R}-1-[4-(spiro[benzothiazoline-2,4'-piperidine]}-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of Example 264, Step B; 204 mg, 0.51 mmol) and lithium hydroxide hydrate (65 mg, 1.53 mmol) in a 2:2:1 rtiucture of tetrahydrofuraNmethanoUwater (5 mL} was stirred at room temperature for 1 h.
The organic solvents were evaporated and the residue was extracted with 10%
isopropanol/chlaroform (3x). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2%
methanol/chlorofoml, 2x) to give a red foam which was further recyrstall'~zed (ethyl acetate) to give 42 mg (25%) of the title compound as a yellow solid. 'H NMR
(CDCI,, 400 MHz) b 8.18 (d, 1 H}, 7.07 (d, 1 H), 6.93 (td, 1 li), 6.78 (td, 1 H), 6.69 (d, 1 H), 6.42 (d, 1 H), 4.69 (m, 1 H); 4.35-4.16 (c, 3H), 4.02 (s, 1 H), 3.41-3.28 (c, 2H), 2.37-2.24 (c, 2H), 1.99-1.85 (c, 2H), 1.49 (d, 3H); MS (APCI) 329 (MH'); [a]o +17.3 (c 1.0, MeOH).
wo oo~s9sio rcr~soomo2~s Example 265 , , 4-f2-l1 R-Hvdroxv-ethvl~ovrimidin-4-v(t-3R.5S-dimethyl-piperazine-1-carboxylic acid methyl, ester. :~_ HO
."~ Me N-~ IN , , To a solution of 9 R-[4-(2R,fiS-dimethyl-piperazin-1-yt)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the procedure of Preparation Four, 70 mg, 23 Nmol) in tetrahydrofuran (2 mL) at room temperature under nitrogen was added triethylamine (63 NL; 46 Nmol) followed by methyl chiorofom~ate (21 IrL, 27 Nmol): This mixture was stirred for 1 h and concentrated. The residue was dissolved in a 3:1:1 mixture of methanoUtetrahydrofuran/water (2 mL) and lithium hydroxide hydrate (29 mg, fig pmol) was added. This mixture was stirred for 1 h, concentrated, re-suspended in water, and extracted with 1 d% isopropanoUchlorofonn (4x). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (1x), dried over sodium sulfate; filtered, and evaporated to give 50 mg (74%, 2 steps) of the tifae compound as a colorless oil. 'H NMR (CDCh, 400 MHz) 8 8.2i (d,1 H), 6.33 (d,1 H), 4.70 (m, 1 H), 4.63-3.92 (c, SH), 3.76 (s, 3H), 3.20-3.02 (c, 2H), 1.50 (d, 3H),1.25 (d, 6H); MS (APCI) 295 (MH'); [aJo +19.0 (c 0.9, MeOH).
Example 26~
1 R,~4~4-(2-f 1 R Butvnrloxv~thvll-pvrimidin~ vtl 2R 6S~imethvl-flioerazin 1 ~rl,~
nvrimidin-2-vll-ethyl but)rrate.
Me To a solution of 1 R-[4-(2R,6S-dimethyl-pipen~zin-1 yi)-pyrimidin-2-yIJ-ethyl butyrate (prepared according to the procedure of Preparation Four, 200 mg, 0 65 mmol) in isopropanot (2 mL) at room temperature was added triethylamine (0.18 mL, 1.31 mmol) followed by (Rr1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the procedure of Preparation seven, 150 mg, 0.65 mmol). This mixture was heated to reflex for 18 h, cooled to room temperature, concentrated and purified by flash column chromatography (1% methanoUchlorofortn) to give 321 mg (99%) of the title compound as a yellow oil. 'H NMR (CDCI3, 400 MHz) 8 8.22 (d, 2H), 6.43 (d,1 H), 6.32 (d, 1 H), 5.68 (q, 2H), 4.72-4.24 (c, 4H), 3.30-3.12 (c, 2H), 2.39 (t, 4H); 1.77-1.63 (c, 4H), 1.57 (d; 6H),1.28-1.17 (c, 6H), fl.96 (t, 6H); MS (APCI) 499 (MH').
yxamole 267 4-(4-f2-(1R-Hvdroxv-ethvll-pvrimidin-4-vl1-2R.6S-dimethYl-oinerazin-1-vl~-6-methyl I1.3.5~triazin-2-ol.
Me Me ,, N
N~N N~ -.- ~N
N ~ N
Meln~,..
Me OH
OH
1R-[4-[4-(4-Chloro-6-methyl-[1,3,5jtriazin-2 yl~3R,5S-dimethylpiperazin-1-yQ-pyrimidin-2-yl}-ethyl butyrate (prepared according to the method of t=xample 213, Step A, 0:30 g, 0.70 mmol) was added to concentrated hydrochloric aad (3 mL) and heated to reflex for 12 h. The mixture was neutralized to pH 7 with solid sodium bicarbonate and extracted into chloroform. The organic extract was dried over sodium sulfate and filtered. The filtrate was concentrated to an oil which was purified by flash chromatography (92:8 chloroform:methanol) to give the title compound as a white solid, 0.15 g (64%). 'H NMR (CDCI,, 300 MHz) 81.21 {d, 6H), 1.49 (d, 3H), 236 (s, 3H), 3.21-3.27 (m, 2H), 4.22-4.43 (m, 2H), 4.63 (m, 2H), 4.69 (q,1 H), 6.42 (d,1 H), 8.18 (d,1 H); mp: 247-248 °C; MS (CI) 346 {MH').
Examotes 268 to 275 Examples 268 to 275 were prepared from the appropriate starting materials in a manner analogous to the method of Example 267.
HC .
HO ~, Rs ..nMe !=N x/12 ,N~ ' N~N ~~~ ~~ /N
R" . sR78 , Example R" ~ R' R' mp (C) ~ MS (MHO
268 , , H 3R-Me 5S-Me > 250 332 _ 269 isopropyl 3R-Me 5S-Me > 250 374 ' 270 cydohexyl 3R-Me 5S-Me > 250 414 271 phenyl 3R Me 5S-Me >: 250 408 272 cydopropyl 3R-Me 5S-Me > 250 ~ 372 273 methyl 2R-Me 6S-Me > 250 346 274 cydopropyl 2R-Me 6S-Me > 250 372 275 phenyl 2R-Me 6S-Me > 250 408 Examoie 27~
(El-f4-Oxo-3-!5-trifiuoromethvl-benzothiaZOl-2-vimethvl~-3 4-dihvdro-ohthafazin-1-yl1-acetic acid 1R-f4-f4-l3-thioahen-2-vl-acrvlovfl-oioerazin-1-vft-ovrimidin 2 ytl-ethyl ester.
. O
~N r ~N, J -ON N
O CH
~N 3 ..
O N.~_ F F
To a solution of {4-oxo-3-(5-trifluoromethyl-benzothiazo!-2-yimethyl~3,4-dihydro-phthalazin_1-ylJ-acetic add (0.59 8,1.41 mmoi) in dichloromethane (30 mL) and dimethyiaminopyridine (0.18 g,1.41 mmol) was added 1-(3-dimethytaminopropyl~3-ethylcarbodiimide hydrochloride (0.54 g, 2.82 mmol) followed by (E}-1-(4-(2-(1R-wo oors9s><o rcrnsooiooz~
hydroxy-ethyl)-pyrirnidin-4-ylj-piperazin-1-y1}-3-thiophen-2-yl-propenone (prepared according to the method of F~cample 127, 0.49 8,1.41 rr~mo() at ambient temperature and stir-ed for 20 h. The mixture'was washed once with saturated aqueous sodium bicarbonate, once with saturated aqueous podium chloride, dried over magnesium sulfate and filtered. The filtrate was concentrated to an oil which was purified by flash chromatography (ethyl acetate) to give the title compound as a white foam, 0.65 g (62%). 'H NMR (CDCI,, 300 MHz) S 1.51 (d, 3H), 3.41-3.77 (m, 8H), 4.28 (m, 2H), 5.18 (q, 1 H), 5:79 (d, 1 H), 6.35 (d, 1 H); 6.68 (d, 1 H), 7.05, (m, 1 H), 7.32 (d, 1 H), 7.68 (m, 1 H), 7.71-7,90 (m, 5H), 8.18 (d, 1 H), 8.27 (d, 1 H), 8.46 (m, 1 H); mp:
105-109 °C;
MS (CI) 746 (MH'); ja]p +49.2 (c 1.0, MeOH).
Example 277 IE~f4-Oxo-3-l5-trifluoromethvl-benzothiazol-2-vlmethvl~-3.4-dihvdro-ot~i~thalazin-1-ytl-acetic acid 1R-f4-(4-ouinoxalin-2-vl-pioerazin-1-vl)-DVrimidin-2-vIl-ethyl ester.
Example 277 was prepared from the appropriate starting materials in a manner analogous to the method of Example 276. 'H NMR (CDCI,, 300 MHz) 81.53 (d, 3H), 3.38-3.87 (m, 8H), 4.28 (ms 2H), 5.18 (q, 7 H),. 6.35 (d, 1 H); 7.68 (m, 1 H), 7.58-?.94 (m, 8H), 8.18~(d, iH), 8.21-8.37 (m, 2H), 8.46 (m,1H); mp: 108-112 °C;
NIS (Ct) 738 (MH').
2-Methoxvmethvl-4-~inerazin-1-vl-wrimidine.
Step A: 2-Methoxvmethvl-pyrimidin-4-vl-methanesulfonate. To an ice cold solution of 2-methoxymethyl-3H-pyrimidin-4-one (35.0 g,~250 mmoi; US 5,215,990) and triethylamine (25.6 g, 250 mmol) in dichloromethane (250 mL) was added methanesuffonyl chloride (28.6 g, 250 mmol) dropwise. This mixture was allowed to warm slowly to room temperature over 1 h then washed successivelysroith saturated aqueous sodium bicarbonate and water. The organic layer was dried ~rer magnesium sulfate, filtered, and evaporated to give the title compound of Preparation One, Step A as a tan solid, 49.2 g (90%). 'H NMR (CDC4~, 300 MHz) 8 3.55 (s, 3H), 3.82 (s, 3H), 4.42 (s, 2H), 6.36 (d; 1 H), 8.12 (d,1 H); mp: 39-40 °C;
MS (TS) 219 (MH'). , ~ , Step B: 2-Methoxvmethyl~-Diberazin-1-vl-ovrimidine. To a solution of 2-methoxymethyl-pyrimidin-4-yl-methanesulfonate (prepared acdrding to the method of Preparation One, Step A, 43.6 g, 200 mmol) in tetrahydrofuran (400 mL) was added piperazine (34.4 g, 400 mmoi). This mixture was heated to reflux for 0.5 h, cooled to room temperature, and filtered. The filtrate was concentrated and dried under reduced pressure to give the title compound as a semi-solid, 36.6 g (85%). 'H
NMR
(CDCI,, 300 MHz) b 2.45 (br s,1 H), 2.88 (m, 4H), 3.45 (s, 3H), 3.72 (m, 4H), 4.46 (s, 2H), 6.38 (d, 1 H), 8.22 (d, 1 H); MS (TS) 209 (MH'). , Preparation Two ~Rl-1-(4-Pioerazin-1 vl-pyrimidin-2-vll-ethvi acetate. A mixture of (R)-i-(4-methanesulfonyloxy-pyrimidin-2-ylrethyl acetate (prepared according to the method of Preparation Six, 24.1 g; 92 mmol) and piperazine (16.0 g, 184 mmol) in tetrahydrofuran (200 mL) was heated at reflex for 1 h. This mixture was doled, 8ltEred, dncentrated, and purified by flash dlurtm chromatography (9:1 dichloromethanelmethanol) to °give 24.4 g (88%) of the title dmpound as an oil. 'H
NMR (CDCI,, 300 MHz) 81.56 (d, 3H), 2.25 (s, 3H), 2.83 (m, 4H), 3.63 (m, 4H), 5.54 (q, 1 H), 6.38 (d, 1 H), 8.24 (d, 1 H); MS (CI) 251 (MH').
Preparation Three 1R-f4-l3R.SS-Dimethvl-oioerazin-1-vl~-oyrtmidin-2-v0-ethvt butyrate. A mixture of (R~ .
1-(4-chloro-pyrimidln-2-yl)-ethyl butyrate (prepared acdniing to the method of Preparation Seven,18.5 g, 80.9 mmol) and as-2,6-dimethytpiperazine (18.6 8,162 mmol) in tetrahydrofuran (400 mL) was stirred at room temperature overnight, diluted with ether, and washed with saturated aqueous sodium bicarbonate (1x) and water (3x). The dmbined aqueous extracts were bade-extracted with 10°~
isopropanoUchloroform (6x). The cornbined~organic extracts were dried over sodium sulfate, filtered; evaporated, and purified by flash dlumn chromatography (1.-~5°h methanoUchloroform) to give 20.9 g (84°~) of the title compound as a waxy yellow solid. 'H NMR (CDCI,, 400 MHz) S 8.14 (d, 1 H), 6.31 (d, 1 H), 5.65 (q, 1 H), 4.53.16 -25i-(c, 2H), 2.89-2.78 (c, 2H), 2.47-2.33 (c, 2H), 2.38 (t, 2H).1.73-1.60 (c, 2H), ~f.55 (d, . 3H), 1.11 (d, 6H), 0.94 (t, 3H); MS (APCI) 307 (MH').
Precaration Four 1 R-f4-12R,.6S-Dimethvl-oioerazin-l:ylj~~rtimidin-2-vli-ethyl butyrate.
Step A: 114-(4-Benzvl-2R.6S-dimethv!-oiderazin-1-vl~dvrimidin-2-vli-ethyl butyrate.
A mixture of (R)-1-(4-trifluoromethanesulfonyloxy-pyrimidin-2-ylrethyl butyrate .. , (prepared according to the method of Preparatioh Nine, 84.8 g, 248 mmol) and cis-1-benzyl-3,5-dimethy1-piperazine (101 g, 496 mmol, Org. Prep. Proceed. Int.1976, 8, 19) in aoetonitrile (310 mL) was stirred at reflex for 15 h, concentrated, and purified by flash column chromatography (15% ethyl acetatelhexanes) to give 52 g (53°~) of the title compound of Preparation Four, Step A as an, orange oil. 'H NMR (COCI3, MHz) 8 8.15 (d,1 H), 7.39-7.24 (c, 5H), 6.25 (d,1 H), 5.66 (q,1 H), 4.45 (m,1 H), 4.24 (m, i H), 3.52 (s, 2H), 2.73 (d, 2H), 2.37 (t, 2H), 2.22 (d, 2H),1.70-1.60 (c, 2H),1.55 (d, 3H), i.30 (d, 3H), 127 (d, 3H), 0.93 (t, 3H); MS (APCI) 398 (MH').
Step B: 1 R-f4-(4-Benzvl-2R.6S-dimethvl-oioerazin-1-vl~vrimidin-2-v(l.ethvl but~rr a and 1S-f4-l4-Benzvl-2R 6S-dimethvl-eioerazin-1-v11-oyrimidin-2- -ethyl bulb. 1-I4-(4-Benzyl-2R,6S-dimethyl-piperazin-1-yl~pyrimidin-2-Y(J-ethyl butyrate (Prepared according to the method of Preparation Four, Step A,131 g, 79% ee) was purified by chiral HPLC under the following conditions (column:15 an id x 25 cm Prochrom column packed with Chiracel AD obtained from Chiral Technologies inc., 730 Springdale Dr., Exton, Pennsylvania,19341; mobile phase: 90:10 n-heptanefsopropanol; flow rate: about 1 Umin; loading: 4.2 glcycle) to provide the title compounds of Preparation Four, Step B (109 g, >98°~ ee) and (12.6 g, 93% ee), respectively, both as yellow oils. The 'H NMR and MS data for the preceding impounds were in agreement with that for scalemic material of Preparation Four, Step A.
Step C: 1R-f4-L4-Benzvl-2R 6S-dimethyl~ieerazin-1-vl~-nvrimidin-2-vi1-ethv!
bu~rrate t~rdrochloride. To a solution of i R-I4-(4-benzyl-2R,6S-dimethyl-piperazin-1 yI~ .
pyrimidin-2-ylJ-ethyl butyrate (prepared according to the method of Preparation Four, Step 8,109 g,. 275 mmot) in methanol (500 mL) was added hydrogen chloride (5 M
in methanol, 56 mL, 278 mmol). This mixture was stirred at room temperature for 5 n~ira and concentrated to give 118 g (990) of the title compound of Preparation four, Step C as a slightly yellow foam.
Step D: 1 R-14-(2R 6S-Dimethyl-oiperazin-1-vl)-pvrimidin-2-vll-ethyl butyrate.
To a solution of 1 R-[4-(4-benzyi-2R,6S-dimethyl-piperazin;l yl)-pyrimidin-2-ylJ-ethyl butyrate hydrochloride (prepares! according to the method of Preparation Four, Step C, 54.2 g, 125 mmol) in methanol (200 mL) was added ammonium formate (79 g, 1.25 mol) followed by a slurry of 10% palladium on carbon (13.5 g, 25 wt%) in methanol (200 mL). This mixture was stirred at reflux for 1 h and filtered through Celite. The filtrate was concentrated, diluted with saturated aqueous sodium bicarbonate, and extracted with chloroform (2x). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give 40.8 g of the title compound as a yellow oil.~'H NMR (CDCl3, 400 MHz) 8 8.16 (d, 1H), 6.26 (d, 1H), 5.66 (q, 1H), 4.39 (m, 1 H), 4.22 (m, 1 H), 2.93 (app s, 4H), 2.38 (t, 2H),1.71-1.62 (c, 2H),1.56 (d, 3H), 1.27 (d, 3H), 1.24 (d, 3H), 0.94 (t, 3H); MS (APC!) 307 (MH').
Preparation Five fR~-1-(4-Chloro-avrimidin-2-vl)~thvf acetate. (R)-2-(1-Acetoxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Thirteen, 3.00 8,16.5 mmol) was added to phosphorus oxychloride (10 mL) at ambient temperature and stin~ed for 3 h. Excess phosphorus oxychloride was removed under vacuum and the resulting oil was partitioned between chloroform and saturated aqueous sodium carbonate.
The layers were separated and °the organic layer was washed twice with water, once with saturated aqueous sodium chloride and dried over magnesium sulfate and filtered. The fltrate was evaporated to give the title compound as an orange oil, 288 g (87%). 'H.NMR (CDCI,, 300 MHz) b.1.56 (d, 3H), 2.18 (s, 3H), 5.68 (q,1 H), 6.32 (d, 1 H), 821 (d, 1 H); MS {CI) 201, 203 (MH'); [ajo +27.6 (c 1.0, MeOH).
Preparation Six (R~-1-l4-Methanesulfonvloxv-oyrimidin-2y11-et~rl acetate. To an ice cold solution of (Rj-2-(1-acetoxy-ethyl)-3H-pyrimidin-4-0ne (prepared according to the method of Preparation Thirteen, 258 g, 142 mmol) and triethylamine (1.43 g, 142 mmol) in dichloromethane (20 mL) was added methanesutfonyl chloride (1.63 g, 14.2 mmol) dropwise and stir-ed for 1 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate and filtered.
The filtFate was evaporated to give the title compound as an oil, 3.15 g (85%). 'H
NMR (CDCI,, 300 MHz) 81.56 (d, 3H), 2.i8 (s, 3H), 3.82 (s, 3H), 5.56 (q, 1H), 6.38 (d, 1 H), 8.24 (d, 1 H); MS (Cl) 261 (MH'); [a]o +53.8 (c 1.1, MeOH).
WO 00!59510 PGT/IBOOI00296 Preparation Seven iRl-i-l4-Chloro-ovrimidin-2-vtl-ethyl butyrate. (R~2-(1-Butyryloxy-ethyl~3H-pyrimidin~-one (prepared accorrJing to the method of Preparation Fourteen, 3.OO g, 16.5 mmol) was added to phosphorus oxychloride (10 mL) at ambient temperature and stirred for 3 h. Excess phosphonrs oxychtoride was removed under vacuum and the resulting oil was partitioned between dicttloromethane and saturated aqueous sodium carbonate. The layers were separated and the organic layer was,washed once with water, once with saturated aqueous sodium chloride and dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound as an orange oil, 3.19 g (85%). 'H NMR (CDCI,, 300 MHz) S 0.98 (t, 3H),1.54 (d, 3H), 1.67 (m, 2H), 2.48 (t, 2H), 5.68 (q,1 H), 6.36 {d, 1 H), 8.21 (d,1 H);
[ajo +27.6 (c 1.0, MeOH ).
Preparation Eiaht (Rl-1-(4-Methanesulfon~x~ pyrimidin-2-vl)~thvl butvr-ate. To an ioe cold solution of (Rr2-(1-butyryloxy-ethyl}-3H-pyrimidin-4-one (prepared according to the method of Preparation Fourteen, 17.8: g, 97.8 mmol) and triethylamine (9.9 g, 97.8 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (11.21 g, 97.8 mmol) dropwise and stirred for 1 h. The mixture was washed successively with saturated aqueous sodium bicarbonate arid water, dried over magnesium sulfate and filtered.
The filtrate was evaporated to give the title compound as an oil, 24.1 g (94%). 'H
NMR (CDCI,, 300 MHz) b 0.99 (t, 3H), 1.54 (d, 3H), 1.68 (m, 2H), 2.48 (t, 2H), 3.81 (s, 3H), 5.54 (q, 1 H), 6.38 (d, 1 H), 8.24 (d, 1 H); MS (CI) 281 {MH'); [ajo +28.8 (c 1.0, MeOH).
Preparation Nine (Rl-1-(4-Triftuoromethanesulfonvloxv-~yrimidin-2-vll-ethyl butyrate. ' Method 1: To a solution of (R~2-(1-bufyryfoxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Fourteen, 52 g, 248 mmol) and triethylamine (36.2 mL, 260 mn~l) in dichloromethane (830 mL) at 0 'C with stirring under nitrogen atmosphere was added a solution of trifluoromethanesulfonic anhydride (44 mL, mmot) in dichloromethane (70 mL) dropwise via addition funnel over 30 min, maintaining an internal temperature of 4-8 °C. This mixture was allowed to stir an additional 15 min at 4 °C, then quenched with water. After stirring for 10 min, the layers were separated and the aqueous layer was extracted with dichloromethane pCT/IB00/00296 (3x). The combined organic extracts were dried over sodium sulfate, filterad, and concentrated to give 47.2 g (-100°~) of the tifie compound as a dark oil which was used immediately in the next step. 'H NMR (CDCI3, 400 MHz) b 8.83 (d, 1H), 7.03 (d, 1 H), 5.82 (q,1 H), 2.41-2.32 (c, ZH),1.72-1.60 (c, 2H),1.62 (d, 3H), 0.95 (t, 3H); MS
(APCI) 343 (MH'). ' Method 2: To a solution of (R~2-(1-butyryloxy-ethyl~3H-pyrimidin-4-one (prepared according to the method of Preparation Fourteen, 4.20 g, 20.0 mmol) and, triethyfamine (2.02 g, 20.0 mmol) in dichloromethane (20 mL) was added trifluoromethanesulfonyl chloride (3.37 g, 20.0 mmol) dropwise, maintaining an intemaf temperature less than -20 °C, and stir=ed for 0.5 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, dried over sodium sulfate and filtered. The filtrate was evaporated to give the title compound as a dark oil, 6.42 g (94%), which was used immediately in the next step. 'H NMR
and MS data were were in agreement with that from Preparation Nine, Method 1.
Preparation Ten lRl-1-(4-Chloro-pvrimidin-2;yl~thanol. To a solution of (R)-i-(4-chioro-pyrimidin 2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 250 mg, 1.1 mmol) in dioxane (0.9 rizL) was added concentrated hydrochloric add (0.9 mL).
This mixture was allowed to stir,at room temperature for 5 h, quend~ed with saturated aqueous sodium bicarbonate followed by solid,sodium bicarbonate until no more gas evolution was evident Dichloromethane was added and the layers were separated.
The aqueous phase was extracted with dichloromethane (3x) and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give 125 mg (71%) of the title compound as a pale yellow oil. 'H NMR (CDCt,, 400 MHz) 8 8.59 (d, 1 H), 7.25 (d, i H), 4.92 (q,1 H), 3.81 (br s, 1 H),1.5fi (d, 3H); MS
(APCI) 159, 161 (MH').
Prenarat;on Eleven fR?-(+1-2-l1-Hvdroxv-ethvll-3H-ovrimidin-4-one hprdro-.
Step A: R-(+~-2-Hvdroxv-orooionamidine hvdrochioride. To a 22L, 3-neck round bottom flask equipped with reflux condenser, mechanical stirrer, themvometer and nitrogen inlet was added tetrahydrofuran (7.3 l-), R-(+~2fiydroxy-propionamide (T31 g, 82 mol) and triethyloxonium tetrafluorQborate (95°x,1.97 kg, 9.8 mol). The resulting yellow solution was allowed to stir at room temperature for 2 h, at which time an NMR sample indicated consumption of starting material and the presence of the desired imidate. The solution was concentrated under vacuum to provide a yellow oil which was taken up in methanol..(2 L). This solution was cooled to 15 °C and anhydrous ammonia was bubbled through the solution for 5 h. The resulting suspension was allowed to stir for 2 h. concentrated to a thick mixture, diluted with ethyl acetate and filtered through Celite. The filtrate was then cooled to ~0 °C, anhydrous hydrogen chloride was bubbled through the solution for 2 h, warmed to room temperature, and filtered to provide 418 g (41 %) of the title compound of Preparation Eleven, Step A. mp: 134-i38 °C;'H NMR (DMSO-ds, 300 MHz) S
1.33 (t, 3H), 4.42 (q, 1 H), 625-6.88 (br s, 1 H), 8.72-9.25 (br s, 3H).
Step B: fR~f+~2-(1-Hydroxv-ethvl~-3H-avrimidin-4-one hydrochloride. To a 22 L, nedc round bottom flask equipped with a reflux condenser, mechanical stirrer, thermometer and nitrogen inlet was added methanol (8 L), potassium hydroxide (946 g, 14.7 mot), R-(+}-2-hydroxy-propionamidine (prepared according to the method of Preparation Eleven, Step A,1848 g, 14.7 mot) and ethyl 3-hydroxy-acrylate sodium salt (prepared according to, the method of Preparation Twelve, Step C, 2030 g, 14.7 mot). The resulting slurty was stirred at room temperature for 3 h. The pH was adjusted from 125 to 7 by the addition of concentrated hydrochloric acid (1.32 L).
The solids were filtered off and washed with isopropanol. The filtrate was concentrated to an oil, diluted with isopropanol.(4 L), cooled to 10 °C
and anhydrous hydrogen chloride was bubbled through the solution for 4 h. The resulting suspension was filtered and the solids were dried to provide 2242 g (87%) of the title compound.
mp: 180-184 °C (dec);'H NMR (DMSO-db, 400 MHz) b 1.46 (d, 3H), 4.84 (q, 1H), 6.52 (d, 1 H), 8.00 (d, 1 H). -Preparation Twelve 2-(1-Hvdroxv-ethyl)-3H-oyrimidin-4-one.
Step A: 2-Hvdroxv-orooionimidic aad ethyl ester hydrochloride. A solution of lactonitrile (378 g, 5.32 mot) in ethyl ether (1.46 L).and ethanol (0.34 L) was saturated with hydrogen chloride gas at 0-5 °C for 0.5 h and kept at 5 °C
for 60 h. The resulting preapitate was filtered off and washed twice with ethyl ether to give the title compound of Preparation Twelve, Step A as a solid, 815 g (99%). mp: 165-168 °C;'H NMR
(CD,OD. 250 MHz) 8 1.45-1.53 (c, 6H): 4.40-4.61 (c, 3H).
p~~B00/00296 -25&
Step B: 2-Hvdroxv-orooionamidine hvdrochioride. A suspension of 2- ~ ~ , , hydroxypropionimidic acid ethyl ester hydrochloride (prepared according to the ..
method of Preparation Twelve, Step A, 751 g, 4.87 mol) in ethanol (3.75 L) at 0 °C
was saturated with ammonia gas, maintajning an ~intemal temperature < 5 °C, for 1 h then sorted at ambient temperatun: for 18 h. The solid was filten:d off and dried under vacuum at 40 °C to give an initial crop of material. The filtrate was concentrated to one-half volume and a second crop was collected and dried under vacuum. The first and second crops were combined to give the title compound of Preparation Twelve, Step B as a yellow solid, 608 g (99%). mp:134-138 °C;'H NMR (DMSO-dg, 400 MHz) s 1.30 (d, ~3H), 4.38 (q,1 H), 6.23 (br s, 1 H), 7.35 (br s, 1 H), 8.78 (br s, 3H).
Step C: Ethv13-hvdroxv-acrvlate sodium salt. To a suspension of sodium hydride (60°!° dispersion in oil, 269 8,16.7 mol) in isopropyl ether (12 L) was addBd slowly ethyl acetate (1280 g, 14.2 moi) at a rate which maintained an internal temperature of 45 °C. This mixture was stin~ed for and additional 0.5 h, then ethyl formats (2232 g, 30.1 mol) was added dropwise at 42 °C and stirred at ambient temperature for i 8 h.
The mixture was filtered and the solids v~re washed twice with ethyl ether and once with hexanes and dried to give the title compound of Preparation Twelve, Step C as a white solid, 1930 g (99%). 'H NMR (DMSO-a16, 300 MHz) b 1.03 (t, 3H), 3.86 (q, 2H), 4.08 (d, 1 H), 8.03 (d, 1 H).
Step D: 2-l1-Hvdroxv~th~rll-3H-ovrfmidin-4-one. To a solution of ethyl 3-hydroxy-acrylate sodium salt (prepared according to the method of Preparation Twelve.
Step C,1301 g, 9.42 rrml) in water (1.3 L) was added a solution of 2-hydroxy-propionamidine hydrochloride (prepared according to the method of Preparation Twelve, Step B, 610 g, 4.9 mol) in water (1.3 L) at ambient temperature and stirred for 48 h. The soluticn was adjusted to pH 7.0 with acetic aad then continuously extracted with chloroform for 48 h. The extract was dried over sodium sulfate and filtered. The filtrate was concentrated to a solid, slurried in ethyl ether, filtered, and dried to give the title compound as a solid, 232 g (38%). mp:121-124 °C;'H NMR (DMSO-de, MHz) S 1.30 (d, 3H), 4.46 (q, 1 H), 5.62 (br s, 1 H), 6.13 (d, 1 H), 7.80 (d, 1 H).
~ Preparation Thirteen 1R~2-l1-A~etoxv-ethvll-3H-ovrimidin-4-one. Ta a solution of vinyl acetate (4.3 g, 50 mmol) in dioxane (63 mL) was added 2-(1-hydroxy-ethyl~3H-pyrimidin-4.~one pCTIIB00/00296 (prepared according to the method of Preparation Twelve, 2.1 g, 15.1 mmol), and the ,, mixture was heated to 50 °C. To the resulting solution was added lipase P30 (0.21 g, , wt%) and the heating was continued for 24 h. The reaction mixture was filtered and the filtrate was evaporated to obtain a thick synrpy,liquid residue. The residue 5 was purified by flash column chromatography (95:5 dichloromethane:methanol) to give the title compound as a colorless liquid, 0.97 g (92% of theory). 'H
NMR.(CDCI,, 300 MHz) 81.61 (d, 3H), 2.20 (s, 3H), 5.65 (q, 1H), 6.35 (d, 1H), 7.97 (d, 1H), 11.94 (s, 1 H); [a]o +39.9 (c 1.0, MeOH).
Preparation Fourteen 10 (R~2-l1-Butvnrloxv-ethyl?-3H-ovrimidin-4-one.
Method 1: To a solution of vinyl butyrate (17.7 g, 310 mmol) in dioxane (650 mL) was added 2-(1-hydroxy-ethyl~3H-pyrimidin-4-one (prepared according to the method of Preparation Twelve, 21.8 g, 155 mmol), and the mixture was heated to 50 °C. To the resulting solution was added lipase P30 (4.35 g, 20 wt%) and the heating was continued for 24 h. The reaction mixture was filtered and the filtrate was evaporated to obtain a thick syrupy liquid residue which was partitioned between dichloromethane and water. The layers were separated and the organic layer was dried over sodium sulfate, filtered, and evaporated to give the title compound as a colorless liquid, 9.35 g (86% of theory). 'H NMR (CDCI,, 300 MHz) 0.95 (t, 3H), 1.65 (m, 5H), 2.40 (m, 2H), 5.65 (q, 1 H), 6.45 (d, 1 H), 8.00 (d, 1 H); [a]o +29.5 (c 1.0, MeOH).
Method 2: To a chilled (5 °C) solution of (R)-(+~2-(1-hydroxy-ethylr3H-pyrimidin-4-one hydrochloride (prepared according to the method of Preparation Eleven, 750 g, 4.3 mol) in dichloromethane (8 L) was added triethylamine (1216 mL, 8.7 mol) followed by 4-dimethylaminopyridine (25.9 g, 0.21 mol). A solution of butyric anhydride (730 mL, 4.4 mol) in dichloromethane (730 mL) was then slowly added over a period of 5 h, keeping the temperature <3 °C. The mixture was washed twice with half saturated brine (4 L) and once with saturated aqueous sodium bicarbonate (4 L), dried over sodium sulfate, filtered, and concentrated under vacuum to give 869 g (96%) of the title compound as an oil. The'H NMR and MS data for this compound are in agreement with that of Preparation Fourteen, Method 1.
Preparation Fifteen 1 R-T4-(2R.6S-Dimethvl-oiperazin-1-vl~-ovrimidin-2-v(l-ethyl butyrate dibenzovl-L-tartrate salt.
pCT/IBOOI003'96 Step A: 1R~4-Benzvl-2R 6S-dimethvl-oioerazin-1-vl)-ovrimidin-2-vl1-ethyl butyrate bis dibenzov!-L-tartrate salt. To a solution of (R)-2-(1-~utyrytoxy-ethyl}-3H-pyrimidin-4-one (prepared according to the method of Preparation Fourteen, 254 8,1.25 mol) and triethylamine (176 mL, 1.3 mol) in dichloromethane (23 L) at 5 °C
was slowly added a solution of trifluoromethanesulfonic anhydride (211 mL, 1.25 mol) in dichloromethane (355 mL) over a period of 3 h. The reaction was then quenched by the addition of cold water (1.4 L) and the layers were separated. The organic taye~
was washed once with saturated aqueous sodium bicarbonate (1.5 L), once with saturated aqueous sodium chloride (1 L), and the solvent was removed under vacuum. The resulting oil was dissolved in dimethylacetamide (890 mL) and added slowly to a solution of as-1-benzy!-3,5-dimethyl-piperazine (735 g, 3.6 mol) in dimethytacetamide (1.3 L) at 80 °C over a 1 h period. Heating at 80 °C was continued for 3.5 h, at which time the reaction was judged complete by gas chromatography:
After cooling to room temperature, water (2.5 L) and isopropyl ether (25 L) were added, the layers were separated, and the organic layer was washed once with water (2 L). The isopropyl ether layer was then mixed well with a solution of CuSO, (126 g) in water (3 L) and filtered through a layer of Celite, washing the filter cake with isopropyl ether (1 L). The aqueous layer of the filtrate was drained off, and the remaining organic.tayer was washed with water (ZL) and treated with a solution of dibenzoyl-L-tartaric acid (619 g, 2.4 mol) in isopropyl ether (5:3 L). The resulting thick white slurry was stirred for 16 h and the solids were filtered off, washed with isopropyl ether (2 L), and vacuum dried at 50 °C to yield 854 g (71 %) of the title compound of Preparation Fifteen, Step A as a white solid.'H NMR (DMSO-ds, 400 MHz) 8 0.89 (t, 3H),1.23 (d, 3N), 1.25 (d, 3H), 1.48 (d, 3H), 1.54 (dd, 2H), 220 (dd, 2H), 2.31 (dt, 2H), 2T7 (d, 2H), 3.57 (s,1 H), 4.45 (m, 1 H), 4.24 (m, 1 H), 5.51 (q, 1 H), 6.60 (d, 1 H), 7.30 (m, 1 H), 7.39 (m, 4N), 7.64 (m, 7H), 7.77 (m, 4 H), 8.05 (c, 7H), 8.17 (d,1H).
Step B: 1 R-f4-f2R.6S-Dimethyl-pioerazin-1-vl)-ovrimidin-2-vll-ethyl butyrate ., dibenzoyl-L-tartrate salt. To a mixture of 1R-[4-(4-benzyl-2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate bis dibenzoyl-L-tartrate salt (prepared according to the method of Preparation Fifteen, Step A, 50 g, 0.045 mol) and 5% palladium on carbon (50% wet, 10 g, 20 wt%) in methanol (400 mL) under a nitrogen atmosphere was added cydohexene {4.6 mL, 0.045 mol). This mixture was heated to reflux for 6 h, at which time the reaction was judged complete by TLC. After cooling to 40 °C, the mixture was filtered through Celite and washed with methanol (100 mL). The methanol was gradually displaced with isopropanol by atmospheric pressure distillation until a constant boiling point of 80-82 °C was attained, and the resulting white slung was cooled to room temperature and stirred for 4 h. The solids were filtered off, washed with isopropanol (100 mL), and vacuum dried at 50 °C to yield 25.7 g (86%) of the title compound as a white solid. 'H NMR (DMSO-ds, 400 MHz) b 0.90 (t, 3H), 7.15 (d, 3H), 1.21 (d, 3H), 1.47 (d, 3H), 1.55 (q, 2H), 2.3 (m, 2H), 3.04 (m, 2H), 3.2 (m, 2 H), 4.4 (br s, 1 H), 4.6 (br s, 1 H), 5.5 (q, 1 H), 5.74 (s, 2H), 6.6 (d;1 H), 7.5 (t, 4 H), 7.6 (m, 2H), 8.0 (m, 4H), 8.2 (d, 1 H).
Claims (7)
1. A compound of the formula Z:
2. A compound of the formula ZZ:
wherein R100 is (C1-C8) alkyl, benzyl or phenyl, wherein the benzyl and phenyl are unsubstituted or substituted with up to three substituents each independently selected from the group consisting of halo and (C1-C4) alkyl .
wherein R100 is (C1-C8) alkyl, benzyl or phenyl, wherein the benzyl and phenyl are unsubstituted or substituted with up to three substituents each independently selected from the group consisting of halo and (C1-C4) alkyl .
3. A compound of the formula III:
wherein:
R100 is (C1-C8) alkyl, benzyl or phenyl, wherein the benzyl and phenyl are unsubstituted or substituted with up to three substituents each independently selected from the group consisting of halo and (C1-C4) alkyl; and R101 is hydrogen, benzyl CO2R90, where R90 is selected from (C1-C4) alkyl, (C1-C4) allyl, trichloroethyl and benzyl substituted with up to two (C1-C4)alkoxy.
wherein:
R100 is (C1-C8) alkyl, benzyl or phenyl, wherein the benzyl and phenyl are unsubstituted or substituted with up to three substituents each independently selected from the group consisting of halo and (C1-C4) alkyl; and R101 is hydrogen, benzyl CO2R90, where R90 is selected from (C1-C4) alkyl, (C1-C4) allyl, trichloroethyl and benzyl substituted with up to two (C1-C4)alkoxy.
4 . The compound of claim 3 wherein R100 is (C1-C4) alkyl and R101 is benzyl or tert-butyloxycarbonyl.
S. The compound of claim 3 or 4 wherein R100 is n-butyl or ethyl and R101 is benzyl.
6. The compound of claim 3 or 4 wherein R100 is n-butyl or ethyl and R101 is tert-butyloxycarbonyl.
7. A process for preparing a compound of the formula Z:
comprising:
a) reacting R-(+)-2-hydroxy-propionamide with triethyloxonium tetrafluoroborate in a reaction inert solvent for 10 minutes to 24 hours at 0°C to ambient temperature to form a corresponding imidate;
b) reacting the corresponding imidate with anhydrous ammonia in a reaction inert solvent for 2 hours to 24 hours at 0°C to ambient temperature to form R-(+)-2-hydroxy-propionamidine hydrochloride; and c) reacting the R-(+)-2-hydroxy-propionamidine hydrochloride with ethyl 3-hydroxy-acrylate sodium salt and a suitable base in a reaction inert solvent to form the compound of formula Z.
comprising:
a) reacting R-(+)-2-hydroxy-propionamide with triethyloxonium tetrafluoroborate in a reaction inert solvent for 10 minutes to 24 hours at 0°C to ambient temperature to form a corresponding imidate;
b) reacting the corresponding imidate with anhydrous ammonia in a reaction inert solvent for 2 hours to 24 hours at 0°C to ambient temperature to form R-(+)-2-hydroxy-propionamidine hydrochloride; and c) reacting the R-(+)-2-hydroxy-propionamidine hydrochloride with ethyl 3-hydroxy-acrylate sodium salt and a suitable base in a reaction inert solvent to form the compound of formula Z.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12743799P | 1999-04-01 | 1999-04-01 | |
| US60/127,437 | 1999-04-01 | ||
| CA002366858A CA2366858A1 (en) | 1999-04-01 | 2000-03-16 | Sorbitol dehydrogenase inhibitors |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002366858A Division CA2366858A1 (en) | 1999-04-01 | 2000-03-16 | Sorbitol dehydrogenase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2484282A1 true CA2484282A1 (en) | 2000-10-12 |
Family
ID=34137134
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002484282A Abandoned CA2484282A1 (en) | 1999-04-01 | 2000-03-16 | Pyrimidine derivatives intermediates for producing aminopyrimidines as sorbitol dehydrogenase inhibitors |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2484282A1 (en) |
-
2000
- 2000-03-16 CA CA002484282A patent/CA2484282A1/en not_active Abandoned
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