SE1451080A1 - Medivir AB, Box 1086, 141 22 Huddinge, SE - Google Patents
Medivir AB, Box 1086, 141 22 Huddinge, SE Download PDFInfo
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- SE1451080A1 SE1451080A1 SE1451080A SE1451080A SE1451080A1 SE 1451080 A1 SE1451080 A1 SE 1451080A1 SE 1451080 A SE1451080 A SE 1451080A SE 1451080 A SE1451080 A SE 1451080A SE 1451080 A1 SE1451080 A1 SE 1451080A1
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- another aspect
- heterocyclyl
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
- C07F9/165—Esters of thiophosphoric acids
Description
M337 prio-lb
Gemcitabine is an example of an anticancer nucleoside, which has been put into clinical trials
by Nucana as a phosphoramidate prodrug (WO2005/01237). Nucana also works with
phosphoramidate prodrugs of other anticancer nucleosides including clofarabine, fludarabin,
cladribine (WO2006/100439) and FUDR (WO2012117246). Nucana's phosphoramidate
prodrugs are typically a diastereomeric mixture at the phosphorous.
Subsequent generations of phosphoramidate prodrugs of an inhibitor of hepatitis C virus RNA-
dependent RNA polymerase, such as Sofosbuvir (WO2008/121634) are diasteromerically pure
at the phosphorous. Notably, the antiviral activity of phosphate prodrugs can markedly depend
upon the chirality of the phosphorous in the prodrug (Gardelli, J. Med. Chem. 2009, 52, 5394-
5407; Meppen, Abstracts of Papers, 236th ACS National Meeting, Philadelphia, PA, United
States, August 17-21, 2008 (2008), MEDI-404.).
Pharmasset, later bought by Gilead, have described chiral phosphoramidate reagents in
WO2010/135569, WO2011/123645 and WO2012/012465 useful in the preparation of
sofosbuvir.
ln view of the importance of anti-HCV therapeutics that are NMP prodrugs with chiral
phosphorous atoms such as sofosbuvir or those described by Gardelli, et al., Perrone et al., and
Meppen, et al., new efficient methods of producing chiral phosphates of these prodrugs are
needed.
WO2012/012465 discloses methods and intermediates for preparing diasteromerically pure
phosphoramidate prodrugs of nucleosides that are useful for the treatment of hepatitis C
infection. The phosphorylating reagent disclosed therein is a phosphoramidate having an
aryloxy or heteroaryloxy group, O-Ar, attached to the phosphorus atom as leaving group, i.e. a
compound of formula Aa or Ab:
R4o,
a, O
O RS O RÖ 'lp/
I O \ l \ _
RÖ N 6 N O Af
\ 111,, R
O 2 I'P\ .
1 O-Af
Rd R° oR4 Rd 'R°
F°rmu|a A3 Formula Ab
wherein Ar is a (C6-C20)ary| or heteroaryl Which is substituted with one or more halogen, N02, or
(C1-C8)ha|oa|ky|, and Ar is different from R4.
SUMMARY OF THE INVENTION
Provided are methods for preparing prodrugs of nucleoside triphosphate inhibitors of cancer, or
of viral infection, such as inhibitors of hepatitis C virus RNA-dependent RNA polymerase.
M337 prio-lb
The compounds are prodrugs of nucleoside monophosphates that, when administered to
animals, are intracellularly converted to nucleoside triphosphates. The chirality of the
phosphorous atom determines the efficiency of the conversion to the nucleoside triphosphate in
the animal. The method disclosed provides a convergent synthesis of these single
diastereomeric prodrugs which is an improvement over the previously disclosed
chromatographic methods of separating a single diastereomer from a mixture of diastereomers.
ln one embodiment, a method for preparing a compound of Formula la or lb is provided:
O Tf) O O
R6\O N//l/,h R4O/III1,_
a, \ \
f? I O o Base 5 l O o Base
Rd R° oR4 R \N
R24 RV 0 R24 RV
R23 R1 :WII/IRC R23 R1
e_
Rzz Rz R o Rd Rzz Rz
Formwa 'a Formula lb
or a pharmaceutically acceptable salt or acid thereof;
wherein:
each R1, Rz, R7, R22, Rzs or R24 is independently H, OR11, NR11R12,
c(o)NR“R12, -oc(o)NR“R12, c(o)oR“, oc(o)oR“, s(o),Ra, s(o)2NR“R12, M3, cN,
halogen, (C1-C8)alkyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl
or ary|(C1-C8)alky|;
or any tvvo R1, Rz, R7, R22, R” or R24 on adjacent carbon atoms when taken together are -
O(CO)O- or -O(CR11R12)O- or when taken together with the ring carbon atoms to which they are
attached form a double bond;
each Base is independently a naturally occurring or modified purine or pyrimidine base linked to
the furanose ring through a carbon or nitrogen atom;
each n is independently 0, 1, or 2;
each Ra, R4 or RB is independently (C1-Cß)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-
C8)carbocyclyl, (C4-C8)carbocyclylalky|, aryl(C1-C8)alky|, heterocyclyl(C1-C8)alky|, (C6-C20)aryl,
heterocyclyl or heteroaryl;
each R° or Rd is independently H, (C1-C8)a|kyl, (C2-C8)alkenyl, (C2-C8)alkyny|, (C3-
Cß)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl,
heterocyclyl or heteroaryl provided that R° and Rd are not the same;
M337 prio-lb
each Rs is independently H, (C1-C8)a|ky|, (C2-C8)a|keny|, (C2-C8)a|kyny|, (C3-C8)carbocyc|yl, (C4-
C8)carbocyclyla|kyl, ary|(C1-C8)alky|, heterocyc|y|(C1-C8)alky|, (Ca-C20)aryl, heterocyclyl or
heteroaryl;
eaeh R” er R” ie independen?y H, (c1-c8)a|ky|, (cz-coaikenyi, (cz-cnaikynyi, (ca,-
C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl,
hetereeyeiyi, heterearyi, -c(=o)(c,-c8)a|ky|, -s(o),(c,-c8)a|ky| er R” and R” raken together
with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring
wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O-, -
S(O),,- or -NRa-; and
wherein each (C1-C8)a|ky|, (C2-C8)a|keny|, (C2-C8)a|kyny|, (C3-C8)carbocyc|y|, (C4-
Cg)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (Ce-C20)aryl, heterocyclyl or
heterearyi ef eaeh R°, Rd, Rt, R2, R22, R23, R24, R4, RS, RB, RV, R” er R” ie, independen?y,
optionally substituted with one or more halo, hydroxy, CN, Ng, N(Ra)2, NH(Ra), NH2, N02,
C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(Ra)2, OC(O)NH(Ra), OC(O)NH2, C(O)ORa,
OC(O)ORa, C(O)Ra, OC(O)Ra, S(O),,Ra S(O)2N(Ra)2, S(O)2NH(Ra), S(O)2NH2, ORE' or Ra:
said method comprising :
(a) providing a compound of Formula ll
HO B
R22 R2
Formula ll
and
(b) treating the compound of Formula ll with a compound of Formula Illa and a base
Formula Illa
thereby forming a compound of Formula la or
(c) treating the compound of Formula ll with a compound of Formula lllb and a base
M337 prio-lb
Formula lllb
thereby forming a compound of Formula lb;
wherein:
each Ar is (C6-C20)ary| or a 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is
substituted with one or more halogen, N02, or (C1-Cß)haloalkyl and optionally substituted with
one or more CN, NS, N(Ra)2, C(O)N(Ra)2, OC(O)N(Ra)2, C(O)OR'“, OC(O)ORa, C(O)Ra,
OC(O)R'°“, S(O),.Ra, S(O)2N(Ra)2, ORa or Ra with the proviso that Ar is different from R4.
ln another aspect, the invention provides novel intermediates disclosed herein which are useful
for preparing compunds of Formula la or Formula lb.
ln other aspects, methods for the synthesis, analysis, separation, isolation, purification, and
characterization of the novel intermediates of this invention are provided.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
Reference will now be made in detail to certain embodiments of the invention, examples of
which are illustrated in the accompanying description, structures and formulas. While the
invention will be described in conjunction with the enumerated embodiments, it will be
understood that they are not intended to limit the invention to those embodiments. On the
contrary, the invention is intended to cover all alternatives, modifications, and equivalents,
which may be included within the scope of the present invention.
Typically, the method of for preparing a compound of Formula la from a compound of Formula ll
and a compound of Formula Illa, or preparing a compound of Formula lb from compound of
Formula ll and a compound of Formula lllb is performed in a suitable solvent. The suitable
solvent is preferably an anhydrous, non- acid, non-hydroxylic solvent. Non-limiting examples of
suitable solvents are ethers, for example, diethyl ether, diisopropyl ether, di i-butyl ether,
tetrahydrofuran, dioxane and various glyme solvents; dimethylformamide or dimethylacetamide.
A preferred solvent is tetrahydrofuran. The concentration of Formula ll in the solvent is typically
about 0.01 to about 1 mole per liter of solvent. The method is performed at a temperature of
about -20 °C to about 90 °C, more preferably about -10 °C to about 60 °C.
The solution of Formula ll is typically treated with a hindered base or a non-nucleophilic base.
Typical, but non-limiting, examples of hindered bases are t-butyllithium, sec-isobutyllithium,
lithium or sodium diisopropylamide and t-butylmagnesium halides. A preferred hindered base is
i-butylmagnesium chloride. Afurther preferred base is t-butylmagnesium chloride. Typical, but
non-limiting, examples of non-nucleophilic bases are sodium hydride, potassium hydride, lithium
5
M337 prio-lb
hydride and calcium hydride. The hindered bases or non-nucleophic bases may be used as
solutions in or as undiluted bases. Preferably, the bases are used as solutions in anhydrous,
non-hydroxylic solvents wherein the concentration of the base in the solvent is about 0.5 to
about 3 moles per liter. The molar ratio of base to the compound of Formula ll will depend on
the Base attached to the furanose ring. The ratio is about 1:1 to about 3:1, preferably about
1.111 to about 2.1:1. The solution of the compound of Formula ll is typically treated with the
base for about 5 minutes to about two hours, preferably less than 30 minutes.
The mixture of the solution of the compound of Formula ll and the base is treated with a
compound of Formula Illa or Formula llllb for about 30 minutes to about 24 hours, preferably
about one to about four hours. The molar ratio of the compound of Formula ll to the compound
of Formula Illa or Formula lllb is typically about 1:1 to about 1:4. Preferably, the molar ratio is
about 121.1 to about 1:2.
ln another embodiment of the method for preparing a compound of Formula la or lb or a
pharmaceutically salt or ester thereof, Formula la is Formula lVa, Formula lb is Formula lVb and
Formula ll is Formula V:
o RS
Re lll l? R4o I?
\ /ln,_ /ll/u,
O '-, P\ P\
a, 1 O O Base 5 I O O Base
Rd R° 4 R\
OR N
R24iw' 'HHIR7 O R24u?' 'HHIR7
R23 _ _ R1 > 1m0//Rc R23 : _ R1
=
Rzz ääz Rs-O Rd Rïsz äz
Formu|a |Va Formula lVb
HO O Base
R24w" "HHR7
Ršz 22
Formula V
ln one embodiment of the method for preparing a compound of Formula lVa or lVb from a
compound of Formula V, R1 is H, halogen, optionally substituted (C1-C8)alkyl, optionally
substituted (C2-C8)alkenyl or optionally substituted (C2-C8)alkyny|. ln another aspect of this
embodiment, R1 is H. ln another aspect of this embodiment, R1 is optionally substituted (C1-
C6)alkyl. ln another aspect of this embodiment, R1 is methyl. ln another aspect of this
embodiment, R1 is optionally substituted (C2-C8)alkeny|. ln another aspect of this embodiment,
R1 is optionally substituted (C2-CB)alkynyl. ln another aspect of this embodiment, R1 is F. ln
another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkynyl. ln another aspect
of this embodiment, R1 is Cl. ln another aspect of this embodiment, Rz is F. ln another aspect of
this embodiment, Rz is OR". ln another aspect of this embodiment, Rz is Cl. ln another aspect
6
M337 prio-lb
of this embodiment, R22 is OH. ln another aspect of this embodiment, R7 is H. ln another aspect
of this embodiment, R? is optionally substituted (C1-C8)a|ky|. ln another aspect of this
embodiment, R7 is optionally substituted (C2-Cß)a|kyny|. ln another aspect of this embodiment,
R? is CN. ln another aspect of this embodiment, R5 is H. ln another aspect of this embodiment,
one of R° or Rd is H. ln another aspect of this embodiment, one of R°or Rd is H and the other of
R° or Rd is optionally substituted (C1-Cg)a|ky|. ln another aspect of this embodiment, Re is
optionally substituted (C1-C8)alky| or optionally substituted (C3-C8)carbocyclyl. ln another aspect
of this embodiment, R4 is optionally substituted (C6-C2o)ary|. ln another aspect of this
embodiment, Ar is optionally substituted phenyl. ln another aspect of this embodiment, R23 is H.
ln another aspect of this embodiment, R22 is OR11. ln another aspect of this embodiment, R22 is
OH. ln another aspect of this embodiment, R24 is Ng. ln another aspect of this embodiment, R24
is H. ln another aspect of this embodiment, Base is selected from the group consisting of:
R* R*
. Ra
/xyxx \ »saw Åzw/ÅQQN lxïlï\,/§,?¿ 'Xílï N
i .xt z X? /i xf, _:
t /,.\ /x \_- i / g . ' _\ f ._-_
\_N//\\ RQ ï/z~\N,/f\R° RQ f\\N.7 \R9
.Nå-vw .Arf-v-.w -rwæcvx
x ÅQN N/šfw xf/ïfN
\ (///j\\ Q škb\ /Lå
N o R o
.xmiwuxv »r 'vx afKl fv~ vv :
wherein:
each X1 is independently N or CRm;
each X2 is independently NR11, O, or S(O),,;
each RB is independently halogen, NRiiRiä N(R“)oR”, NRiiNRiiRiå M3, No, N02, cHo, cN,
-cH(=NR“), -cH=NNHR“, -cH=N(oR“), -cH(oR“)2, -c(=o)NR“R12, -c(=s)NR“R12, -
C(O)OR11, (C1-C8)a|kyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)carbocyclyla|kyl, (C6-C20)ary|,
heterocyclyl, heteroaryl, -C(=O)(C1-C8)a|ky|, -S(O),,(C1-C8)alky|, aryl(C1-C8)a|kyl, OR11 or SR11;
each n is independently 0, 1, or 2;
each Rg or R1° is independently H, halogen, NR11R12, N(R11)OR11,
NR11NR11R12, Ng, NO, N02, CHO, CN, -CH(=NR“), -CH=NHNR", -CH=N(OR“), -CH(OR“)2, -
C(=O)NR11R12, -C(=S)NR11R12, -C(=O)OR", R11, OR” or SR11; each R11 or R12 is independently
H, (C1-C8)a|kyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocycly|, (C4-C8)carbocyc|ylalky|,
ary|(C1-C8)alky|, heterocyc|yl(C1-C8)a|kyl, (C6-C20)aryl, heterocyclyl, heteroaryl, -C(=O)(C1-
Cß)a|ky|, -S(O),,(C1-Cß)alkyl or R11 and R12 taken together with a nitrogen to which they are both
attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said
heterocyclic ring can optionally be replaced with -O-, -S(O),,- or -NRa-;
7
M337 prio-lb
wherein each (C1-C8)a|ky|, (C2-C8)a|keny|, (C2-C8)a|kyny|, (Cg-Cgcarbocyclyl, (C4-
C8)carbocyc|y|a|ky|, ary|(C1-C8)a|ky|, heterocyc|y|(C1-Cg)a|ky|, (C6-C20)ary|, heterocyclyl or
heteroary| of each R°, Rd, R1, R2, R22, R23, R24, R4, Rs, RB, RV, Rß, RQ, R1°, R“ or R” is,
independently, optionally substituted with one or more halo, hydroxy, CN, Na, N(Ra)¿NH(Ra),
NH2, N02, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(Ra)2, OC(O)NH(Ra), OC(O)NH2,
C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)Ra, S(O),.Ra, S(O)2N(Ra)2, S(O)2NH(Ra), S(O)2NH2, ORa or
Ra.
ln another aspect of this embodiment, Base is selected from the group consisting of:
NR» o NHZ tåg H NH;
ß / “tt ff' “NH <>f5° "tf/fw (fïf/“N ”M F/*w
\ I , *g A M -\ i \ .i * ' t
ïšlik\ N/l/ Nf/ \\ /ff \ fï-f'^\\ N/j/f \\ N f/í \ \ Né/
Na» NH: NH: MH, H RH,
_ / \ S\\ ///'\ \ \ \ //í.\\
<0* “f íli “f f* W VÄ? N/Nïí Ü*
\ i \ t 1 \\ _ s
\ \ /ß ~ \ 44” \~ f/K // M/N /2 \ f ff,
ä» z N \ f \ /' f
š f N ï N
NH: N?z
A i
I t t
, ,= \.\ g
\_N4» ï/rgNf/t
- :
m”. am; RÅuM
ln another aspect of this embodiment, Base is selected from the group consisting of
NH; O
/iqç N F /LÅNH H3C\ ÅK NH F -Nš /CONHQ
Ü\\ ,,.- \\ \Ü\ /l\\\ ?\ fk ¶ l\\
:ïr \o \o *o *o
t? v f? NH?
raïízkwH {-æ&c\_\{=_,.ßl-\NH s=\u/N\\¿co:\:h~2 HñY/RNH HN/lšèN
fis, »ts å, /šs is Ås, k Ås
f? ~o f? ~o \-o ~f o “f <9
mmm WW *Mmm N w (md m,
M337 prio-lb
ln another embodiment of the method for preparing a compound of Formula IVa or IVb from a
compound of Formula V, R1 is H, halogen, optionally substituted (C1-C8)alky|, optionally
substituted (C2-Cß)alkenyl or optionally substituted (C2-C8)alkynyl; R2 is OR" or halogen; R22 is
OR” and each RS, R” and R24 is H. ln another aspect of this embodiment, R1 is H. ln another
aspect of this embodiment, R1 is optionally substituted (C1-C8)alky|. ln another aspect of this
embodiment, R1 is methyl. ln another aspect of this embodiment, R1 is optionally substituted
(C2-C8)alkenyl. ln another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkynyl.
ln another aspect of this embodiment, R1 is F. ln another aspect of this embodiment, R1 is Cl. ln
another aspect of this embodiment, R2 is F. ln another aspect of this embodiment, R2 is OH. ln
another aspect of this embodiment, Rz is Cl. ln another aspect of this embodiment, R” is OH. ln
another aspect of this embodiment, each R2 and R” is OH. ln another aspect of this
embodiment, R7 is H. ln another aspect of this embodiment, R7 is optionally substituted (C1-
C8)alkyl. ln another aspect of this embodiment, R7 is optionally substituted (C2-C8)alkynyl. ln
another aspect of this embodiment, R7 is CN. ln another aspect of this embodiment, one of R°
or Rd is H. ln another aspect of this embodiment, one of R° or Rd is H and the other of R° or Rd
is optionally substituted (C1-C8)alkyl. ln another aspect of this embodiment, Re is optionally
substituted (C1-C8)alkyl. ln another aspect of this embodiment, Re is (C3-C8)carbocyclyl. ln
another aspect of this embodiment, R4is optionally substituted (C6-C20)ary|. ln another aspect of
this embodiment, Ar is optionally substituted phenyl. ln another aspect of this embodiment,
Base is selected from the group consisting of:
H3 RB RS
/Å í/ V; N x/ yñ//ÄX :X ~ 1 \\\ !Xë\ç_r/
\ i X* i: . > ?
N "A\ NJNRQ ïß\ N"””\ R° I? k ”f” RQ \ ”k ÖNRQ
R( RS Rš
'11 »Q Sif/itä N
ii , i i “L
\ N /šo \ ” AW* kxël/Äššc
V\.;L.~,,\. W» amg Ash-v..
wherein:
each X1 is independently N or CR1°;
each X2 is independently NR", O, or S(O),,;
each RB is independently halogen, NR11R12, N(R“)OR", NR11NR11R12, Ng, NO, N02, CHO, CN, -
cH(=NR“),-cH=NNHR“, -cH=N(oR“),-cH(oR“)2,-c(=o)NR“R12,-c(=s)NR“R12, -
c(o)oR“, (cvcgaikyi, (cz-clgaikenyi, (cz-cgaikynyi, (cfcgcarbocyciyiaikyi, (cß-czmaryi,
heterocyclyl, heteroaryl, -C(=O)(C1-C8)alky|, -S(O),,(C1-C8)alky|, aryl(C1-C8)a|kyl, OR” or SR11;
each n is independently 0, 1, or 2;
M337 prio-lb
each RQ or R1° is independently H, halogen, NR11R12, N(R“)OR11,
NR11NR11R12, M3, No, N02, cHo, cN, -CH(=NR“), -CH=NHNR", -cH=N(oR“), -cH(oR“)2, -
C(=O)NR"R12, -C(=S)NR11R12, -C(=O)OR11, R11, OR” or SR11; each R" or R” is independently
H, (C1-C8)alky|, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocycly|alkyl,
aryl(C1-C8)alkyl, heterocyc|yl(C1-C8)a|kyl, (C6-C20)aryl, heterocyclyl, heteroaryl, -C(=O)(C1-
C8)alkyl, -S(O)n(C1-C8)alkyl or R" and R” taken together With a nitrogen to which they are both
attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said
heterocyclic ring can optionally be replaced with -O-, -S(O),,- or -NRa-;
wherein each (C1-C8)alky|, (C2-C8)alkeny|, (C2-C8)alkyny|, (C3-C8)carbocyc|y|, (C4-
Cß)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (Cß-C20)aryl, heterocyclyl or
heteroaryl of each R°, Rd, R1, R2, R22, R23, R24, R4, RS, RB, R7, RB, RQ, RW, R11 or R” is,
independently, optionally substituted with one or more halo, hydroxy, CN, NG, N(Ra)2,NH(Ra),
NH2, N02, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(Ra)2, OC(O)NH(Ra), OC(O)NH2,
C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)Ra, S(O),.Ra, S(O)2N(Ra)2, S(O)2NH(R“"'), S(O)2NH2, ORa or
Ra.
ln another aspect of this embodiment, Base is selected from the consisting of:
Nr» o NH: NH; NH.
N\ /g\¿ ~ //U\\ N ”'í\\\ ~ /$\ ä: /í-N 2
f., *N f, jr 'NH “f m \ N f f “N
\N/^\\ ff? N./”'\*\ f, \_ N \\ .í?l \ A*N.--*'\\ -íßš \\
ä N NHQ š N NHQ N i N
i i
Na, NM, m, H MHz
O, \\ S~N ,//\\\. _.~\_ /i\\ \ ,/ \\ N., /?\
f * W / f t* /~~== w: _/*~<~ï \N f n *N
<<.\ /Lå f; \§\__, i /Éj S\\¿_~:Z=\ :J §\\'\ N /§ N\ f! /çš
i' N” š N” W i” w N”
z
NHz ïYHz
i z
Pšïšw/ N IN'.~ I* \ \ N
HN i (_
\;;“l\ _44 N,\V___.N__\ /Å
. ä
.lvl/W ançš vmånm
ln another aspect of this embodiment, Base is selected from the group
ä l i: g
\\\ N f-/QQO \ N //<\\\\O \\ ~\ /Å-QO
\ v .
\ . .
vvvxfvwv uvxzuvvx .A.v\.«\;~.::r\.- Mnm-.m
10
M337 prio-lb
r L; r
r /K r-rc. .,=ï\ F M .Conn /k L
v; nn ^° *rf Na *yf *w :in :än HN-f ïsN
i z z = i
's \ 1 ** ß x \ R \
\§ A1 QO \N f QQO \\&, \\_:O xx: Allw., vèv, -QO
i l i f
.Rn/.Mfa 3 .Am-»vvo 3 .luv/avs 5 suv”- and gav/_
ln another embodiment of the method for preparing a compound of Formula IVa or lVb from a
compound of Formula V, R1 is H, halogen or CH3; R2 is OR" or halogen; RB is optionally
substituted (C1-C8)alky| or (C3-C8)carbocyc|y|; one of R° and Rd is H and the other one is
optionally substituted (C1-C8)alkyl; R” is OR", and each R5, R23 and R24 is H. ln another aspect
of this embodiment, R1 is H. ln another aspect of this embodiment, R1 is Cl. ln another aspect of
this embodiment, R1 is CH3. ln another aspect of this embodiment, R2 is F. ln another aspect of
this embodiment, R2 is OH. ln another aspect of this embodiment, R2 is Cl. ln another aspect of
this embodiment, R” is OH. ln another aspect of this embodiment, each Rz and R22 is OH. ln
another aspect of this embodiment, R7 is H. ln another aspect of this embodiment, R7 is CH3. ln
another aspect of this embodiment, R7 is ethynyl. ln another aspect of this embodiment, R7 is
CN. ln another aspect of this embodiment, R4 is optionally substituted (C6-C20)ary|. ln another
aspect of embodiment, R4 is optionally substituted phenyl. ln another aspect of this
embodiment, R4 is optionally substituted napthyl. ln another aspect of this embodiment, Ar is
optionally substituted phenyl. ln another aspect of this embodiment, Base is selected from the
group consisting of:
ii S
F53 i? få
J. i i
ß/*XN sif/š? xß zšw
s å i
\\ /'"'\\\\O \\í///\\..Rg '\\\ //'\\\O
wherein: each X1 is independently N or CR1°;
each X2 is independently NR", O, or S(O),.;
11
M337 prio-lb
each RB is independently halogen, NR11R“2, N(R“)oR", NR11NR“R12, M3, No, N02, ci-io, CN,
-CH(=NR“), -ci-|=NNHR“, -cH=N(oR“), -cH(oR“)2, -c(=o)NR“R12, -c(=s)NR“R12, -
C(O)OR11, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)carbocyclylalkyl, (C6-C20)aryl,
heterocyclyl, heteroaryl, -C(=O)(C1-C8)a|ky|, -S(O),,(C1-C8)a|ky|, ary|(C1-C8)a|ky|, OR” or SR11;
each n is independently 0, 1, or 2;
each RQ or R1° is independently H, halogen, NR11R12, N(R11)OR11,
NR11NR11R12, M3, No, N02, ci-io, CN, -ci-|(=NR“), -c|-|=NHNR“, -cH=N(oR“), -c|-|(oR“)2, -
C(=O)NR11R12, -C(=S)NR11R12, -C(=O)OR11, R11, OR” or SR11; each R11 or R” is independently
H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl,
ary|(C1-C8)a|ky|, heterocyc|yl(C1-C8)a|kyl, (C6-C20)ary|, heterocyclyl, heteroaryl, -C(=O)(C1-
Cg)alkyl, -S(O),,(C1-Cß)alkyl or R11 and R” taken together with a nitrogen to which they are both
attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said
heterocyclic ring can optionally be replaced with -O-, -S(O),,- or -NRa-;
wherein each (C1-C8)a|ky|, (C2-C8)a|keny|, (C2-C8)a|kyny|, (C3-C8)carbocyc|y|, (C4-
C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyc|y|(C1-Cg)alkyl, (C6-C20)aryl, heterocyclyl or
heteroaryi of each R°, Rd, Rl, R2, R22, R23, R24, R4, RS, Re, RV, Ra, RQ, R“°, R“ or R12is,
independently, optionally substituted with one or more halo, hydroxy, CN, NG, N(Ra)¿NH(Ra),
NH2, N02, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(Ra)2, OC(O)NH(R'°'), OC(O)NH2,
C(O)OR'““, OC(O)ORE, C(O)Ra, OC(O)R'““, S(O),,Ra, S(O)2N(Ra)2, S(O)2NH(Ra), S(O)2NH2, ORa or
Ra.
ln another aspect of this embodiment, Base is selected from the group consisting of:
JTH; O NH; NHZ H RH;
NM' ..- _,\ N \ ff \ i ,f,\\\ _,_\\ ,/\\ \ f
.f/ ät? f/ x g NH \ N (ff “j N (N \ = \ N
' ' i \ i ; _' 5 = f * ' i
\ “Il-k ß' Å; /'«"'L\ \ ,-“"¿\. fi* \ li f) \\ ix IÖ”
i? N N N' NR N *av *NHE N N i N'
-Aršzvw wvm. iv* -\,\.\/\.^ 14A»
NH, Nta NRQ NHE NH?
O /jfx S~\ .f -fšš\ \ / \\__ ä
/ vi? (f \ ë x /pšxff/ VN ¿/“\:¿'f \~ N / i \ N
\ il = '§\ _ i f? 3 ,,: i \“.\_ f* N\\ i .j
:ff \. f' \\ / \\,_'É.Û/"\_ _45' \ /N\_ f? f* \ f?
tN N .N/ Y N, 1 .Nf
VN! RÅÅ! '\fš\fv JKñš-N?. JJÉVW Jqgß
NW NW:
HW \ ä* /jšalf /NQ ”j/Lš* N
. i
fl\ /f/'J Q/ N \ /í-J
N
ln another aspect of this embodiment, Base is selected from the group
12
M337 prio-lb
NHz O
i ii L
(f/ïš F-\ f” \\ f» \ F\\I_f N å flcoNHtr
ts ut tt tm
N \O i? \O *O N O
i i i W
i=\'É_/=\_,$H ii c\â_š,.« WH av» \ ?oNiv WS »ÄN HN/'sšN
iW/'QQO Em Aïëø \ N/QQO :i-šèí/JQQO Lïë /Atšço
MÄN _ V; m
ln another embodiment of the method for preparing a compound of Formula IVa or IVb from a
compound of Formula V, R1 is H, Cl or CH3; R2 is OR" or halogen; RB is optionally substituted
(C1-C8)a|ky|; one of R° or Rd is H and the other of R° or Rd is optionally substituted (C1-C8)a|ky|;
R” is OR11, each R5, R” and R24 is H and Base is selected from the group consisting of:
šfï RES 3333
' /å-\ 's 3 » _ 1
'\¿t;¥ xáx?ääïíyfššN XCII-(gèšf/ 433%: XšX-tï/f QQN
V\ 15 5 \ i? M _ ' \ :_
' _,.-f'-\> _/'^\ _ \\ XJ' z/y \. _:__«;_, \\(__,§~;_ _,_//':\
\N./ \~\ Nf/ \\ Rs ^\. \ \N/~ \R§
.saw _ ' NM
Rß Re' RS
, ȧ fix ./'>\
X' ”ff N. \ N X2 \ N
5 E , S i _ i
\N"“°= §\\'í”/\;>ß *sr/“ïfri
mia/x» »xx-v a :x fvvvvv
wherein:
each X1 is independently N or CR1°;
each X2 is independently NR", O, or S(O)n;
each RS is independen?y haiogen, NR11R12, N(R“)oR“, NR“NR“R”, M3, No, N02, cHo, CN, -
CH(=NR“), -CH=NNHR“, -cH=N(oR“), -oH(oR“)2, -c(=o)NR“R“2, -c(=s)NR“R12, -
C(O)OR“, (C1-C8)a|ky|, (C2-C8)a|keny|, (C2-C8)a|kyny|, (C4-C8)carbocyc|y|a|ky|, (C6-C20)ary|,
heterocyclyl, heteroaryl, -C(=O)(C1-C8)a|ky|, -S(O),.(C1-C8)a|ky|, ary|(C1-C8)a|ky|, OR11 or SR11;
each n is independently 0, 1, or 2;
each RQ or R1° is independently H, halogen, NR11R12, N(R“)OR“,
NR11NR“R12, M3, No, N02, cHo, CN, -CH(=NR“), -CH=NHNR“, -cH=N(oR“), -cH(oR“)2, -
C(=O)NR"R12, -C(=S)NR11R12, -C(=O)OR11, R11, OR” or SR11; each RM or R” is independently
13
M337 prio-lb
H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl,
aryl(C1-C8)alkyl, heterocyclyl(C1-C8)a|kyl, (C6-C20)ary|, heterocyclyl, heteroaryl, -C(=O)(C1-
Cß)alkyl, -S(O)n(C1-Cß)alkyl or R" and R12 taken together with a nitrogen to which they are both
attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said
heterocyclic ring can optionally be replaced with -O-, -S(O),,- or -NRa-;
wherein each (C1-C8)alky|, (C2-C8)alkeny|, (C2-C8)alkyny|, (C3-C8)carbocycly|, (C4-
Cß)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or
heteroaryi of each R°, Rd, Rt, R2, R22, R23, R24, R4, RS, RB, RV, RB, RQ, R“°, R” or R” is,
independently, optionally substituted With one or more halo, hydroxy, CN, Ng, N(Ra)¿NH(Ra),
NH2, N02, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(Ra)2, OC(O)NH(Ra), OC(O)NH2,
C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)R"°', S(O),,Ra, S(O)2N(Ra)2, S(O)2NH(Ra), S(O)2NH2, ORa or
Ra.
ln another aspect of this embodiment, R1 is H. ln another aspect of this embodiment, R1 is CH3.
ln another aspect of this embodiment, R1 is Cl. ln another aspect of this embodiment, R2 is F. ln
another aspect of this embodiment, Rz is OH. ln another aspect of this embodiment, R2 is Cl. ln
another aspect of this embodiment, R1 is F and R2 is Cl. ln another aspect of this embodiment,
R1 is CH3 and Rz is Cl. ln another aspect of this embodiment, R1 R2 are both Cl. ln another
aspect of this embodiment, R” is OH. ln another aspect of this embodiment, each RZ and R” is
OH. ln another aspect of this embodiment, R7 is H. ln another aspect of this embodiment, R7 is
CH3. ln another aspect of this embodiment, R7 is ethynyl. ln another aspect of this embodiment,
R? is CN. ln another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryl. ln
another aspect of embodiment, R4 is optionally substituted phenyl. ln another aspect of this
embodiment, R4 is optionally substituted napthyl. ln another aspect of this embodiment, one of
R° or Rd is H and the other of R° or Rd is CH3. ln another aspect of this embodiment, Ar is
optionally substituted
phenyl. ln another aspect of this embodiment, Ar is phenyl which is substituted with 1 to 5
halogen atoms. ln another aspect of this embodiment, Ar is halo pentafluorophenyl. ln another
aspect of this embodiment, Ar is 3,5-dichlorophenyl. ln another aspect of this embodiment,
Base is adenine.
ln another aspect of this embodiment, Base is guanine.
ln another aspect of this embodiment, Base is 2,6 diaminopurine.
ln another aspect of this embodiment, Base is 7-deazaadenine.
NHZ
\
Nf)
ln another aspect of this embodiment, Base is ~>~
14
M337 prio-lb
NH2
S \N
\ | /J
ln another aspect of this embodiment, Base is ”f” N
NH2
\ \N
S/ /J
N
ln another aspect of this embodiment, Base is ~>~
NH2
\\N
\ N_NJ
ln another aspect of this embodiment, Base is ”v”
ln another aspect of this embodiment, Base is ~>~
ln another aspect of this embodiment, Base is "v"
ln another aspect of this embodiment, Base is cytosine.
ln another aspect of this embodiment, Base is 5-fluorouracil.
ln another aspect of this embodiment, Base is thymine.
coNH2
O
ln another aspect of this embodiment, Base is -~
O
| NH
NÅO
ln another aspect of this embodiment, Base is ~|w
15
M337 prio-lb
Åk
HN NH
ufto
ln another aspect of this embodiment, Base is ~w .
NHZ
A
HN \N
\ o
ln another aspect of this embodiment, Base is -~
ln another embodiment of the method for preparing a compound of Formula la or lb or a
pharmaceutically acceptable salt or ester thereof, Formula la is Formula Vla, Formula lb is
Formula Vlb and Formula ll is Formula Vll:
Rs RB
o F25
RS ill I? \N O \N
\O I' ”~«-P\ | Å Rfo//mhg/ | Ä
Rd äR° OIRL: O o N O Rs\Ä\O o N O
|-|\\\\"' "'IIIR7 O N Hlnnu ”fu/R7
H = _ Rl Hemy/RC H _ Rl
R2\2 §2 R6_O Rd RÉ ÉQ
Formula Vla Formula Vlb
RB
\N
I NÅO
HO O
Hmm" ”IIUR7
H i . Ri
R
Formula Vll
ß Ill:
“nu
12)
wherein each Rl is independently H, halogen, optionally substituted (C1-C8)alky|, optionally
substituted (C2-C8)alkenyl or optionally substituted (C2-C8)alkynyl;
each Rz is independently halogen or OR" ;
each Rs is H;
each R” is OR" and
the remaining variables are defined as for Formulae la or lb or ll or Illa or lllb.
ln one embodiment of the method for preparing a compound of Formula Vla or Formula Vlb
from a compound of Formula Vll, X1 is CR”. ln another aspect of this embodiment, R1° is H. ln
another aspect of this embodiment, R1 is H. ln another aspect of this embodiment, R1 is F. ln
16
M337 prio-lb
another aspect of this embodiment, Rl is Cl. ln another aspect of this embodiment, Rl is
optionally substituted (C1-C8)a|ky|. ln another aspect of this embodiment, R1 is methyl. ln
another aspect of this embodiment, R1 is optionally substituted (C2-C8)a|keny|. ln another aspect
of this embodiment, Rl is optionally substituted ethenyl. ln another aspect of this embodiment,
R1 is optionally substituted(C2-C8)alkyny|. ln another aspect of this embodiment, R1 is optionally
substituted ethynyl. ln another aspect of this embodiment, R2 is F. ln another aspect of this
embodiment, R2 is Cl. ln another aspect of this embodiment, R2 is OH. ln another aspect of this
embodiment R” is OH. ln another aspect of this embodiment, each R2 and R” is OH. ln
another aspect of this embodiment, R7 is H. ln another aspect of this embodiment, R7 is
optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R? is optionally
substituted (C2-Cß)a|kynyl. ln another aspect of this embodiment, R7 is CN. ln another aspect of
this embodiment, one of R° or Rd is H. ln another aspect of this embodiment, one of R°or Rd is
H and the other of R° or Rd is optionally substituted (C1-C8)a|kyl. ln another aspect of this
embodiment, RS is optionally substituted (C1-C8)alkyl. ln another aspect of this embodiment, RB
is (C3-C8)carbocyc|y|. ln another aspect of this embodiment, R4 is optionally substituted (C6-
C2o)'ary|. ln another aspect of this embodiment, Ar is optionally substituted phenyl.
ln another embodiment of the method for preparing a compound of Formula Vla or Formula Vlb
from a compound of Formula Vll, X1 is CH, R1 is H, Cl or CH3 and one of R° or Rd is H. ln
another aspect of this embodiment, R2 is F. ln another aspect of this embodiment, R2 is Cl. ln
another aspect of this embodiment, R2 is OH. ln another aspect of this embodiment R” is OH.
ln another aspect of this embodiment, each R2 and R” is OH. ln another aspect of this
embodiment, R7 is H. ln another aspect of this embodiment, R7 is optionally substituted (C1-
C8)a|ky|. ln another aspect of this embodiment, R7 is CH3. ln another aspect of this embodiment,
R? is optionally substituted (C2-C8)a|kynyl. ln another aspect of this embodiment, R7 is ethynyl.
ln another aspect of this embodiment, R? is CN. ln another aspect of this embodiment, one of R°
or Rd is H and the other of R° or Rd is optionally substituted (C1-C8)alky|. ln another aspect of
this embodiment, Re is optionally substituted (C1-C8)a|ky|. . ln another aspect of this
embodiment, RS is optionally substituted (C3-C8)cyc|oa|ky|. ln another aspect of this
embodiment, R4 is optionally substituted (C6-C20)ary|. ln another aspect of this embodiment, Ar
is optionally substituted phenyl. ln another aspect of this embodiment, Rs is NR11R12. ln another
aspect of this embodiment, Ra is OR". ln another aspect of this embodiment, Ra is NH2. ln
another aspect of this embodiment, Ra is OH.
ln another embodiment of the method for preparing a compound of Formula Vla or Formula Vlb
from a compound of Formula Vll, X1 is CH, Rl is H, Cl or CH3 one of R° or Rd is H and R7 is H. ln
another aspect of this embodiment, R2 is F. ln another aspect of this embodiment, R2 is Cl. ln
another aspect of this embodiment, R2 is OH. ln another aspect of this embodiment, Rl is Cl
and RZ is F. ln another aspect of this embodiment, R1 is CH3 and R2 is Cl. ln another aspect of
17
M337 prio-lb
this embodiment, R1 and Rz are both Cl. ln another aspect of this embodiment, each Rzand R”
is OH. ln another aspect of this embodiment, one of R° and Rd is H and the other of R°and Rd is
optionally substituted (C1-C8)a|ky|. ln another aspect of this embodiment, one of R°and Rd is H
and the other of R° and Rd is CH3. ln another aspect of this embodiment, Reis optionally
substituted (C1-Cß)alkyl. ln another aspect of this embodiment, RB is optionally substituted (CC-
C8)cyc|oa|ky|. ln another aspect of this embodiment, R4 is optionally substituted (C6-C20)ary|. ln
another aspect of this embodiment, R4 is optionally substituted phenyl. ln another aspect of this
embodiment, Ar is optionally substituted phenyl. ln another aspect of this embodiment, Ar is
phenyl which is substituted with 1-5 halogen atoms. ln another aspect of this embodiment, Ar is
pentafluorophenyl. ln another aspect of this embodiment, Ar is 3,5-dichlorophenyl. ln another
aspect of this embodiment, Rs is NRMR”. ln another aspect of this embodiment, Ra is NH2. ln
another aspect of this embodiment, Rs is OR”. ln another aspect of this embodiment, Rs is OH.
ln another embodiment of the method for preparing a compound of Formula la or lb or a
pharmaceutically acceptable salt or ester thereof, Formula la is Formula VI, Formula lb is
Formula Vlb and Formula ll is Formula VII:
Formula Vlb
18
M337 prio-lb
Formula Vll
wherein each R1 is independently H, halogen, optionally substituted (C1-Cg)alky|, optionally
substituted (C2-Cg)alkenyl or optionally substituted (C2-C8)alkyny|;
each R2 is independently halogen or OR" ;
each R5 is H;
each R” is OR" and
the remaining variables are defined as for Formulae la or lb or ll or Illa or lllb.
ln one embodiment of the method for preparing a compound of Formula Vla or Formula Vlb
from a compound of Formula Vll, X1 is CR”. ln another aspect of this embodiment, R1° is H. ln
another aspect of this embodiment, R1 is H. ln another aspect of this embodiment, R1 is F. ln
another aspect of this embodiment, R1 is Cl. ln another aspect of this embodiment, R1 is
optionally substituted (C1-C8)alky|. ln another aspect of this embodiment, R1 is methyl. ln
another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkenyl. ln another aspect
of this embodiment, R1 is optionally substituted ethenyl. ln another aspect of this embodiment,
R1 is optionally substituted(C2-C8)a|kyny|. ln another aspect of this embodiment, R1 is optionally
substituted ethynyl. ln another aspect of this embodiment, R2 is F. ln another aspect of this
embodiment, R2 is Cl. ln another aspect of this embodiment, R2 is OH. ln another aspect of this
embodiment R” is OH. ln another aspect of this embodiment, each R2 and R” is OH. ln
another aspect of this embodiment, R7 is H. ln another aspect of this embodiment, R7 is
optionally substituted (C1-C8)alky|. ln another aspect of this embodiment, R? is optionally
substituted (C2-Cß)alkynyl. ln another aspect of this embodiment, R7 is CN. ln another aspect of
this embodiment, one of R° or Rd is H. ln another aspect of this embodiment, one of R°or Rd is
H and the other of R° or Rd is optionally substituted (C1-C8)a|ky|. ln another aspect of this
embodiment, RS is optionally substituted (C1-C8)a|ky|. ln another aspect of this embodiment, RB
is optionally substituted optionally substituted (C3-C8)cyc|oalky|. ln another aspect of this
embodiment, R4 is optionally substituted (C6-C20)ary|. ln another aspect of this embodiment, Ar
is optionally substituted phenyl.
ln another embodiment of the method for preparing a compound of Formula Vla or Formula Vlb
from a compound of Formula Vll, X1 is CH, R1 is H, Cl or CH3 and one of R° or Rd is H. ln
19
M337 prio-lb
another aspect of this embodiment, Rs is F. ln another aspect of this embodiment, Rs is Cl. ln
another aspect of this embodiment, Rs is OH. ln another aspect of this embodiment Rss is OH.
ln another aspect of this embodiment, each Rs and Rss is OH. ln another aspect of this
embodiment, R7 is H. ln another aspect of this embodiment, R7 is optionally substituted (C1-
C8)a|ky|. ln another aspect of this embodiment, R7 is CH3. ln another aspect of this embodiment,
R? is optionally substituted (C2-C8)a|kyny|. ln another aspect of this embodiment, R7 is ethynyl.
ln another aspect of this embodiment, R? is CN. ln another aspect of this embodiment, one of R°
or Rs is H and the other of R° or Rs is optionally substituted (C1-C8)a|ky|. ln another aspect of
this embodiment, Rs is optionally substituted (C1-C8)a|ky|. . ln another aspect of this
embodiment, Rs is optionally substituted (C3-C8)cyc|oa|ky|. ln another aspect of this
embodiment, Rs is optionally substituted (C6-C20)ary|. ln another aspect of this embodiment, Ar
is optionally substituted phenyl. ln another aspect of this embodiment, Rs is NR11R12. ln another
aspect of this embodiment, Rs is OR”. ln another aspect of this embodiment, Rs is NH2. ln
another aspect of this embodiment, Rs is OH. ln another aspect of this embodiment, Rs is H. ln
another aspect of this embodiment, Rs is NR11R12. ln another aspect of this embodiment, Rs is
OR”. ln another aspect of this embodiment, Rs is NR11N12 and Rs is H. ln another aspect of this
embodiment, Ra is NRllR” and Rsis NRllR”.
ln another embodiment of the method for preparing a compound of Formula Vla or Formula Vlb
from a compound of Formula Vll, X1 is CH, Rs is H, Cl or CH3 one of Rs or Rs is H and R7 is CN.
ln another aspect of this embodiment, Rs is F. ln another aspect of this embodiment, Rs is Cl. ln
another aspect of this embodiment, Rs is OH. ln another aspect of this embodiment, each Rs
and Rss is OH. ln another aspect of this embodiment, one of Rs and Rs is H and the other of Rs
and Rs is optionally substituted (C1-C8)a|ky|. ln another aspect of this embodiment, one of R°
and Rs is H and the other of R° and Rs is CH3. ln another aspect of this embodiment, Rsis
optionally substituted (C1-C8)a|ky|. ln another aspect of this embodiment, Rsis optionally
substituted (C3-C8)cyc|oa|ky|. ln another aspect of this embodiment, Rs is optionally substituted
(C6-C20)ary|. ln another aspect of this embodiment, Rs is optionally substituted phenyl. ln
another aspect of this embodiment, Ar is optionally substituted phenyl. ln another aspect of this
embodiment, Rsis NR11R12. ln another aspect of this embodiment, Rs is OR". ln another aspect
of this embodiment, Rs is NH2. ln another aspect of this embodiment, Rs is OH. ln another
aspect of this embodiment, Rs is H. ln another aspect of this embodiment, Rs is NR11R12. ln
another aspect of this embodiment, Rs is OR”. ln another aspect of this embodiment, Rs is
NR11R12 and Rs is H. ln another aspect of this embodiment, Rs is NHs and Rs is H. ln another
aspect of this embodiment, Rs is NR11R12 and Rs is NR11R12. ln another aspect of this
embodiment, Rs is NH2 and Rs is NH2. ln another aspect of this embodiment, Rsis OH and Rs is
NH2.
20
M337 prio-lb
ln another embodiment of the invention, a method is provided for the preparation of a
compound of Formula Illa or Formula lllb
Formula Illa Formula lllb
Ol'
wherein:
each Ra, R4 or RB is independently (C1-Cß)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-
C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl,
heterocyclyl or heteroaryl;
each R° or Rd is independently H, (C1-C8)a|kyl, (C2-C8)alkeny|, (C2-C8)alkyny|, (C3-
Cg)carbocyclyl, (C4-C8)carbocyclylalkyl, ary|(C1-C8)a|kyl, heterocycly|(C1-C8)alky|, (C6-C20)aryl,
(C2-C20)heterocyclyl or heteroaryl provided that R° and Rd are not the same;
each Rs is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-
C8)carbocycly|alkyl, aryl(C1-C8)alky|, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or
heteroaryl;
wherein each (C1-C8)alky|, (C2-C8)alkenyl, (C2-C8)alkyny|, (C3-C8)carbocycly|, (C4-
Cß)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or
heteroaryl of each R°, Rd, R4, Rs or Re is, independently, optionally substituted with one or more
halo, hydroxy, CN, Na, N(Ra)2; NH(Ra), NH2, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(Ra)2,
OC(O)NH(Ra), OC(O)NH2, C(O)ORa, OC(O)ORa, S(O),.Ra, S(O)2N(Ra)2, S(O)2NH(Ra),
S(O)2NH2, ORa or Ra; and each Ar is (C6-C20)ary| or a 5 to 20 membered heteroaryl wherein
said aryl or heteroaryl is optionally substituted with one or more halogen, N02, (C1-C8)ha|oalkyl,
CN, Ng, N(Ra)2, C(O)N(Ra)2, OC(O)N(Ra)2, C(O)OR'““, OC(O)ORa, C(O)Ra, OC(O)Ra, S(O),,Ra
S(O)2N(Ra)2, ORa or Ra with the proviso that Ar is different from R4;
said method comprising:
(d) providing a diastereomeric compound of Formula Vlll
Formula Vlll
and
M337 prio-lb
(e) dissolving the compound of Formula VIII in a suitable solvent and inducing crystallization by
cooling the solution;
thereby forming a pure diasteromer of Formula lla or Formula lllb.
ln one embodiment of the method of preparing a compound of Formula Illa or Formula Illb, RB is
H and one of RB or RB is H. ln another aspect of this embodiment, one of RB or RB is H and the
other of RB or RB is optionally substituted (C1-C8)alky|. ln another aspect of this embodiment, one
of RB or RB is H and the other of RB or RB is CH3. ln another aspect of this embodiment, RB is
optionally substituted (C1-C8)alkyl. ln another aspect of this embodiment, RB is optionally
substituted Ca-Cgcycoalkyl. ln another aspect of this embodiment, RB is optionally substituted
(Ci-CB) secondary or tertiary alkyl. ln another aspect of this embodiment, R4 is optionally
substituted (C6-C20)aryl. ln another aspect of this embodiment, R4 is optionally substituted
phenyl. ln another aspect of this embodiment, Ar is optionally substituted phenyl. ln another
aspect of this embodiment, Ar is phenyl which is substituted With 1 to 5 halogen atoms. ln
another aspect of this embodiment, Ar is pentafluorophenyl. ln another aspect of this
embodiment, Ar is 3,5-dichlorophenyl. ln another aspect of this embodiment, the chirality at the
carbon directly attached to RB and RB is S. ln another aspect of this embodiment, the chirality at
the carbon directly attached to RB and RB is R.
ln another embodiment of the method of preparing a compound of Formula Illa or Formula Illb,
RS is H, ons of R° or Rd is H, RB is opiionaiiy substituted (ci-cigaikyi, and R4 is opiionaiiy
substituted (C6-C20)aryl. ln another aspect of this embodiment, one of R° or RB is H and the
other of RB or RB is optionally substituted (C1-C8)alky|. ln another aspect of this embodiment, one
of RB or RB is H and the other of RB or RB is CH3. ln another aspect of this embodiment, RBis
optionally substituted (C1-C8) secondary or tertiary alkyl. ln another aspect of this embodiment,
RB is optionally substituted 2-propyl. ln another aspect of this embodiment, R4 is optionally
substituted phenyl. ln another aspect of this embodiment, Ar is optionally substituted phenyl. ln
another aspect of this embodiment, Ar is phenyl which is substituted with 1-5 halogens. ln
another aspect of this embodiment, Ar is pentafluorophenyl. ln another aspect of this
embodiment, Ar is 3,5-dichlorophenyl. ln another aspect of this embodiment, the chirality at the
carbon directly attached to RB and RB is S. ln another aspect of this embodiment, the chirality at
the carbon directly attached to RB and RB is R.
ln another embodiment of the method of preparing a compound of Formula Illa or Formula Illb,
RB is H, one of RB or RB is H and the other of RB or RB is optionally substituted (C1-C8)alkyl, RB is
optionally substituted (C1-C8)alky|, and R4 is optionally substituted phenyl. ln another aspect of
this embodiment, one of RB or RB is H and the other of RB or RB is CH3. ln another aspect of this
embodiment, RB is optionally substituted (C1-C8) secondary or tertiary alkyl. ln another aspect of
this embodiment, RB is optionally substituted 2-propyl. ln another aspect of this embodiment, R4
is phenyl. ln another aspect of this embodiment, Ar is optionally substituted phenyl. ln another
22
M337 prio-lb
aspect of this embodiment, Ar is phenyl which is substituted with 1-5 halogen atoms. ln another
aspect of this embodiment, Ar is pentafluorophenyl. ln another aspect of this embodiment, Ar is
3,5-dich|oropheny|. ln another aspect of this embodiment, the chirality at the carbon directly
attached to R” and Rd is S. ln another aspect of this embodiment, the chirality at the carbon
dirsstiy attasnsd ts R° and Rf* is R.
ln another embodiment of the method of preparing a compound of Formula Illa or Formula lllb,
RS is H, dns of R°sr Rd is H and ins dtnsr of R° dr Rd is cHs, RB is dptidnaiiy substituted (ci-
C8)alkyl, and R4 is optionally substituted phenyl. ln another aspect of this embodiment, RB is
optionally substituted (C1-C8)secondary or tertiary alkyl. ln another aspect of this embodiment,
RB is optionally substituted 2-propyl. ln another aspect of this embodiment, RB is 2-propyl. ln
another aspect of this embodiment, R4 is phenyl. ln another aspect of this embodiment, Ar is
optionally substituted phenyl. ln another aspect of this embodiment, Ar is phenyl which is
substituted With 1-5 halogen atoms. ln another aspect of this embodiment, Ar is
pentafluorophenyl. ln another aspect of this embodiment, Ar is 3,5-dich|oropheny|. ln another
aspect of this embodiment, the chirality at the carbon directly attached to R° and Rd is S. ln
another aspect of this embodiment, the chirality at the carbon directly attached to R” and Rd is
R.
The diastereomeric mixture of the compound of Formula Vlll is typically resolved by
crystallization of the compound of Formula Vlll from a suitable solvent. Non-limiting examples of
suitable solvents are diethyl ether, dipropyl ether, di i-butyl ether, methyl i-butyl ether, C1-
Cshalogenated alkanes, Cs-Cghydrocarbons, tetrahydrofuran, toluene, xylene, dioxane and the
like. ln another embodiment, the compound of Formula Vlll is dissolved in a suitable solvent
and crystallization is induced by addition of a Cs-Cghydrocarbon or Cs-Cg cyclic hydrocarbon. ln
one embodiment, the compound of Formula Vlll is dissolved in an ether solvent and
crystallization is induced by addition of a Cs-Cg hydrocarbon. ln a typical embodiment, the
compound of Formula Vlll is dissolved in diethyl ether and crystallization is induced by the
addition of hexane.
ln a further embodiment, the compound of Formula Vlll is dissolved in a Cs-Cßhydrocarbon and
crystallization is induced by cooling the solution. ln a preferred embodiment, the compound of
Formula Vlll is dissolved in hexane or heptane and crystallization is induced by cooling the
solution.
The diastereomeric mixture of the compound of Formula Vlll is typically resolved by
crystallization of the compound of Formula Vlll from a suitable solvent at a temperature of about
80 °C to about -20 °C. Preferably, the temperature is about 30 °C to about -20 °C, more
preferably about ambient to -10 °C.
23
M337 prio-lb
The diastereomeric mixture of the compound of Formula VIII is typically resolved by
crystallization of the compound of Formula VIII from a suitable solvent wherein the
concentration of the compound of Formula VIII in solution is about 25 g to about 1000 g per liter
of solvent. More typically, the concentration of the compound of Formula VIII is about 50 to 500
g per liter of solvent. The resolution of the diastereomeric mixture of the compound of Formula
VIII by crystallization may be promoted by the addition of seed crystals of the pure
diastereomer. Seed crystals of pure diastereomers may be obtained through puri?cation of the
diastereomeric mixture of the compound of Formula VIII by liquid chromatography, chiral liquid
chromatography, high pressure liquid chromatography, or chiral high pressure liquid
chromatography such as by the non-limiting methods described herein.
Typically, the crystallization of the diastereomeric mixture of the compound of Formula VIII
produces a mixture of diastereomers containing at least 60 % of a single diastereomer. l\/lore
typically, the mixture produced contains at least 70 % of a single diastereomer, most typically, at
least 80 % of a single diastereomer, preferably at least 90 % of a single diastereomer, and more
preferably at least 95 % of a single diastereomer. Higher diastereomeric purity, for example at
least 99 % diastereomeric purity, may be obtained by one or more subsequent crystallizations.
The yield of crystalline material from a single crystallization is typically about 10 to 45 %, more
typically about 20-35 %.
ln another embodiment, a compound of formula VIII
Formula VIII
is prepared as illustrated in the scheme 1:
O Iïö 5 5
o o RQ NH O Ff O Ff
|| || 0 ._ RQ N\ ,/O Rel N\ /IO
Cl-Ff-Cl R4OH Cl-P-C' Ra 'RC o . P Hs-Ar O . P
í> I 4 1b d z /\ i, d z /\
cl base oR F* R R°o cl base R R°o s-Ar
base \R4 *R4
18 1c v|||
§che? 1
Condensation of phosphoryl trichloride with a desired alcohol R4OH in the presence of a base
such as EtgN or DIEA or similar in an inert solvent like dichloromethane, diethyl ether,
tetrahydrofuran or the like, followed by reaction with an amino acid derivative (1b) in the
presence of a base like Et3N or DIEA or similar provides the chlorophosphoramidate (1 c). The
obtained chlorophosphoramidate is then converted to the phosphorylating agent (VIII) by
24
M337 prio-lb
reaction with the desired thiophenol Ar-SH in the presence of a base like triethylamine or
similar.
Alternatively, the synthesis of a compound of formula Vlll can start from a phosphorus trihalide,
and oxidation to the desired phosphate performed as the last step. This method is illustrated in
Scheme 2.
oRö
R4oH /P\ RÖ rliH o F55
X/T\X í> X (I) X \Ö&I Rio N\P/X
x base \R4 1b Ru Rc Rd 'gR cl)
2a base zb c \R4
5 Ar O Rs o
ArSH R5\ [i] /š oxidation Re Ill_P//
b \ m \
base O ä, I? o 2,, 6\S-Ar
Rd Rc O\R4 Rd 'Rc \R4
Scheme 2 2° X is a halogen VIII
Reaction of phosphorus trihalide with the desired alcohol R4-OH in an inert solvent such as
dichloromethane, or an ether like diethyl ether or tetrahydrofuran or the like, in the presence of a
base such as triethylamine or similar followed by reaction with an amino acid derivative (1 b) in
the presence of a base like Et3N or DIEA or similar provides the phosphinamine 2b.
Displacement of the remaining halo atom with a thioaryl or thioheteroaryl derivative ArSH,
carried out in a solvent like DCl\/I or similar in the presence of a base such as EtgN or similar,
provides the thio detivative (2d). Oxidation finally, effected for instance by treatment with
mCPBA, tert-butylhydroperoxide or any other convenient oxidation agent, provides the
phosphoramidate reagent (Vlll).
ln another embodiment, a compound of Formula Illa or Formula lllb is provided
Formula Illa Or Formula lllb
or a salt or ester thereof;
wherein:
each Ra, R4 or RS is independently (C1-Cg)alkyl, (C2-C8)a|kenyl, (C2-C8)alkynyl, (C3-
C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl,
heterocyclyl or heteroaryl;
25
M337 prio-lb
each R” or R” is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-
C8)carbocyclyl, (C4-C8)carbocyclylalkyl, ary|(C1-C8)alky|, heterocyclyl(C1-C8)alky|, (C6-C20)aryl,
heterocyclyl or heteroaryl;
each R” is independently H, (C1-C8)alkyl, (C2-C8)a|keny|, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-
C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)ary|, heterocyclyl or
heteroaryl;
wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-
Cß)carbocyclylalkyl, aryl(C1-C8)alky|, heterocycly|(C1-C8)alky|, (C6-C20)aryl, heterocyclyl or
heteroaryl of each R”, Rd, R4, R” or R” is, independently, optionally substituted with one or more
halo, hydroxy, CN, N3, N(R”)2, NH(R”), NH2, C(O)N(R”)2, C(O)NH(R”), C(O)NH2, OC(O)N(R”)2,
OC(O)NH(R”), OC(O)NH2, C(O)OR”, OC(O)OR”, S(O),,R”, S(O)2N(R”)2, S(O)2NH(R”),
S(O)2NH2, OR” or Ra; and
each Ar is a (C6-C20)aryl or a 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is
optionally substituted with one or more halogen, N02, (C1-C8)haloa|kyl, CN, Na, N(R”)2;
C(O)N(R”)2, OC(O)N(R”)2, C(O)OR”, OC(O)OR”, C(O)R”, OC(O)R”, S(O),,R”, S(O)2N(R”)2, OR”
or R” with the proviso that Ar is different from R4.
ln another embodiment of the compound of Formula Illa or Formula lllb, R” is H and one of R”
or R” is H. ln another aspect of this embodiment, one of R” or R” is H and the other of R” or R”
is optionally substituted (C1-C8)alkyl. ln another aspect of this embodiment, one of R” or R” is H
and the other of R” or R” is CH3. ln another aspect of this embodiment, RB is optionally
substituted (C1-C8)alkyl. ln another aspect of this embodiment, RB is optionally substituted (C3-
C8)cycloalkyl.ln another aspect of this embodiment, R” is optionally substituted (C1-Cg)
secondary or tertiary alkyl. ln another aspect of this embodiment, R” is optionally substituted
(C6-C20)aryl. ln another aspect of this embodiment, R4 is optionally substituted phenyl. ln
another aspect of this embodiment, Ar is optionally substituted phenyl. ln another aspect of this
embodiment, Ar is phenyl which is substituted with 1-5 halogen atoms. ln another aspect of this
embodiment, Ar is pentafluorophenyl. ln another aspect of this embodiment, Ar is 3,5-
dichlorophenyl. ln another aspect of this embodiment, the chirality at the carbon directly
attached to R” and R” is S. ln another aspect of this embodiment, the chirality at the carbon
directly attached to R” and R” is R. ln another aspect of this embodiment, the moiety
oR5
|
RïoÄgíNïrrr
Rd Rc
of Formula Illa or Formula lllb comprises a nitrogen-linked ester of a naturally occurring a-amino
acid.
26
M337 prio-lb
ln another embodiment of the compound of Formula llla or Formula lllb, R” is H, one of R” or R”
is H, R” is optionally substituted (C1-C8)a|kyl and R” is optionally substituted (C6-C20)ary|. ln
another aspect of this embodiment, one of R” or R” is H and the other of R” or R” is optionally
substituted (C1-C8)alky|. ln another aspect of this embodiment, one of R” or R” is H and the
other is CH3. ln another aspect of this embodiment, R”is optionally substituted (C1-C8)
secondary or tertiary alkyl. ln another aspect of this embodiment, R” is optionally substituted 2-
propyl. ln another aspect of this embodiment, R” is optionally substituted phenyl. ln another
aspect of this embodiment, Ar is optionally substituted phenyl. ln another aspect of this
embodiment, Ar is henyl which is substituted with 1-5 halogen atoms. ln another aspect of this
embodiment, Ar is pentafluorophenyl. ln another aspect of this embodiment, Ar is 3,5-
dichlorophenyl. ln another aspect of this embodiment, the chirality at the carbon directly
attached to R” and R” is S. ln another aspect of this embodiment, the chirality at the carbon
directly attached to R” and R” is R. ln another aspect of this embodiment, the moiety
o R5
RB fi:
\O 'a \É:r
Rd IRC
of Formula llla or Formula llllb comprises a nitrogen-linked ester of a naturally occurring oi-
amino acid.
ln another embodiment of the compound of Formula llla or Formula lllb, R” is H, one of R” or R”
is H and the other of R” or R” is optionally substituted (C1-C8)a|kyl, R” is optionally substituted
(C1-C8)alkyl and R” is optionally substituted phenyl. ln another aspect of this embodiment, one
of R” or R” is H and the other is CH3. ln another aspect of this embodiment, R” is optionally
substituted (C1-C8) secondary or tertiary alkyl. ln another aspect of this embodiment, R”is
optionally substituted 2-propyl. ln another aspect of this embodiment, R” is phenyl. ln another
aspect of this embodiment, Ar is optionally substituted phenyl. ln another aspect of this
embodiment, Ar is phenyl which is substituted with 1-5 halogen atoms. ln another aspect of this
embodiment, Ar is pentafluorophenyl. ln another aspect of this embodiment, Ar is 3,5-
dichlorophenyl. ln another aspect of this embodiment, the chirality at the carbon directly
attached to R” and R” is S. ln another aspect of this embodiment, the chirality at the carbon
directly attached to R” and R” is R. ln another aspect of this embodiment, the moiety
oR5
|
RíoÄga/Nïf;
Rd ”RC
of Formula llla or Formula lllb comprises a nitrogen-linked ester of a naturally occurring oi-
amino acid.
27
M337 prio-lb
ln another embodiment of the compound of Formula llla or Formula lllb Rs is H, one of R°or Rd
is H and the other of R° or Rd is CH3, Re is optionally substituted (C1-C8)alky|, and R4 is
optionally substituted phenyl. ln another aspect of this embodiment, RS is optionally substituted
(C1-C8) secondary or tertiary alkyl. ln another aspect of this embodiment, RB is optionally
substituted 2-propyl. ln another aspect of this embodiment, RS is 2-propyl. ln another aspect of
this embodiment, R4 is phenyl. ln another aspect of this embodiment, Ar is optionally substituted
phenyl. ln another aspect of this embodiment, Ar is phenyl which is substituted with 1-5 halogen
atoms. ln another aspect of this embodiment, Ar is pentafluorophenyl. ln another aspect of this
embodiment, Ar is 3,5-dichlorophenyl. ln another aspect of this embodiment, the chirality at the
carbon directly attached to R” and Rd is S. ln another aspect of this embodiment, the chirality at
the carbon directly attached to R° and Rd is R. ln another aspect of this embodiment, the moiety
o 35
RQ N
o , :ß
Rd 'R°
of Formula Illa or Formula lllb comprises a nitrogen-linked ester of a naturally occurring oi-
amino acid.
ln one embodiment, a compound of Formula Illa is provided
R5
Zl
O
Formula Illa
ln another embodiment, a compound of Formula lllb is provided
Formula lllb
ln one embodiment of the compound of formula Vlll or diastereomer of formula Illa or lllb, Rs is
H and one of R° and Rd is H.
ln one embodiment of the compound of formula Vlll or diastereomer of formula Illa or lllb, Re is
optionally substituted (C1-C8)alky| or (C3-C8)cycloa|kyl. ln one aspect of this embodiment, RB is
methyl, ethyl, 1-methylbutyl, 2-ethylbutyl, cyclopentyl or preferably isopropyl.
28
M337 prio-lb
ln one embodiment of the compound of formula VIII or diastereomer of formula Illa or lllb, R4 is
phenyL
ln one embodiment of the compound of formula VIII or diastereomer of formula Illa or lllb, one
of R° and Rd is H and the other one is CH3. ln one aspect of this embodiment, the
stereochemistry at the chiral center to which R° and Rd are attached, is S, i.e. that of an L-amino
acid.
ln one embodiment of the compound of formula VIII or diastereomer of formula Illa or lllb, Aris
3,5-dichlorophenyl or pentafluorophenyl.
ln another embodiment, compounds of Formula Illa or Formula lllb are provided which
compounds are selected from the group consisting of:
OI' 'Ü_O
-|||l|
OI' 'Ü_O
O N' '\s
H
O
\/O Nr
H
O
c|
c|
c|
'\s cl \/O _ N*'Fi>\s cl
I Jil i i Jil
Û mig
c|
29
M337 prio-lb
_:_| _:_|
_:_| _:_:
_:_: _:_:
E:
\s \s \s s s F
OHPAO oHP.|o oHP.|o O \ O o \ O \s
\\ \ \ HP] HP]
NH NH NH .x .x OHPAO
___... ___... ___... NH NH \NH
___... ___...
O ___...
O O
O O O O
O O
...___ L W O
Q U U F F
_:_: _:_:
E: E:
F
x x \S s s F
OHPw. .O OHPQ .O OHPQ .O \ \ \S
OHP__.._O OHP._.._O
NH NH NH I I OHD.._.._O
NH NH I
___... ___... ___... NH
___... ___...
O ___...
O
O O O O
...___ O
30
M337 prio-lb
and or salts or esters thereof.
In another embodiment, a method is provided for the preparation of a compound of Formula VIII
O R5
e | O
R\ N\ l
O .,, P
d 2, / \
R R° O S-Ar
\
R4
Formula VIII
or a salt or ester thereof, wherein
each Ra, R4 or RS is independently (C1-Cg)alkyl, (C2-C8)a|kenyI, (C2-C8)aIkynyI, (C3-
Cß)carbocyclyl, (C4-Cg)carbocyclylalkyl, aryI(C1-C8)aIkyI, heterocyclyl(C1-C8)aIkyI, (C6-C20)aryI,
heterocyclyl or heteroaryl;
31
M337 prio-lb
each R° or Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-
C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryI(C1-C8)alky|, heterocyclyl(C1-C8)alky|, (C6-C20)aryl,
heterocyclyl or heteroaryl provided that R° and Rd are not the same;
each R5 is independently H, (C1-C8)alkyl, (C2-C8)a|keny|, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-
C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or
heteroaryl;
wherein each (C1-Cg)alkyl, (C2-C8)aIkenyI, (C2-C8)aIkynyI, (Cs-Cgcarbocyclyl, (C4-
Cß)carbocyclylalkyl, aryl(C1-C8)alky|, heterocycly|(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or
heteroaryl of each R°, Rd, R4, Rs or Re is, independently, optionally substituted with one or more
halo, hydroxy, CN, N3, N(Ra)2, NH(Ra), NH2, C(O)N(R'°“)2, C(O)NH(Ra), C(O)NH2, OC(O)N(R*')2,
OC(O)NH(Ra), OC(O)NH2, C(O)ORa, OC(O)ORa, S(O),,Ra S(O)2N(Ra)2, S(O)2NH(Ra), S(O)2NH2,
ORa or Ra; and
each Ar is (C6-C20)aryl or a 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is
optionally substituted with one or more halogen, N02, (C1-C8)haloa|kyI, CN, Na, N(Ra)2)
C(O)N(Ra)2, OC(O)N(R'°“)2, C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)Ra, S(O),,Ra, S(O)2N(Ra)2, ORa
or Ra with the proviso that Ar is different from R4;
said method comprising:
(f) providing a chirally pure amino acid ester of Formula IX or a salt thereof
o R5
I
Rà NH
Oka
Rd 'IRC
Formula IX
(g) treating the compound of Formula IX With a compound of Formula X in the presence of a
base
f?
X3_F|)_X3
O\
R4
Formula X
wherein each X3 is halogen; and
(h) treating the resulting mixture with ArSH; thereby forming a compound of Formula Vlll.
Typically, the chirally pure amino acid of Formula IX or a salt thereof is dissolved or suspended
in a suitable non-nucleophilic solvent. Non-limiting non-nucleophilic solvents include
haloalkanes, e.g. dichloromethane, dichloroethane and ethers, e.g. dioxane, tetrahydrofuran,
32
M337 prio-lb
diethyl ether and glymes. Typically, the suspension or solution contains about 0.1 to about 5
moles of the compound of Formula IX per liter of solvent.
The suspension or solution of the chirally pure amino acid of Formula IX is treated with a
compound of Formula X. Typically, the reaction is conducted at about -20 to about 60 °C. The
mole ratio of the compound of Formula IX to the compound of Formula X is about 1:2 to about
2:1, preferably about 1:1. The reaction is generally conducted in the presence of a non-
nucleophilic base. Non-limiting examples of non-nucleophilic bases are tertiary amines, e.g.
diisopropylethylamine and triethylamine; metal hydrides, e.g. LiH, NaH and CaH2; and nitrogen
containing heterocycles, e.g. pyridine and dimethylaminopyridine. In a preferred embodiment,
the base is a tertiary amine such as triethylamine. When the compound of Formula IX is a salt
of a mono-protic acid, the molar ratio of base to the compound of Formula IX is typically about
2:1. Ifthe compound of Formula IX is a free base, the molar ratio of base to the compound of
Formula IX is about 1:1.
The reaction of the compound of Formula IX with the compound of Formula X may be followed
by many conventional means known to those skilled in the art. Such means include thin-Iayer
chromatography and hplc. When the reaction between the compound Formula IX and the
compound of Formula X is complete, the reaction is treated with a thiophenolic compound ArSH
where Ar is defined as herein. The mole ratio of the compound of Formula X to ArSH is typically
about 1.1:1 to about 1:1.1, preferably about 1:1. After the addition of ArSH, additional base is
required, typically enough base to neutralize the acid generated in the reaction. Typically, the
additional base is a non-nucleophilic base such as described above.
The compound of Formula VIII is isolated by conventional means known to those skilled in the
art. For example, the salt formed in the reaction may be precipitated from the reaction mixture
and the compound of Formula VIII isolated by evaporation of the solvent followed by
crystallization or chromatography.
In one embodiment of the method of preparing a compound of Formula VIII, Rs is H and one of
R° or Rd is H. In another aspect of this embodiment, one of R° or Rd is H and the other is
optionally substituted (C1-Cg)alkyl. In another aspect of this embodiment, one of R° or Rd is H
and the other of R° or Rd is CH3. In another aspect of this embodiment, Rs is optionally
substituted (C1-Cß)alkyl. ln another aspect of this embodiment, RB is optionally substituted (C1-
Cs) secondary or tertiary alkyl. ln another aspect of this embodiment, RB is (Cs-Ca) cycloalkyl. ln
another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryI. In another aspect of
this embodiment, R4 is optionally substituted phenyl. In another aspect of this embodiment, Ar is
optionally substituted phenyl. In another aspect of this embodiment, Ar is phenyl which is
substituted with 1-5 halogen atoms. In another aspect of this embodiment, Ar is
pentafluorophenyl. In another aspect of this embodiment, Ar is 3,5-dichlorophenyl. In another
33
M337 prio-lb
aspect of this embodiment, the chirality at the carbon directly attached to Rs and Rs is S. ln
another aspect of this embodiment, the chirality at the carbon directly attached to Rs and Rs is
R. ln another aspect of this embodiment, the compound of Formula IX or salt thereof, is an ester
of a naturally occurring oi-amino acid.
ln another embodiment of the method of preparing a compound of Formula Vlll, Rs is H, one of
Rs or Rd is H, Rs is optionally substituted (C1-C8)alkyl, and R4 is optionally substituted (C6-
C20)aryl. ln another aspect of this embodiment, one of RC or Rd is H and the other is optionally
substituted (C1-C8)alkyl. ln another aspect of this embodiment, one of Rs or Rs is H and the
other is CH3. ln another aspect of this embodiment, Rs is optionally substituted (Ci-Co)
secondary or tertiary alkyl. ln another aspect of this embodiment, Rs is optionally substituted 2-
propyl. ln another aspect of this embodiment, R4 is optionally substituted phenyl. ln another
aspect of this embodiment, Ar is optionally substituted phenyl. ln another aspect of this
embodiment, Ar is phenyl which is substituted with 1-5 halogen atoms. ln another aspect of this
embodiment, Ar is pentafluorophenyl. ln another aspect of this embodiment, Ar is 3,5-
dichlorophenyl. ln another aspect of this embodiment, the chirality at the carbon directly
attached to Rs and Rs is S. ln another aspect of this embodiment, the chirality at the carbon
directly attached to Rs and Rs is R. ln another aspect of this embodiment, the compound of
Formula IX or salt thereof, is an ester of a naturally occurring oi-amino acid.
ln another embodiment of the method of preparing a compound of Formula Vlll, Rs is H, one of
Rs or Rs is H and the other one is optionally substituted (C1-C8)alkyl, Rs is optionally substituted
(C1-C8)alkyl, and R4 is optionally substituted phenyl. ln another aspect of this embodiment, one
of Rs or Rs is H and the other one is CHS. ln another aspect of this embodiment, Rs is optionally
substituted (Ci-Cs) secondary or tertiary alkyl. ln another aspect of this embodiment, Rs is
optionally substituted 2-propyl. ln another aspect of this embodiment, Rs is phenyl. ln another
aspect of this embodiment, Ar is optionally substituted phenyl. ln another aspect of this
embodiment, Ar is phenyl which is substituted with 1-5 halogen atoms. ln another aspect of this
embodiment, Ar is pentafluorophenyl. ln another aspect of this embodiment, Ar is 3,5-
dichlorophenyl. ln another aspect of this embodiment, the chirality at the carbon directly
attached to Rs and Rs is S. ln another aspect of this embodiment, the chirality at the carbon
directly attached to Rs and Rs is R. ln another aspect of this embodiment, the compound of
Formula IX or salt thereof, is an ester of a naturally occurring alpha-amino acid.
ln another embodiment of the method of preparing a compound of Formula Vlll, Rs is H, one of
R° or Rd is H arioi ins oirior of R° or Rd is ci-is, RS is opiionaiiy siiosiiiiiioo (ci-cbaikyi, and R4 is
optionally substituted phenyl. ln another aspect of this embodiment, Rs is optionally substituted
(Ci-Cs) secondary or tertiary alkyl. ln another aspect of this embodiment, Rs is optionally
substituted 2-propyl. ln another aspect of this embodiment, Rs is 2-propyl. ln another aspect of
this embodiment, Rs is (C3-C8)carbocyclyl ln another aspect of this embodiment, R4 is phenyl. ln
34
M337 prio-lb
another aspect of this embodiment, Ar is optionally substituted phenyl. ln another aspect of this
embodiment, Ar is phenyl which is substituted with 1-5 halogen atoms. ln another aspect of this
embodiment, Ar is pentafluorophenyl. ln another aspect of this embodiment, Ar is 3,5-
dichlorophenyl. ln another aspect of this embodiment, the chirality at the carbon directly
attached to R” and Rd is S. ln another aspect of this embodiment, the chirality at the carbon
directly attached to R° and Rd is R. ln another aspect of this embodiment, the compound of
Formula IX or salt thereof, is an ester of a naturally occurring oi-amino acid.
ln another embodiment of the method for preparing a compound of Formula la or lb or a
pharmaceutically acceptable salt or ester thereof, Formula la is Formula Xla, Formula lb is
Formula Xlb and Formula ll is Formula Xll:
o Rs 1
6 l ° /
R\ N,,,,, //
O 'P\o N
d 2 c l O
R R oR4
Huw" "IIHR7
H . ,_ Ri
=
R22 âR2
Formula Xla
Formula XII
wherein:
each Rl is independently H, halogen, optionally substituted (C1-C8)a|ky|, optionally substituted
(C2-C8)alkeny| or optionally substituted (C2-C8)alkynyl; each R2 is independently halogen or
ORM;
each Rs is H;
each R” is OR"; and
the remaining variables are defined as for Formulae la or lb or ll or Illa or lllb.
ln one embodiment of the method for preparing a compound of Formula Xla or Formula Xlb
from a compound of Formula Xll, X1 is CR”. ln another aspect of this embodiment, R1° is H. ln
another aspect of this embodiment, Rl is H. ln another aspect of this embodiment, Rl is F. ln
another aspect of this embodiment, R1 is Cl. ln another aspect of this embodiment, R1 is
optionally substituted (C1-C8)alkyl. ln another aspect of this embodiment, Rl is methyl. ln
35
M337 prio-lb
another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkenyl. ln another aspect
of this embodiment, R1 is optionally substituted ethenyl. ln another aspect of this embodiment,
R1 is optionally substituted (C2-Cß)alkynyl. ln another aspect of this embodiment, R1 is optionally
substituted ethynyl. ln another aspect of this embodiment, R2 is F. ln another aspect of this
embodiment, R2 is Cl. ln another aspect of this embodiment, R2 is OH. ln another aspect of this
embodiment R” is OH. ln another aspect of this embodiment, each R2 and R” is OH. ln another
aspect of this embodiment, each R2 is F and R” is OH. ln another aspect of this embodiment,
each R2 is Cl and R” is OH. ln another aspect of this embodiment, R7 is H. ln another aspect of
this embodiment, R7 is optionally substituted (C1-C8)alkyl. ln another aspect of this embodiment,
R? is optionally substituted (C2-Cg)alkyny|. ln another aspect of this embodiment, R7is CN. ln
another aspect of this embodiment, one of R° or Rd is H. ln another aspect of this embodiment,
one of R° or Rd is H and the other of R° or Rd is optionally substituted (C1-C8)alkyl. ln another
aspect of this embodiment, RS is optionally substituted (C1-C8)alky|. ln another aspect of this
embodiment, RS is optionally substituted (C3-C8)cycloalkyl. ln another aspect of this
embodiment, R4 is optionally substituted (C6-C20)aryl. ln another aspect of this embodiment, Ar
is optionally substituted phenyl.
ln another embodiment of the method for preparing a compound of Formula Xla or Formula Xlb
from a compound of Formula XII, X1 is CH, R1 is H, Cl or CH3 and one of R° or Rd is H. ln
another aspect of this embodiment, R2 is F. ln another aspect of this embodiment, R2 is OH. ln
another aspect of this embodiment, R2 is Cl. ln another aspect of this embodiment R” is OH. ln
another aspect of this embodiment, each R2 and R” is OH. ln another aspect of this
embodiment, each R2 is F and R” is OH. ln another aspect of this embodiment, each R2 is Cl
and R” is OH. ln another aspect of this embodiment, R? is H. ln another aspect of this
embodiment, R7 is optionally substituted (C1-Cg)alkyl. ln another aspect of this embodiment, R7
is CH3. ln another aspect of this embodiment, R7 is optionally substituted (C2-C8)alkynyl. ln
another aspect of this embodiment, R? is ethynyl. ln another aspect of this embodiment, R7 is
CN. ln another aspect of this embodiment, one of R° or Rd is H and the other of R° or Rd is
optionally substituted (C1-C8)alky|. ln another aspect of this embodiment, Rßis optionally
substituted (C1-Cß)alkyl. ln another aspect of this embodiment, RB is optionally substituted (C3-
C8)cycloalkyl. ln another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryl. ln
another aspect of this embodiment, Ar is optionally substituted phenyl. ln another aspect of this
embodiment, Rs is NRMR”. ln another aspect of this embodiment, Ra is OR”. ln another
aspect of this embodiment, Rs is NH2. ln another aspect of this embodiment, Rg is OH. ln
another aspect of this embodiment, Rgis H. ln another aspect of this embodiment, RQ is
NR11R12. ln another aspect of this embodiment, RQ is OR”. ln another aspect of this
embodiment, Ra is NR11R12and RQ is H. ln another aspect of this embodiment, Rs is NR11R12
and RQ is NRitR”.
36
M337 prio-lb
ln another embodiment of the method for preparing a compound of Formula Xla or Formula Xlb
from a compound of Formula XII, X1 is CH, R1 is H, Cl or CH3, one of R° or Rd is H and R7 is H.
ln another aspect of this embodiment, R2 is F. ln another aspect of this embodiment, R2 is Cl. ln
another aspect of this embodiment, R2 is OH. ln another aspect of this embodiment R ” is OH.
ln another aspect of this embodiment, each Rzand R” is OH. ln another aspect of this
embodiment, each Rzis F and R” is OH. ln another aspect of this embodiment, each Rzis Cl
and R” is OH. ln another aspect of this embodiment, one of R° or Rd is H and the other of R° or
Rd is optionally substituted (C1-C8)a|ky|. ln another aspect of this embodiment, one of R° or Rd is
H and the other of R° or Rd is CH3. ln another aspect of this embodiment, Re is optionally
substituted (C1-Cß)a|ky|. ln another aspect of this embodiment, RB is optionally substituted (C3-
Cg) cycloalkyl. ln another aspect of this embodiment, R4 is optionally substituted (C6-C20)ary|. ln
another aspect of this embodiment, R4 is optionally substituted phenyl. ln another aspect of this
embodiment, Ar is optionally substituted phenyl. ln another aspect of this embodiment, Ra is
NR11R12. ln another aspect of this embodiment, Rs is OR11 _ ln another aspect of this
embodiment, Rs is NH2. ln another aspect of this embodiment, Ra is OH. ln another aspect of
this embodiment, Rg is H. ln another aspect of this embodiment, Rg is NR11R12. ln another
aspect of this embodiment, RQ is OR11. ln another aspect of this embodiment, RS is NR11R12 and
Rg is H. ln another aspect of this embodiment, RS is NH2 and RQ is H. ln another aspect of this
embodiment, Ra is NR11R12 and RQ is NR11R12. ln another aspect of this embodiment, RB is NH2
and Rg is NH2. ln another aspect of this embodiment, Ra is OR" and RQ is NH2. ln another
aspect of this embodiment, RS is oi-i and RQ is Ni-iz.
ln one embodiment of the method for preparing a compound of Formula Xla or Formula Xlb
from a compound of Formula XII, X1 is N. ln another aspect of this embodiment, R1 is H. ln
another aspect of this embodiment, R1 is F. ln another aspect of this embodiment, R1 is Cl. ln
another aspect of this embodiment, R1 is optionally substituted (C1-C8)a|ky|. ln another aspect of
this embodiment, R1 is methyl. ln another aspect of this embodiment, R1 is optionally substituted
(C2-C8)a|kenyl. ln another aspect of this embodiment, R1 is optionally substituted ethenyl. ln
another aspect of this embodiment, R1 is optionally substituted (C2-C8)a|kyny|. ln another aspect
of this embodiment, R1 is optionally substituted ethynyl. ln another aspect of this embodiment,
R2 is F. ln another aspect of this embodiment, R2 is Cl. ln another aspect of this embodiment, R2
is OH. ln another aspect of this embodiment R” is OH. ln another aspect of this embodiment,
each R2 and R” is OH. ln another aspect of this embodiment, each Rzis F and R” is OH. ln
another aspect of this embodiment, each R2 is Cl and R” is OH. ln another aspect of this
embodiment, each R' is Cl and each R2 is F. ln another aspect of this embodiment, each Rl is
CH3 and each Rz is Cl. ln another aspect of this embodiment, each R1 and R2 is Cl. ln another
37
M337 prio-lb
aspect of this embodiment, R7 is H. ln another aspect of this embodiment, R7 is optionally
substituted (C1-C8)alkyl. ln another aspect of this embodiment, R7 is optionally substituted (C2-
Cß)alkynyl. ln another aspect of this embodiment, R7 is CN. In another aspect of this
embodiment, one of RC or Rd is H. ln another aspect of this embodiment, one of R” or Rd is H
and the other of R° or Rd is optionally substituted (C1-C8)alkyl. ln another aspect of this
embodiment, RS is optionally substituted (C1-Cg)alkyl. In another aspect of this embodiment, RB
is optionally substituted (C3-C8)cycloalky|. ln another aspect of this embodiment, R4 is optionally
substituted (C6-C20)aryl. ln another aspect of this embodiment, Ar is optionally substituted
phenyL
ln another embodiment of the method for preparing a compound of Formula Xla or Formula Xlb
from a compound of Formula XII, X1 is N, R1 is H, CI or CH3 and one of R°or Rd is H. In another
aspect of this embodiment, R2 is F. ln another aspect of this embodiment, Rzis Cl. ln another
aspect of this embodiment, R2 is OH. ln another aspect of this embodiment R” is OH. ln
another aspect of this embodiment, each R2 and R” is OH. ln another aspect of this
embodiment, each R2 is F and R” is OH. ln another aspect of this embodiment, each R2 is Cl
and R” is OH. ln another aspect of this embodiment, each RI is Cl and each R2 is F. ln another
aspect of this embodiment, each RI is CH3 and each R2 is Cl. ln another aspect of this
embodiment, each R1 and R2 is Cl. ln another aspect of this embodiment, R7is H. ln another
aspect of this embodiment, R7 is optionally substituted (C1-C8)alkyl. ln another aspect of this
embodiment, R7 is CH3. ln another aspect of this embodiment, R7 is optionally substituted (C2-
Cß)alkynyl. ln another aspect of this embodiment, R? is ethynyl. ln another aspect of this
embodiment, R7 is CN. In another aspect of this embodiment, one of R° or Rd is H and the other
of R° or Rd is optionally substituted (C1-Cg)alkyl. ln another aspect of this embodiment, Rs is
optionally substituted (C1-C8)alkyl. ln another aspect of this embodiment, R4 is optionally
substituted (C6-C20)aryl. ln another aspect of this embodiment, Ar is optionally substituted
phenyl. In another aspect of this embodiment, Rs is NR11R” _ ln another aspect of this
embodiment, RQ is OR". In another aspect of this embodiment, Ra is NH2. In another aspect of
this embodiment, Rs is OH. ln another aspect of this embodiment, RQ is H. ln another aspect of
this embodiment, RQ is NR11R”. ln another aspect of this embodiment, RQ is OR”. In another
aspect of this embodiment, Ra is NRIINR” and Rgis H. ln another aspect of this embodiment,
RB is NRIIR” and RQ is NRIIR”.
ln another embodiment of the method for preparing a compound of Formula Xla or Formula Xlb
from a compound of Formula XII, X1 is N, R1 is H, CI or CH3, one of R° or Rd is H and R? is H. ln
another aspect of this embodiment, R2 is F. In another aspect of this embodiment, Rz is CI.In
another aspect of this embodiment, R2 is OH. ln another aspect of this embodiment, R” is OH.
ln another aspect of this embodiment, each R2 and R” is OH. ln another aspect of this
embodiment, each R2 is F and R” is OH. ln another aspect of this embodiment, each R2 is Cl
38
M337 prio-lb
and R” is OH. ln another aspect of this embodiment, each R1 is Cl and each Rz is F. ln another
aspect of this embodiment, each R1 is CH3 and each R2 is Cl. ln another aspect of this
embodiment, each R1 and R2 is Cl. ln another aspect of this embodiment, one of R° or Rd is H
and the other of R° or Rd is optionally substituted (C1-C8)alkyl. ln another aspect of this
embodiment, one of R° or Rd is H and the other of R° or Rd is CH3. ln another aspect of this
embodiment, RS is optionally substituted (C1-C8)a|ky|. ln another aspect of this embodiment, RB
is optionally substituted (C3-C8)cyc|oalky|. ln another aspect of this embodiment, R4 is optionally
substituted (C6-C20)ary|. ln another aspect of this embodiment, R4 is optionally substituted
phenyl. ln another aspect of this embodiment, Ar is optionally substituted phenyl. ln another
aspect of this embodiment, Rs is NR11R12 _ ln another aspect of this embodiment, Rs is OR11. ln
another aspect of this embodiment, Ra is NH2. ln another aspect of this embodiment, Rs is OH.
ln another aspect of this embodiment, RQ is H. ln another aspect of this embodiment, RQ is
NR11R12. ln another aspect of this embodiment, RQ is OR”. ln another aspect of this
embodiment, Rs is NR11R12 and Rg is H. ln another aspect of this embodiment, Ra is NH; and RQ
is H. ln another aspect of this embodiment, Ra is NR11R12 and RQ is NR11R12. ln another aspect
of this embodiment, Ra is NH2 and RQ is NH2. ln another aspect of this embodiment, Ra is OR"
and Rg is NH2. ln another aspect of this embodiment, Ra is OH and RQ is NH2.
ln another embodiment of the method for preparing a compound of Formula la or lb or a
pharmaceutically acceptable salt or ester thereof, Formula la is Formula Xllla, Formula lb is
Formula Xlllb and Formula ll is Formula XIV:
R O
H|R7 O o “N Hm" qHR7 O
H = _ R1 *WU/RC H :_ _: Rl
R? Rz R6_O Rd Ršz ëz
FormulaXllla FormulaXlllb
RB
X14\<
Ho O Náš
HNHI' *IIIHR7 O
H __. _; Rt
R2=2 ERZ
Formula XIV
39
M337 prio-lb
wherein: each R1 is independently H, halogen, optionally substituted (C1-C8)a|ky|, optionally
substituted (C2-C8)alkeny| or optionally substituted (C2-C8)alkynyl;
each Rz is independently halogen or ORM;
each RS is H;
each R” is OR" and
the remaining variables are defined as for Formulae la or lb or ll or llla or lllb.
ln one embodiment of the method for preparing a compound of Formula Xllla or Formula Xlllb
from a compound of Formula XIV, X1 is CR”. ln another aspect of this embodiment, R1° is H. ln
another aspect of this embodiment, R1° is CH3. ln another aspect of this embodiment, R1 is H. ln
another aspect of this embodiment, R1 is F. ln another aspect of this embodiment, R1 is Cl. ln
another aspect of this embodiment, R1 is optionally substituted (C1-C8)a|ky|. ln another aspect of
this embodiment, R1 is methyl. ln another aspect of this embodiment, R1 is optionally substituted
(C2-C8)alkenyl. ln another aspect of this embodiment, R1 is optionally substituted ethenyl. ln
another aspect of this embodiment, R1 is optionally substituted (C2-C8)a|kynyl. ln another aspect
of this embodiment, R1 is optionally substituted ethynyl. ln another aspect of this embodiment,
R2 is F. ln another aspect of this embodiment, R2 is Cl. ln another aspect of this embodiment, R2
is OH. ln another aspect of this embodiment R” is OH. ln another aspect of this embodiment,
each RZ and R” is OH. ln another aspect of this embodiment, each R2 is F and R” is OH. ln
another aspect of this embodiment, each Rz is Cl and R” is OH. ln another aspect of this
embodiment, each R1 is Cl and each R2 is F. ln another aspect of this embodiment, each R1 is
CH3 and each R2 is Cl. ln another aspect of this embodiment, each R1 and R2 is Cl.ln another
aspect of this embodiment, R7 is H. ln another aspect of this embodiment, R7 is optionally
substituted (C1-Cg)alkyl. ln another aspect of this embodiment, R7 is optionally substituted (C2-
C8)alkynyl. ln another aspect of this embodiment, R7 is CN. ln another aspect of this
embodiment, one of R° or Rd is H. ln another aspect of this embodiment, one of R° or Rd is H
and the other of R° or Rd is optionally substituted (C1-C8)alkyl. ln another aspect of this
embodiment, RB is optionally substituted (C1-C8)alky|. ln another aspect of this embodiment, RB
is optionally substituted (C3-C8)cyc|oalkyl. ln another aspect of this embodiment, R4 is optionally
substituted (C6-C20)aryl. ln another aspect of this embodiment, Ar is optionally substituted
phenyL
ln another embodiment of the method for preparing a compound of Formula Xllla or Formula
Xlllb from a compound of Formula XIV, X1 is CH, R1 is H, Cl or CH3 and one of R° or Rd is H. ln
another aspect of this embodiment, Rz is F. ln another aspect of this embodiment, Rz is Cl. ln
another aspect of this embodiment, R2 is OH. ln another aspect of this embodiment R” is OH.
ln another aspect of this embodiment, each R2 and R22 is OH. ln another aspect of this
embodiment, each R2 is F and R22 is OH. ln another aspect of this embodiment, each R2 is Cl
40
M337 prio-lb
and R22 is OH. ln another aspect of this embodiment, each R1 is Cl and each R2 is F. ln another
aspect of this embodiment, each R1 is CH3 and each R2 is Cl. ln another aspect of this
embodiment, each R1 and R2 is Cl. ln another aspect of this embodiment, R7 is H. ln another
aspect of this embodiment, R7 is optionally substituted (C1-C8)alky|. ln another aspect of this
embodiment, Ry is CH3. ln another aspect of this embodiment, R7 is optionally substituted (C2-
C8)alkynyl. ln another aspect of this embodiment, R7 is ethynyl. ln another aspect of this
embodiment, R7 is CN. ln another aspect of this embodiment, one of R° or Rd is H and the other
of R° or Rd is optionally substituted (C1-Cg)alkyl. ln another aspect of this embodiment, RB is
optionally substituted (C1-C8)alkyl. ln another aspect of this embodiment, R4 is optionally
substituted (C6-C20)aryl. ln another aspect of this embodiment, Ar is optionally substituted
phenyl. ln another aspect of this embodiment, Rs is NR11R12. ln another aspect of this
embodiment, Ra is OR11. ln another aspect of this embodiment, RB is NH2. ln another aspect of
this embodiment, Ra is OH.
ln another embodiment of the method for preparing a compound of Formula Xllla or Formula
Xlllb from a compound of Formula XIV, X1 is CH, R1 is H, Cl or CH3, one of R° or Rd is H and R7
is H. ln another aspect of this embodiment, R2 is F. ln another aspect of this embodiment, R2 is
Cl. ln another aspect of this embodiment, R2 is OH. ln another aspect of this embodiment R22 is
OH. ln another aspect of this embodiment, each R2 and R” is OH. ln another aspect of this
embodiment, each R2 is F and R” is OH. ln another aspect of this embodiment, each R2 is Cl
and R22 is OH. ln another aspect of this embodiment, one of R° or Rd is H and the other of R° or
Rd is optionally substituted (C1-C8)alkyl. ln another aspect of this embodiment, one of R° or Rd is
H and the other of R° or Rd is CH3. ln another aspect of this embodiment, RB is optionally
substituted (C1-C8)alkyl. ln another aspect of this embodiment, R4 is optionally substituted (C6-
C20)aryl. ln another aspect of this embodiment, R4 is optionally substituted phenyl. ln another
aspect of this embodiment, Ar is optionally substituted phenyl. ln another aspect of this
embodiment, Rs is NR11R12. ln another aspect of this embodiment, Ra is OR”. ln another aspect
of this embodiment, Rs is NH2. ln another aspect of this embodiment, Rßis OH.
ln one embodiment of the method for preparing a compound of Formula Xllla or Formula Xlllb
from a compound of Formula XIV, X1 is CF. ln another aspect of this embodiment, R1 is H. ln
another aspect of this embodiment, R1 is F. ln another aspect of this embodiment, R1 is Cl. ln
another aspect of this embodiment, R1 is optionally substituted (C1-C8)alkyl. ln another aspect of
this embodiment, R1 is methyl. ln another aspect of this embodiment, R1 is optionally substituted
(C2-C8)alkenyl. ln another aspect of this embodiment, R1 is optionally substituted ethenyl. ln
another aspect of this embodiment, Rl is optionally substituted (C2-C8)a|kynyl. ln another aspect
of this embodiment, R1 is optionally substituted ethynyl. ln another aspect of this embodiment,
R2 is F. ln another aspect of this embodiment, R2 is Cl. ln another aspect of this embodiment, R2
is OH. ln another aspect of this embodiment R22 is OH. ln another aspect of this embodiment,
41
M337 prio-lb
each R2 and R22 is OH. ln another aspect of this embodiment, each R2 is F and R” is OH. ln
another aspect of this embodiment, each R2 is Cl and R” is OH. ln another aspect of this
embodiment, R7 is H. ln another aspect of this embodiment, R7 is optionally substituted (C1-Cß
)a|ky|. ln another aspect of this embodiment, R7 is optionally substituted (C2-C8)a|kyny|. ln
another aspect of this embodiment, R7 is CN. ln another aspect of this embodiment, one of R°
or Rd is H. ln another aspect of this embodiment, one of R° or Rd is H and the other of R° or Rd is
optionally substituted (C1-C8)a|kyl. ln another aspect of this embodiment, Rsis optionally
substituted (C1-C8)a|ky|. ln another aspect of this embodiment, RB is optionally substituted (C3-
C8)cyc|oa|ky|. ln another aspect of this embodiment, R4 is optionally substituted (C6-C20)ary|. ln
another aspect of this embodiment, Ar is optionally substituted phenyl.
ln another embodiment of the method for preparing a compound of Formula Xla or Formula Xlb
from a compound of Formula XII, X1 is CF, R1 is H, Cl or CH3 and one of R° or Rd is H. ln
another aspect of this embodiment, R2 is F. ln another aspect of this embodiment, R2 is Cl. ln
another aspect of this embodiment, R2 is OH. ln another aspect of this embodiment R” is OH.
ln another aspect of this embodiment, each Rzand R” is OH. ln another aspect of this
embodiment, each R2 is F and R” is OH. ln another aspect of this embodiment, each R2 is Cl
and R” is OH. ln another aspect of this embodiment, R7is H. ln another aspect of this
embodiment, R7 is optionally substituted (C1-Cß)a|ky|. ln another aspect of this embodiment, R7
is CH3. ln another aspect of this embodiment, R? is optionally substituted (C2-C8)a|kyny|. ln
another aspect of this embodiment, R7is ethynyl. ln another aspect of this embodiment, R7 is
CN. ln another aspect of this embodiment, one of R° or Rd is H and the other of R° or Rd is
optionally substituted (C1-C8)a|kyl. ln another aspect of this embodiment, RB is optionally
substituted (C1-C8)a|ky|. ln another aspect of this embodiment, R4 is optionally substituted (C6-
C20)ary|. ln another aspect of this embodiment, Ar is optionally substituted phenyl. ln another
aspect of this embodiment, Ra is NR11R12. ln another aspect of this embodiment, Rs is OR”. ln
another aspect of this embodiment, Ra is NH2. ln another aspect of this embodiment, Ra is OH.
ln another embodiment of the method for preparing a compound of Formula Xllla or Formula
xiiib from a oompounoi of Formuia xiv, X1 is ci=, Rt is i-i, ci or cHs, ons of R° or Rd is H and RV
is H. ln another aspect of this embodiment, Rz is F. ln another aspect of this embodiment, R2 is
Cl. ln another aspect of this embodiment, Rz is OH. ln another aspect of this embodiment R” is
OH. ln another aspect of this embodiment, each R2 and R” is OH. ln another aspect of this
embodiment, each R2 is F and R” is OH. ln another aspect of this embodiment, each R2 is Cl
and R” is OH. ln another aspect of this embodiment, one of R° or Rd is H and the other of R° or
Rd is optionally substituted (C1-C8)a|ky|. ln another aspect of this embodiment, one of R°or Rd is
H and the other of R° or Rd is CH3. ln another aspect of this embodiment, Re is optionally
substituted (C1-C8)a|ky|. ln another aspect of this embodiment, RB is optionally substituted (C3-
Cg)cycloalkyl. ln another aspect of this embodiment, R4 is optionally substituted (C6-C20)ary|. ln
42
M337 prio-lb
another aspect of this embodiment, R4 is optionally substituted phenyl. ln another aspect of this
embodiment, Ar is optionally substituted phenyl. ln another aspect of this embodiment, Rs is
NR11R12. ln another aspect of this embodiment, R8is OR”. ln another aspect of this
embodiment, Ra is NH2. ln another aspect of this embodiment, RS is OH.
DEFINITIONS
Unless stated othenNise, the following terms and phrases as used herein are intended to have
the following meanings: When trade names are used herein, applicants intend to independently
include the tradename product and the active pharmaceutical ingredient(s) of the tradename
product.
As used herein, "a compound of the invention" or "a compound of Formula l" means a
compound of Formula I or a pharmaceutically acceptable salt, thereof. Similarly, with respect to
isolatable intermediates, the phrase "a compound of Formula (number)" means a compound of
that formula and pharmaceutically acceptable salts, thereof.
"Alkyl" is hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. For
example, an alkyl group can have 1 to 20 carbon atoms (i.e, C1-C20alkyl), 1 to 8 carbon atoms
(i.e. C1-C8alkyl), or 1 to 6 carbon atoms (i.e. C1-C6alkyl). Examples of suitable alkyl groups
include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -
CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-
methyl-l-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-
methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-
CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-
2-butyl (-CH(CH3)CH(CH3)2), 3 -methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-
CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3),
3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-
pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-
pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-
C(CH3)2CH(CHa)z), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, and octyl (-(CH2)7CH3).
"Alkoxy" means a group having the formula -O-alkyl, in which an alkyl group, as defined above,
is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group can
have 1 to 20 carbon atoms (i.e. C1-C20alkoxy), 1 to 12 carbon atoms(i.e. C1-C12 alkoxy), or 1 to 6
carbon atoms (i.e. C1-C6alkoxy). Examples of suitable alkoxy groups include, but are not limited
to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), t-butoxy (-O-C(CH3)3 or -OtBu) and
the like.
"Haloalkyl" is an alkyl group, as defined above, in which one or more hydrogen atoms of the
alkyl group is replaced with a halogen atom. The alkyl portion of a haloalkyl group can have 1 to
20 carbon atoms (i.e. C1-C20haloalkyl), 1 to 12 carbon atoms (i.e. C1-C12haloalkyl), or 1 to 6
43
M337 prio-lb
carbon atoms (i.e. C1-C6alkyl). Examples of suitable haloalkyl groups include, but are not limited
to, -CF3, -CHF2, -CFH2, -CH2CF3, and the like.
"Alkenyl" is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at
least one site of unsaturation, i.e. a carbon-carbon, sp2 double bond. For example, an alkenyl
group can have 2 to 20 carbon atoms (i.e. C2-C2o alkenyl), 2 to 8 carbon atoms (i.e. Cz-Cß
alkenyl), or 2 to 6 carbon atoms (i.e. Cz-Cßalkenyl). Examples of suitable alkenyl groups include,
but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7),
and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).
"Alkynyl" is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at
least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. For example, an alkynyl
group can have 2 to 20 carbon atoms (i.e. C2-C20 alkynyl), 2 to 8 carbon atoms (i.e. Cg-Cg
alkynyl), or 2 to 6 carbon atoms (i.e. Cz-Cß alkynyl). Examples of suitable alkynyl groups include,
but are not limited to, acetylenic (-CECH), propargyl (-CH2CECH), and the like.
"A|kylene" refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having
two monovalent radical centers derived by the removal of two hydrogen atoms from the same or
two different carbon atoms of a parent alkane. For example, an alkylene group can have 1 to 20
carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene radicals include,
but are not limited to, methylene (-CH2-), 1,1-ethy| (-CH(CH3)-), 1,2-ethy| (-CH2CH2-), 1,1-propy|
(-CH(CH2CH3)-), 1,2-propyl (-CH2CH(CH3)-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-
CHZCHZCHZCHT), and the like.
"Alkenylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical
having two monovalent radical centers derived by the removal of two hydrogen atoms from the
same or two different carbon atoms of a parent alkene. For example, an alkenylene group can
have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkenylene
radicals include, but are not limited to, 1,2-ethylene (-CH=CH-).
"Alkynylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical
having two monovalent radical centers derived by the removal of two hydrogen atoms from the
same or two different carbon atoms of a parent alkyne. For example, an alkynylene group can
have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkynylene
radicals include, but are not limited to, acetylene (-CEC-), propargyl (-CH2CEC-), and 4-pentynyl
(-CH2CH2CH2CEC-).
"Amino" refers generally to a nitrogen radical which can be considered a derivative of ammonia,
having the formula -N(X)2, where each "X" is independently H, substituted or unsubstituted alkyl,
substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, etc. The
hybridization of the nitrogen is approximately spg. Nonlimiting types of amino include -NH2, -
N(alkyl)2, -NH(alkyl), -N(carbocyclyl)2, - NH(carbocyclyl), -N(heterocyclyl)2, -NH(heterocyclyl), -
44
M337 prio-lb
N(ary|)2, -NH(ary|), - N(a|ky|)(ary|), -N(alkyl)(heterocyclyl), -N(carbocyclyl)(heterocyclyl), -
N(ary|)(heteroary|), -N(a|ky|)(heteroary|), etc. The term "alky|amino" refers to an amino group
substituted with at least one alkyl group. Nonlimiting examples of amino groups include - NH2 -
NH(CH3), -N(CH3)2, -NH(CH2CH3), - N(CH2CH3)2, - NH(pheny|), -N(pheny|)2, -NH(benzy|), -
N(benzyl)2, etc. Substituted alkylamino refers generally to alkylamino groups, as defined above,
in which at least one substituted alkyl, as defined herein, is attached to the amino nitrogen
atom. Non-limiting examples of substituted alkylamino includes -NH(alkylene-C(O)-OH), -
NH(alkylene-C(O)-O-alkyl), -N(alkylene-C(O)-OH)2, -N(alkylene-C(O)-O-alkyl)2, etc.
"Ary|" means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom
from a single carbon atom of a parent aromatic ring system. For example, an aryl group can
have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups
include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted
benzene, naphthalene, anthracene, biphenyl, and the like.
"Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a
carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl radical. Typical
arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-
naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. The arylalkyl group
can comprise 7 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms and the aryl
moiety is 6 to 14 carbon atoms.
"Ary|alkeny|" refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a
carbon atom, typically a terminal or sp3 carbon atom, but also an sp2 carbon atom, is replaced
with an aryl radical. The aryl portion of the arylalkenyl can include, for example, any of the aryl
groups disclosed herein, and the alkenyl portion of the arylalkenyl can include, for example, any
of the alkenyl groups disclosed herein. The arylalkenyl group can comprise 8 to 20 carbon
atoms, e.g., the alkenyl moiety is 2 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon
atoms.
"Arylalkynyl" refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a
carbon atom, typically a terminal or sp3 carbon atom, but also an sp2 carbon atom, is replaced
with an aryl radical. The aryl portion of the arylalkynyl can include, for example, any of the aryl
groups disclosed herein, and the alkynyl portion of the arylalkynyl can include, for example, any
of the alkynyl groups disclosed herein. The arylalkynyl group can comprise 8 to 20 carbon
atoms, e.g., the alkynyl moiety is 2 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon
atoms.
The term "substituted" in reference to alkyl, alkylene, aryl, arylalkyl, alkoxy, heterocyclyl,
heteroaryl, carbocyclyl, etc., for example, "substituted alkyl","substituted alkylene", "substituted
aryl", "substituted ary|a|kyl", "substituted heterocyc|y|", and "substituted carbocyclyl" means,
45
M337 prio-lb
unless otherwise stated, alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl respectively, in
which one or more hydrogen atoms are each independently replaced with a non-hydrogen
substituent. Typical substituents include, but are not limited to, -X, -Rb, -O', =O, -ORb, -SRb, -S',
-NRb2, -N*Rb3, =NR'“, -CX3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N2, -N3, -
NHc(=o)Rb, -oc(=o)Rb, -NHc(=o)NRb2, -s(=o)2-, -s(=o)2oH, -s(=o)2Rb, -os(=o)2oRb, -
S(=0)2NR*'2, -S(=0)Rb, -0P(=0)(0Rb)2, -P(=0)(0Rb)2, -P(=0)(0R')2, -P(=0)(0H)2, -
P(O)(ORb)(O'), -C(=O)Rb, -C(=O)X, -C(S)R”, -C(O)ORb, -C(O)O', -C(S)OR”, -C(O)SRb, -
c(s)sRb, -c(o)NRb2, -c(s)NRb2, -c(=NRb)NRb2, where each x is independently a halogen: F,
Cl, Br, or I; and each Rb is independently H, alkyl, aryl, arylalkyl, a heterocycle, or a protecting
group or prodrug moiety. Alkylene, alkenylene, and alkynylene groups may also be similarly
substituted. Unless otherwise indicated, when the term "substituted" is used in conjunction with
groups such as arylalkyl, which have two or more moieties capable of substitution, the
substituents can be attached to the aryl moiety, the alkyl moiety, or both.
The term "prodrug" as used herein refers to any compound that when administered to a
biological system generates the drug substance, i.e. active ingredient, as a result of
spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or
metabolic chemical reaction(s). A prodrug is thus a covalently modified analog or latent form of
a therapeutically active compound.
One skilled in the art will recognize that substituents and other moieties of the compounds of
Formula I-XIV should be selected in order to provide a compound which is sufficiently stable to
provide a pharmaceutically useful compound which can be formulated into an acceptably stable
pharmaceutical composition. Compounds of Formula I-XIV which have such stability are
contemplated as falling within the scope of the present invention.
"Heteroalkyl" refers to an alkyl group where one or more carbon atoms have been replaced with
a heteroatom, such as, O, N, or S. For example, if the carbon atom of the alkyl group which is
attached to the parent molecule is replaced with a heteroatom (e.g., O, N, or S) the resulting
heteroalkyl groups are, respectively, an alkoxy group (e.g., -OCH3, etc.), an amine (e.g. -
NHCH3, -N(CH3)2, etc.), or a thioalkyl group (e.g. -SCH3). lf a non-terminal carbon atom of the
alkyl group which is not attached to the parent molecule is replaced with a heteroatom (e.g., O,
N, or S) the resulting heteroalkyl groups are, respectively, an alkyl ether (e.g., -CH2CH2-O-CH3,
etc.), an alkyl amine (e.g., -CH2NHCH3, -CH2N(CH3)2, etc.), or a thioalkyl ether (e.g.,-CH2-S-
CH3). lf a terminal carbon atom of the alkyl group is replaced with a heteroatom (e.g., O, N, or
S), the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (e.g.,-CH2CH2-OH),
an aminoalkyl group (e.g., -CH2NH2), or an alkyl thiol group (e.g. -CHzCHz-SH). A heteroalkyl
group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon
atoms. A C1-C6 heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms.
46
M337 prio-lb
"Heterocycle" or "heterocyclyl" as used herein includes by way of example and not limitation
those heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry
(W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of
Heterocyclic Compounds, A Series of Monographs" (John Wiley & Sons, New York, 1950 to
present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 8225566.
ln one specific embodiment of the invention "heterocycle" includes a "carbocycle" as defined
herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a
heteroatom (e.g. O, N, or S). The terms "heterocyc|e" or "heterocyc|yl" includes saturated rings,
partially unsaturated rings, and aromatic rings (i.e. heteroaromatic rings). Substituted
heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents
disclosed herein including carbonyl groups. A non-limiting example of a carbonyl substituted
heterocyclyl is:
.ïNm/NH
O
Examples of heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl,
tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl,
pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl,
thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-
piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-
1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl,
chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl,
indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl,
naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, ß-
carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,
furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,
pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl,
benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl:
ko)
By way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3,
4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine,
position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran,
thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole,
position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine,
47
M337 prio-lb
position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4,
5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-
pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3 -pyridazinyl, 4-pyridazinyl, 5- pyridazinyl, 6-
pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5 -pyrimidinyl, 6- pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-
pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4- thiazolyl, or 5-thiazolyl.
By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of
an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3- pyrroline, imidazole, imidazolidine, 2-
imidazoline, 3 -imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine,
piperazine, indole, indoline, 1H- indazole, position 2 of a isoindole, or isoindoline, position 4 of a
morpholine, and position 9 of a carbazole, or ß-carboline. Still more typically, nitrogen bonded
heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1 -pyrazolyl, and 1-
piperidinyl.
"Heterocyclylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded
to a carbon atom, typically a terminal or sps carbon atom, is replaced with a heterocyclyl radical
(i.e. a heterocyclyl-alkylene- moiety). Typical heterocyclylalkyl groups include, but are not limited
to heterocyclyl-CH2-, 2-(heterocyclyl)ethan-1-yl, and the like, wherein the "heterocyc|yl" portion
includes any of the heterocyclyl groups described above, including those described in Principles
of Modem Heterocyclic Chemistry. One skilled in the art will also understand that the
heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by means of a
carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is
chemically stable. The heterocyclyl alkyl group comprises 3 to 20 carbon atoms, e.g., the alkyl
portion of the arylalkyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14
carbon atoms. Examples of heterocyclylalkyls include by way of example and not limitation 5-
membered sulfur, oxygen, and/or nitrogen containing heterocycles such as thiazolylmethyl, 2-
thiazolylethan-l-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered
sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylm ethyl,
piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl,
pyrazinylmethyl, etc.
"Heterocyclylalkenyl" refers to an acyclic alkenyl radical in which one of the hydrogen atoms
bonded to a carbon atom, typically a terminal or spa carbon atom, but also a sp2 carbon atom, is
replaced with a heterocyclyl radical (i.e. a heterocyclyl-alkenylene-moiety). The heterocyclyl
portion of the heterocyclylalkenyl group includes any of the heterocyclyl groups described
herein, including those described in Principles of Modern Heterocyclic Chemistry, and the
alkenyl portion of the heterocyclylalkenyl group includes any of the alkenyl groups disclosed
herein. One skilled in the art will also understand that the heterocyclyl group can be attached to
the alkenyl portion of the heterocyclylalkenyl by means of a carbon-carbon bond or a carbon-
heteroatom bond, with the proviso that the resulting group is chemically stable. The
48
M337 prio-lb
heterocyclylalkenyl group comprises 4 to 20 carbon atoms, e.g., the alkenyl portion of the
heterocyclylalkenyl group is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon
atoms.
"Heterocyclylalkyny|" refers to an acyclic alkynyl radical in which one of the hydrogen atoms
bonded to a carbon atom, typically a terminal or sps carbon atom, but also an sp2 carbon atom,
is replaced With a heterocyclyl radical (i.e. a heterocyclylalkynylene- moiety). The heterocyclyl
portion of the heterocyclylalkynyl group includes any of the heterocyclyl groups described
herein, including those described in Principles of Modern Heterocyclic Chemistry, and the
alkynyl portion of the heterocyclylalkynyl group includes any of the alkynyl groups disclosed
herein. One skilled in the art will also understand that the heterocyclyl group can be attached to
the alkynyl portion of the heterocyclylalkynyl by means of a carbon-carbon bond or a carbon-
heteroatom bond, with the proviso that the resulting group is chemically stable. The
heterocyclylalkynyl group comprises 4 to 20 carbon atoms, e.g., the alkynyl portion of the
heterocyclyl alkynyl group is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon
atoms.
"Heteroaryl" refers to an aromatic heterocyclyl having at least one heteroatom in the ring. Non-
limiting examples of suitable heteroatoms which can be included in the aromatic ring include
oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include all of those
aromatic rings listed in the definition of "heterocyclyl", including pyridinyl, pyrrolyl, oxazolyl,
indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl,
thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc.
The term "purine" or "pyrimidine" base comprises, but is not limited to, adenine, NS-alkylpurines,
NG-acylpurines (wherein acyl is C(O)(alky|, aryl, alkylaryl, or arylalkyl), NB-benzylpurine, N6-
halopurine, Ns-vinylpurine, NG-acetylenic purine, NG-acyl purine, NG-hydroxyalkyl purine, N6-
allylaminopurine, Nö-thioallyl purine, Nz-alkylpurines, N-alkyl-6-thiopurines, thymine, cytosine, 5-
fluorocytosine, 5- methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-
mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil, Cs-alkylpyrimidines, C5-
benzylpyrimidines, Cs-halopyrimidines, Cö-vinylpyrimidine, G5- acetylenic pyrimidine, Cö-acyl
pyrimidine, Cs-hydroxyalkyl purine, Cs-amidopyrimidine, Cs-cyanopyrimidine, C5-5-
iodopyrimidine, Ce-iodo-pyrimidine, G5- Br-vinyl pyrimidine, Ce-Br- vinyl pyrimidine, C5-
nitropyrimidine, Cö-amino- pyrimidine, Nz-alkylpurines, NZ-alkyl-G-thiopurines, 5-azacytidinyl, 5-
azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl.
Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine,
and 6-chloropurine. Additional non-classical purine bases include pyrrolo[1,2-?[1,2,4] triazines,
imidazo[1,5-f][1,2,4]triazines, imidazo[1,2-f][1,2,4]triazines, and [12,4]triazolo[4,3-
t][1,2,4]triazines, all of which are optionally substituted. The purine and pyrimidine bases of
Formula ll are linked to the ribose sugar, or analog thereof, through a nitrogen atom or carbon
49
M337 prio-lb
atom of the base. Functional oxygen and nitrogen groups on the base can be protected as
necessary or desired. Suitable protecting groups are well known to those skilled in the art, and
include, but are not limited to, trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-
butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl,
methanesulfonyl, and p-toluenesulfonyl.
"Carbocycle" or "carbocyc|y|" refers to a saturated (i.e. cycloalkyl), partially unsaturated (e.g.,
cycloakenyl, cycloalkadienyl, etc.) or aromatic ring having 3 to 7 carbon atoms as a monocycle,
7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. l\/lonocyclic
carbocycles have 3 to 7 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles
have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10
ring atoms arranged as a bicyclo [5,6] or [6,6] system, or spiro-fused rings. Non-limiting
examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-
enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,
1-cyclohex-3-enyl, and phenyl. Non-limiting examples of bicyclocarbocycles includes naphthyl,
tetrahydronapthalene, and decaline.
"Carbocyc|ylalky|" refers to to an acyclic alkyl radical in which one of the hydrogen atoms
bonded to a carbon atom is replaced with a carbocyclyl radical as described herein. Typical, but
non-limiting, examples of carbocyclylalkyl groups include cyclopropylmethyl, cyclopropylethyl,
cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
"Arylheteroalkyl" refers to a heteroalkyl as defined herein, in which a hydrogen atom (which may
be attached either to a carbon atom or a heteroatom) has been replaced with an aryl group as
defined herein. The aryl groups may be bonded to a carbon atom of the heteroalkyl group, or to
a heteroatom of the heteroalkyl group, provided that the resulting arylheteroalkyl group provides
a chemically stable moiety. For example, an arylheteroalkyl group can have the general
formulae -alkylene- O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-
aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl, etc. ln addition, any of the alkylene moieties in
the general formulae above can be further substituted with any of the substituents defined or
exemplified herein.
"Heteroaryla|kyl" refers to an alkyl group, as defined herein, in which a hydrogen atom has been
replaced with a heteroaryl group as defined herein. Non- limiting examples of heteroaryl alkyl
include -CHz-pyridinyl, -CHz-pyrrolyl, -CHz-oxazolyl, -CHz-indolyl, -CHz-isoindolyl, -CHz-purinyl, -
GHz-furanyl, -CHg-thienyl, -CHz-benzofuranyl, -CHz-benzothiophenyl, -CHz-earbazolyl, -CHZ-
imidazolyl, -CHz-thiazolyl, -CHz-isoxazolyl, -CHz-pyrazolyl, -CHz-isothiazolyl, -CHz-quinolyl, -
CHz-isoquinolyl, -CHz-pyridazyl, -CHz-pyrimidyl, -CHg-pyrazyl, -CH(CH3)-pyridiny|, -CH(CH3)-
pyrrolyl, -CH(CH3)-oxazoly|, -CH(CH3)-indolyl, -CH(CH3)-isoindoly|, -CH(CH3)-purinyl, -CH(CH3)-
furanyl, -CH(CH3)-thieny|, -CH(CH3)-benzofurany|, -CH(CH3)-benzothiopheny|, -CH(CH3)-
50
M337 prio-lb
carbazolyl,-CH(CH3)-imidazolyl, -CH(CH3)-thiazolyl, -CH(CH3)-isoxazolyl,-CH(CH3)-pyrazolyl, -
CH(CH3)-isothiazo|y|, -CH(CH3)-quinolyl,-CH(CH3)-isoquino|y|, -CH(CH3)-pyridazyl, -CH(CH3)-
pyrimidyl, -CH(CH3)-pyrazy|, etc.
The term "optiona|ly substituted" in reference to a particular moiety of the compound of Formula
I-XIV (e.g., an optionally substituted aryl group) refers to a moiety wherein all substituents are
hydrogen or wherein one or more of the hydrogens of the moiety may be replaced by
substituents such as those listed under the definition of "substituted".
The term "optiona|ly replaced" in reference to a particular moiety of the compound of Formula I-
XIV (e.g., the carbon atoms of said (C1-C8)alkyl may be optionally replaced by -O-, -S-, or -NRa-)
means that one or more of the methylene groups of the (C1-C8)alkyl may be replaced by 0, 1, 2,
or more of the groups specified (e.g., -O-, -S-, or -NRa-).
The term "non-terminal carbon atom(s)" in reference to an alkyl, alkenyl, alkynyl, alkylene,
alkenylene, or alkynylene moiety refers to the carbon atoms in the moiety that intervene
between the first carbon atom of the moiety and the last carbon atom in the moiety. Therefore,
by way of example and not limitation, in the alkyl moiety -CH2(C*)H2(C*)H2CH3 or alkylene
moiety -CH2(C*)H2(C*)H2CH2- the C* atoms would be considered to be the non-terminal carbon
atoms.
"Linker" or "|ink" means a chemical moiety comprising a covalent bond or a chain of atoms.
Linkers include repeating units of alkyloxy (e.g. polyethyleneoxy, PEG, polymethyleneoxy) and
alkylamino (e.g. polyethyleneamino, JeffamineTM); and diacid ester and amides including
succinate, succinamide, diglycolate, malonate, and caproamide.
The terms such as "oxygen-linked", "nitrogen-|inked", "carbon-|inked", "su|fur-|inked", or
"phosphorous-linked" mean that if a bond between tvvo moieties can be formed by using more
than one type of atom in a moiety, then the bond formed between the moieties is through the
atom specified. For example, a nitrogen-Iinked amino acid would be bonded through a nitrogen
atom of the amino acid rather than through an oxygen or carbon atom of the amino acid.
Some embodiments of the compounds of Formula I-XIV comprise the moiety
O lï5
Rkoßïšuïf
Rd Rc
which may comprise a radical of a nitrogen-linked ester of a naturally occurring alpha amino
acid. Examples of naturally occurring amino acids include isoleucine, leucine, lysine,
methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid,
cysteine, glutamic acid, glutamine, glycine, proline, selenocysteine, serine, tyrosine, arginine,
histidine, ornithine and taurine. The esters of these amino acids comprise any of those
51
M337 prio-lb
described for the substitutent RS, particularly those in which RB is optionally substituted (C1-
Cg)alkyl.
Unless otherwise specified, the carbon atoms of the compounds of Formula l- XIV are intended
to have a valence of four. ln some chemical structure representations where carbon atoms do
not have a sufficient number of variables attached to produce a valence of four, the remaining
carbon substituents needed to provide a valence of four should be assumed to be hydrogen.
For example,
has the same meaning as
"Protecting group" refers to a moiety of a compound that masks or alters the properties of a
functional group or the properties of the compound as a whole. The chemical substructure of a
protecting group varies widely. One function of a protecting group is to serve as an intermediate
in the synthesis of the parental drug substanoe. Chemical protecting groups and strategies for
protection/deprotection are well known in the art. See: "Protective Groups in Organic
Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991. Protecting groups
are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of
desired chemical reactions, e.g. making and breaking chemical bonds in an ordered and
planned fashion. Protection of functional groups of a compound alters other physical properties
besides the reactivity of the protected functional group, such as the polarity, lipophilicity
(hydrophobicity), and other properties which can be measured by common analytical tools.
Chemically protected intermediates may themselves be biologically active or inactive.
Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro
and in vivo, such as passage through cellular membranes and resistance to enzymatic
52
M337 prio-lb
degradation or sequestration. ln this role, protected compounds with intended therapeutic
effects may be referred to as prodrugs. Another function of a protecting group is to convert the
parental drug into a prodrug, whereby the parental drug is released upon conversion of the
prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental
drug, prodrugs may possess greater potency in vivo than the parental drug. Protecting groups
are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of
prodrugs. With chemical intermediates, it is not particularly important that the resulting products
after deprotection, e.g. alcohols, be physiologically acceptable, although in general it is more
desirable if the products are pharmacologically innocuous.
"Prodrug moiety" means a labile functional group which separates from the active inhibitory
compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or
by some other process (Bundgaard, Hans, "Design and Application of Prodrugs" in Textbook of
Drug Design and Development ( 1991 ), P . Krogsgaard-Larsen and H. Bundgaard, Eds.
Harwood Academic Publishers, pp. 113- 191). Enzymes which are capable of an enzymatic
activation mechanism with the prodrug compounds of the invention include, but are not limited
to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and
phosphases. Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to
optimize drug delivery, bioavailability and efficacy.
A prodrug moiety may include an active metabolite or drug itself.
lt is to be noted that all enantiomers, diastereomers, and racemic mixtures, tautomers,
polymorphs, pseudopolymorphs of compounds within the scope of Formula l- IV and
pharmaceutically acceptable salts thereof are embraced by the present invention. All mixtures
of such enantiomers and diastereomers are within the scope of the present invention.
A compound of Formula I-XIV and its pharmaceutically acceptable salts may exist as different
polymorphs or pseudopolymorphs. As used herein, crystalline polymorphism means the ability
of a crystalline compound to exist in different crystal structures. The crystalline polymorphism
may result from differences in crystal packing (packing polymorphism) or differences in packing
between different conformers of the same molecule (conformational polymorphism). As used
herein, crystalline pseudopolymorphism means the ability of a hydrate or solvate of a compound
to exist in different crystal structures. The pseudopolymorphs of the instant invention may exist
due to differences in crystal packing (packing pseudopolymorphism) or due to differences in
packing between different conformers of the same molecule (conformational
pseudopolymorphism). The instant invention comprises all polymorphs and pseudopolymorphs
of the compounds of Formula I-IV and their pharmaceutically acceptable salts.
A compound of Formula I-XIV and its pharmaceutically acceptable salts may also exist as an
amorphous solid. As used herein, an amorphous solid is a solid in which there is no long-range
order of the positions of the atoms in the solid. This definition applies as Well when the crystal
53
M337 prio-lb
size is two nanometers or less. Additives, including solvents, may be used to create the
amorphous forms of the instant invention. The instant invention comprises all amorphous forms
of the compounds of Formula I-IV and their pharmaceutically acceptable salts.
Selected substituents comprising the compounds of Formula I-XIV are present to a recursive
degree. ln this context, "recursive substituent" means that a substituent may recite another
instance of itself. Because of the recursive nature of such substituents, theoretically, a large
number of compounds may be present in any given embodiment. One of ordinary skill in the art
of medicinal chemistry understands that the total number of such substituents is reasonably
limited by the desired properties of the compound intended. Such properties include, by way of
example and not limitation, physical properties such as molecular weight, solubility or log P,
application properties such as activity against the intended target, and practical properties such
as ease of synthesis. Recursive substituents are an intended aspect of the invention. One of
ordinary skill in the art of medicinal chemistry understands the versatility of such substituents.
To the degree that recursive substituents are present in an embodiment of the invention, they
may recite another instance of themselves, 0, 1, 2, 3, or 4 times. The modifier "about" used in
connection with a quantity is inclusive of the stated value and has the meaning dictated by the
context (e.g., includes the degree of error associated with measurement of the particular
quantity).
Any reference to the compounds of the invention described herein also includes a reference to
a physiologically acceptable salt thereof. Examples of physiologically acceptable salts of the
compounds of the invention include salts derived from an appropriate base, such as an alkali
metal or an alkaline earth (for example, Na+, Li+, K+, Ca+2 and |V|g+2, ammonium and NRT
(wherein Ra is defined herein). Physiologically acceptable salts of a nitrogen atom or an amino
group include (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid,
hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric acid and the like; (b) salts
formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic
acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid,
isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid,
naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid,
naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid,
2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic
acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine,
isoleucine, leucine and the like; and (c) salts formed from elemental anions for example,
chlorine, bromine, and iodine.
Physiologically acceptable salts of a compound of a hydroxy group include the anion of said
compound in combination with a suitable cation such as Na* and NRT.
54
M337 prio-lb
For therapeutic use, salts of active ingredients of the compounds of the invention will be
physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid
or base. However, salts of acids or bases which are not physiologically acceptable may also
find use, for example, in the preparation or purification of a physiologically acceptable
compound. All salts, whether or not derived form a physiologically acceptable acid or base, are
within the scope of the present invention. Finally, it is to be understood that the compositions
herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and
combinations with stoichiometric amounts of water as in hydrates.
The compounds of the invention, exemplified by Formula I-XIV have chiral centers, e.g. chiral
carbon or phosphorus atoms. For example, the phosphorous atoms of Formula I-XIV may be
chiral because they have four different substituents. The compounds of the invention thus
include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and
atropisomers. ln addition, the compounds of the invention include enriched or resolved optical
isomers at any or all asymmetric, chiral atoms. ln other words, the chiral centers apparent from
the depictions are provided as the chiral isomers or racemic mixtures. Both racemic and
diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized,
substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the
invention. The racemic mixtures are separated into their individual, substantially optically pure
isomers through well-known techniques such as, for example, the separation of diastereomeric
salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to
the optically active substances. ln most instances, the desired optical isomer is synthesized by
means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired
starting material.
The term "chiral" refers to molecules which have the property of non-superimposability of the
mirror image partner, while the term "achiral" refers to molecules which are superimposable on
their mirror image partner.
The term "stereoisomers" refers to compounds which have identical chemical constitution, but
differ with regard to the arrangement of the atoms or groups in space.
"Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose
molecules are not mirror images of one another. Diastereomers have different physical
properties, e.g. melting points, boiling points, spectral properties, reactivities and biological
properties. For example, the compounds of Formula I-XIV may have a chiral phosphorus atom
when phosphorus has four different substitutents, e.g., Formula XIV, where the chirality is R or
S. When R” and Rd of the amino acid of the phosphoramidate of Formula IV are different, there
are two centers of chirality in the molecule leading to potential diastereomeric mixtures of
compounds, e.g. R,S; S,R; S,S and R,R isomers. Mixtures of diastereomers may be separate
55
M337 prio-lb
under high resolution analytical procedures such as electrophoresis, crystallization and/or
chromatography. Diastereomers may have different physical attributes such as, but not limited
to, solubility, chemical stabilities and crystallinity and may also have different biological
properties sue as, but not limited to, enzymatic stability, absorption and metabolic stability.
"Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror
images of one another.
Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed.,
l\/lcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc.,
New York. Many organic compounds exist in optically active forms, i.e. they have the ability to
rotate the plane of plane-polarized light. ln describing an optically active compound, the prefixes
D and L or R and S are used to denote the absolute configuration of the molecule about its
chiral center(s). The prefixes d and I, D and L, or (+) and (-) are employed to designate the sign
of rotation of plane-polarized light by the compound, with S, (-), orl meaning that the compound
is levorotatory while a compound prefixed with R, (+), or d is dextrorotatory. For a given
chemical structure, these stereoisomers are identical except that they are mirror images of one
another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of
such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred
to as a racemic mixture or a racemate, which may occur where there has been no
stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic
mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of
optical activity.
Whenever a compound described herein is substituted with more than one of the same
designated group, e.g., "Ra" or "R1", then it will be understood that the groups may be the same
or different, i.e. each group is independently selected. Wavy lines, , indicate
the site of covalent bond attachments to the adjoining substructures, groups, moieties, or
atoms.
The compounds of the invention can also exist as tautomeric isomers in certain cases. Although
only one delocalized resonance structure may be depicted, all such forms are contemplated
within the scope of the invention. For example, ene-amine tautomers can exist for purine,
pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible
tautomeric forms are within the scope of the invention.
One skilled in the art will recognize that nucleoside bases such as the pyrrolo[1,2-
f][1,2,4]triazine nucleosides can exist in tautomeric forms. For example, but not by way of
limitation, structures (a) and (b) can have equivalent tautomeric forms as shown below:
56
M337 prio-lb
om o
*w « *w
\\..««~*\ \ øff\ \= N X \
M; N 'RQ , N e
R S3
f .x _,
~ w- f W
f\\ § o, l J
\\___,.r\1 \ ¿_ç-\_\ \\;_ N \ 'qè
v' “aa 0
vw we ll
Nit-z W
ff ~~~~ f/*Xw /Law/ Wii
»VK i L *<::¿=:.=.~_~_~____"2~=_ (_\ '
\\ x; f. \, g; f»
-' \ xx \ f \
* m” RS* w' v
All possible tautomeric forms of the heterocycles and nucleobases in all of the embodiments
disclosed herein are within the scope of the invention.
The compounds of Formula I-XIV also include molecules that incorporate isotopes of the atoms
specified in the particular molecules. Non-limiting examples of these isotopes include D, T, 14C,
'3C and 15N. All such isotopic variations of these molelcules are provided by the instant
invention.
Detailed Description of the Embodiments
Various embodiments of the invention will now be illustrated by the following examples. The
Examples are just intended to further illustrate the invention and are by no means limiting the
scope of the invention. The compound names were generated by ChemDraw Ultra software,
Cambridgesoft, version 12.0.2.
Certain abbreviations and acronyms are used in describing the experimental details. Although
most of these would be understood by one skilled in the art, Table 1 contains a list of many of
these abbreviations and acronyms.
Table 1. List of abbreviations and acronyms.
Ac acetyl
Bz benzoyl
DCM dichloromethane
DIBAI Diisobutylaluminium hydride
DMAP 4-dimethylaminopyridine
DME 1,2-dimethoxyethane
DMSO dimethylsulfoxide
57
D|\/IF
dr
EtOAc
ES
ES+
ES-
H|\/IDS
HPLC
LDA
mCPBA
MeCN
MeOH
m/z or m/e
[IVIHT
llVlHl'
MsOH
Ms
MS or ms
NBS
NCS
NFSI
N|\/IR
rt
TBAF
TMSCI
TMSBr
TMSI
TEA or EtgN
TBA
TBAP
TBSCI
TEAB
TFA
TIPS
TIPS-Cl
TLC
Tr
dimethylform amide
diastereomeric ratio
ethyl acetate
electrospray ionization
electrospray ionization positive mode
electrospray ionizationnegative mode
hexamethyldisilazane
High performance liquid chromatography
lithium diisopropylamide
meta-chloroperbenzoic acid
acetonitrile
methanol
mass to charge ratio
mass plus 1
mass minus 1
methanesulfonic acid
methanesulfonyl
mass spectrum
N-bromosuccinimide
N-chlorosuccinimide
N-fluorobenzenesulfonimide
nuclear magnetic resonance
room temperature
tetrabutylammonium fluoride
chlorotrimethylsilane
bromotrimethylsilane
iodotrimethylsilane
triethylamine
tributylamine
tributyl ammonium pyrophosphate
t-butyldimethylsilyl chloride
triethylammonium bicarbonate
trifluoroacetic acid
triisopropylsilyl
triisopropylsilyl chloride
thin layer chromatography
triphenylmethyl
58
M337 prio-lb
M337 prio-lb
Tol 4-methylbenzoyl
ö parts per million down field from tetramethylsilane
Examgle R1
I / \ ||
0 ï C' 'CI -F-Ph-sH O N'P*s
w :W pä» Y :m i
Et3N Et3N Û
R1
(2S)-lsopropvl 2-((((4-fluorophenvl)thio)(phenoxv)phosphorvl)amino)propanoate (R1)
Phenyl dichlorophosphate (1 .30 g, 6.14 mmol) was added under nitrogen to a solution at -10 °C
of (S)-isopropy| 2-aminopropanoate hydrochloride (1 .03 g, 6.14 mmol) in DCl\/I (10 mL) followed
by dropwise addition of triethylamine (2 eq.) over 20 min. The mixture was stirred between -10
°C and 0 °C for 1h, then cooled to -100 °C and a solution of 4-fluorothiophenol in DCM (2 mL)
was added followed by dropwise addition of triethylamine (1 .1 eq.) over 10-15min. The reaction
was stirred for 30 min, then solids were filtered off and the solids were washed with DCM (10
mL) and discarded. The solution was concentrated, the residue taken into ethyl acetate (15 mL)
and remaining solids were removed by filtration and the solids were washed with ethyl acetate
(5 mL). The solution was concentrated and the residue dried under vacuum which gave the title
compound as a colourless oil (2.33 g, 95%). “P-NIVIR showed a 1:1 mixture of P-diastereomers.
The racemic reagent was used in coupling to the nucleoside.
Examgle R2
F
o |= F
1 E» 2 E?
' / \ :
O f cl | cl o ,P
Y WNHZ Oph F5~Pn-sH Y fu äs F
o EtsN EtaN 0
ÛF
R2
(2S)-lsoprobvl 2-((((perfluorophenvl)thio)(phenoxv)phosbhorvl)amino)propanoate (R2)
Phenyl dichlorophosphate (2.60 g, 11.9 mmol) was added under N2 to a solution at -10 °C of
(S)-isopropy| 2-aminopropanoate hydrochloride (2.00 g, 11.9 mmol) in dry DCl\/I (20 mL)
followed by dropwise addition of Et3N (2.1 Eq.) over 20 min. The thick white slurry was stirred at
-10 °C for 45 min, then pentafluorophenol (2.46 g, 11.9 mmol) in dry DCM (4 mL) was added via
syringe followed by dropwise addition of Et3N (1.1 eq.) over 10 min. The reaction mixture was
stirred at -10 °C for 30 min, then the precipitate was filtered off and the filtrated was diluted with
methyl terf-butyl ether (40 mL). The organic layer was washed with HCI (0.1 M aq.), twice with
KHCO3 (sat. aq.), dried (lVlgSO4) and concentrated under reduced pressure. The residue was
59
M337 prio-lb
purified by flash chromatography (hexane:EtOAc 5:1) which gave a diastereomeric mixture on
the P-atom of the title compound; one pure fraction (900 mg, 16%, diastereomeric ratio 44:56)
and one impure fraction (1.05 g, 19%, diastereomeric ratio: 85:15). MS (ES+) 470.00 [M+H]+.
Crystallization:
The impure fraction was dissolved in hexanes and concentrated twice, then dissolved in
hexanes (5 mL). Crystallization was induced by scratching and cooling in an ice-bath, then the
slurry was left at room temperature for 72h. The crystals were filtered off and washed with cold
hexanes which gave a single diastereomer at the P-atom of the title compound as colourless
needles (166 mg, 9%, dr >95:5 according to 19F- and 31 P-NMR).
The mother liquor was concentrated and the crystallization was repeated using hexanes (5 mL)
which gave further single diastereomer of the title compound (150 mg, 8%, dr >95:5 according
to ”F- and “P-NMR).
The purified 44:56-diastereomeric mixture from above (700 mg) was dissolved in hexanes (5
mL), cooled to 0 °C and seeded with crystals of single diastereomer (5 mg). The mixture was
stored at 4 °C over night, then formed crystals were filtered off and washed with cold hexanes
which gave further single diastereomer of the title compound as large colourless needles (120
mg, 6%, dr >95:5 according to 19F- and 31 P-NMR).
9? o
2 CVFIxCI O i 'g
o ' - « \
w WNW oPh :æs-dl-cl-Ph-SH Y i s cl
o Et3N Et3N 0
Example R3
((2S)-lsopropvl 2-((((3,5-dichlorophenvI)thio)(phenoxv)phosphorvl)amino)propanoate (R3)
Phenyl dichlorophosphate (3.78 g, 17.9 mmol) was added under nitrogen to a solution at -10 °C
of (S)-isopropyl 2-aminopropanoate hydrochloride (1 .03 g, 6.14 mmol) in DCM (36 mL) followed
by dropwise addition of triethylamine (2.1 eq.) over 20 min. The mixture was stirred between -10
°C and 0 °C for 45 min. The temperature was lowered to -10 °C and a solution of 3,5-
dichlorothiophenol in DCM (8 mL) was added followed by dropwise addition of triethylamine (1 .1
eq.) over 10-15 min. The reaction was stirred for 30 min, then concentrated. The residue was
dissolved in isopropyl acetate (60 mL) and solids were filtered off, washed with isopropyl
acetate (2x10 mL) and discarded. The organic layer was washed with an aqueous solution of
KHCOg (5%, 2x20 mL), dried (Na2SO4), filtered and concentrated. The afforded crude product
was purified by column chromatography on silica eluted with 25% EtOAc in hexanes, which
gave the title compound as a mixture of diastereomers at the P-atom (4.82 g, 60%).
60
M337 prio-lb
Example R4
c|
e ß 5 (R
0 E CI/PC' -ci-Ph-sH O I 'Fk
YW/Wyi-lz OPh=P :YWMÖS
o Et3N Et3N O
MÛ
(2S)-lsopropyl 2-((((4-chlorophenyl)thio)(phenoxy)phosphorvl)amino)propanoate (R4)
Phenyl dichlorophosphate (2.56 g, 12.1 mmol) was added under nitrogen to a solution at -10 °C
of (S)-isopropy| 2-aminopropanoate hydrochloride (2.03 g, 12.1 mmol) in DCM (36 mL) followed
by dropwise addition of triethylamine (2.1 eq.) over 20 min. The mixture was stirred between -10
°C and 0 °C for 45 min. The temperature was lowered to -10 °C and a solution of 4-
dichlorothiophenol in DCM (4 mL) was added followed by dropwise addition of triethylamine (1 .1
eq.) over 10-15 min. The reaction was stirred for 30 min, then concentrated. The residue was
dissolved in tert-butyl methyl ether (40 mL) and solids Were filtered off, washed with terf-butyl
methyl ether (2x10 mL) and discarded. The organic combined layers were washed twice with
saturated KHCOS, dried (Na2SO4), filtered and concentrated. The afforded crude product was
purified by column chromatography on silica eluted with 30% EtOAc in hexanes, which gave the
title compound as a mixture of diastereomers at the P-atom (4.00 g, 80%). MS (ES-) 412.02 [M-
H]'.
Example C1
C| C| RO O o TolO O OH
O O\( Step a \\¶_:C| Step c _ C| Step d
*O OH 0 RÖ CI Told CI
Sæpbct?rëï.
, H
o N o
OYÜNHBZ
o
Toio O oàruoph Toio O N / RO 0 N /
I C' OPh Stepe . C' Stepf __ C|
Toiö CI Toiö CI RÖ C'
c1d C1e (c1f, R = Toi
Stepg c1g,R=H
š “P / O
Rs YOWNJÉKO O N NH
t-Buivigci 0 HO W
a _. c|0
Steph Hö cl
c1
SteD a) (4R,5R)-3,3-Dichloro-4-hvdroxv-S-(hvdroxvmethvl)dihvdrofuran-2(3H)-one lactone
formation (C1a)
M337 prio-lb
A solution of (R)-isopropy| 2,2-dichloro-4-((S)-2,2-dimethyl-1,3-dioxo|an-4-y|)-3-
hydroxybutanoate (16.4 g, 54.3 mmol) prepared as described in J. Chem. Perkin Trans I, 1982,
2063-2066, in acetonitrile (150 mL), water (4.2 mL) and TFA was refluxed for 3 hours, then p-
toluene sulfonic acid monohydrate (516 mg, 2.71 mmol) and toluene (60 mL) were added. The
solvent was distilled off and new portions of toluene (3x60 mL) were added during the
distillation, which lasted about three hours. The reaction solution was concentrated in vacuo and
used crude in the next step.
Step b) (2R,3R)-4,4-Dichloro-2-(((4-methvlbenzovl)oxv)methvl)-5-oxotetrahvdrofuran-3-vi 4-
methylbenzoate (G1 b)
Et3N (16.5 g, 163 mmol) was added at 0 °C to a solution of the crude compound C1a in dry THF
followed by drop wise addition of p-toluoyl chloride (21.9 g, 136 mmol). The mixture was stirred
at rt over night, then cooled to 0 °C and DMAP (332 mg, 2.71 mmol), Et3N (1 .65 g, 16.3 mmol)
and p-toluoyl chloride were added. The mixture was stirred for 2 h at rt then the reaction was
quenched with MeOH. Most of the THF was removed in vacuo and about of EtOAc (500 mL)
was added. The organic phase was washed twice with 0.5M HCI, once with a saturated solution
of sodium hydrogen carbonate and once with brine. The organic phase was dried (Na2SO4),
filtered and concentrated under reduced pressure. The product was crystallized from isohexane
(50 mL) and toluene (25 mL). The crystals were filtered of, washed with isohexane (50 mL) then
tolueneïisohexane 2/1, and dried in vacuo. The mother liquid was concentrated and purified by
chromatography on a short silica column eluted with isohexane and 20% EtOAc. The product
was crystallized from isohexane and dried in vacuo. Total yield: 20.7 g, 87%.
Step c) (2R,3R)-4,4-dichloro-5-hvdroxv-2-(((4-methvlbenzov|)oxv)methvl)tetrahvdrofuran-3-vi 4-
methylbenzoate (C1c)
A 1M solution of lithium tri-tert-butoxyaluminohydride (52.1 mL, 52.1 mmol) was added drop
wise at -25 °C to a solution of C1b (19.0 g, 43.4 mmol) was dissolved in dry THF (180 mL) the
reaction was stirred for 15 min at -20°C. The cooling bath was removed and the reaction was
allowed to come to 10°C. The reaction was quenched with saturated ammonium chloride
solution (400 ml) and crashed ice. EtOAc (400 ml) was added and the mixture was stirred for 1
h _ The organic phase was separated and the water phase was extracted four times with of
EtOAc (4 x 100ml). The combined organic phases were washed with 0.5M HCl (150 mL), brine
(2 x 100 mL), dried (Na2SO4), filtered and concentrated. The afforded crude product was used in
the next step without further purification
Step d) (2R,3R)-4,4-Dichloro-5-((diphenoxyphosphorvl)oxv)-2-(((4-methvlbenzovl)oxv)methvl)-
tetrahvdrofuran-3-vl 4-methvlbenzoate (C1d)
62
M337 prio-lb
A solution of phosphoric acid diphenyl ester chloride in toluene (40 mL) was added drop wise at
10 °C to a solution of the crude product from previous step in a mixture of toluene (140 mL) and
Et3N (5.25 g, 51.9 mmol). The mixture was stirred at rt for 64h, then cooled to 0 °C, and a
mixture of 1M HCI (50 mL) diluted with EtOAc (200 mL) was added. The phases were
separated and the organic phase was washed with water, saturated sodium hydrogen
carbonate solution and brine. The organic phase was dried (Na2SO4), filtered and concentrated.
The product was crystallized from isopropanol / EtOAc and dried under vacuum which gave
11.8 g of the title compound. The mother liquid Was concentrated and the residue crystallized
from isopropanol dried under vacuum which gave further 7.5 g of the title compound. The
mother liquid was concentrated and purified by silica gel chromatography eluted with isohexane
and 5 to 10% EtOAc which gave further 8.5 g of the title compound. Total yield: 96%. MS (ES+)
688.1 [M+NH4]*.
Step e) (2R,3R,5R)-5-(4-benzamido-2-oxopvrimidin-1(2H)-VI)-4,4-dich|oro-2-(((4-
methvlbenzovl)oxv)methv|)tetrahvdrofuran-3-VI 4-methvlbenzoate (C1 e)
A suspension of N-benzoyl cytosine (1 .92 g, 8.94 mmol) and ammonium sulfate (4.72 mg, 0.036
mmol) in HDMS (13.6 mL, 65.4 mmol) was boiled under argon for two hours, then cooled to rt
and concentrated in vacuo. The residue was dissolved in chlorobenzene (100 mL) and a
solution of C1d (3.00 g, 4.49 mmol) in chlorobenzene (70 mL) was added under argon. Tin (IV)
tetrachloride was added drop wise at rt and the mixture was refluxed for 90 min. The reaction
was cooled and poured into a saturated solution of ammonium chloride. The product was
extracted four times with EtOAc and the combined organic phases were washed with brine,
dried (Na2SO4), filtered and concentrated. The product was purified by silica gel
chromatography with DCM and 2 to 4% methanol and then crystallized from ethanol. Yield 1.11
g, 35%
Step f) (2R,3R,5R)-4,4-Dichloro-5-(2,4-dioxo-3,4-dihvdropvrimidin-1(2H)-v|)-2-(((4-
methvlbenzovl)oxv)methvl)tetrahvdrofuran-3-vi 4-methvlbenzoate
(C1f)
A suspension of C1e (1 _06 g, 1.33 mmol) in 70% acetic acid was refluxed for 20h, then
concentrated onto silica and purified by silica gel column chromatography eluted with DCM and
0 to 20% ethyl acetate, which gave the title compound (537 mg, 76%). MS (ES+) 533.0 [M+H]+.
Step q) 1-((2R,4R,5R)-3,3-Dichloro-4-hvdroxv-5-(hvdroxvmethv|)tetrahvdrofuran-2-v|)pvrimidine-
2,4(1 H,3H )-dione (C1 g)
A suspension of C1f (2.78 g, 5.21 mmol) in 7M ammonia in methanol (110 mL) was stirred
overnight at rt. TLC not ready. The reaction was allowed to stay over weekend at rt. The
63
M337 prio-lb
mixture was evaporated on silica gel and purified by column chromatography with DCM and 3 to
10% methanol and diethyl ether and 4% methanol. The product was dried in vacuo. Yield 558
mg, 36%. MS (ES+) 297.0 [M+H]*.
1H NMR (500 MHz, DlVlSO-dß) ö 11.57 (s, 1H, 14), 8.06 (d, J = 8.2 Hz, 1H, 12), 6.76 (d, J = 6.3
Hz, 1H, 6), 6.41 (s, 1H, 7), 5.72 (dd, J = 8.1,1.4 Hz, 1H, 17), 5.47 (t, J = 4.6, 4.6 Hz, 1H, 13),
4.35 - 4.27 (m, 1H, 2), 3.87 - 3.76 (m, 2H), 3.68 - 3.62 (m, 2H).
”C NMR (126 MHz, DMSO-dß) ö 162.60, 150.29, 138.96, 101.93, 93.47, 90.12, 81.38, 75.36,
66.23, 58.01, -0.00.
Step h) (2S)-lsopropvl 2-(((((2R,3R,5R)-4,4-dichloro-5-(2,4-dioxo-3,4-dihvdropvrimidin-1(2H)-v|)-
3-hvdroxvtetrahvdrofuran-2-VI)methoxV)(phenoxV)phosphorVl)amino)propanoate (C1)
A flame dried two-necked flask was loaded with sugar C1f (100 mg, 0.337 mmol) and the
system placed under nitrogen. THF (2 mL) was added and the suspension was gently heated to
obtain a clear solution. The solution was cooled to -10 °C and a solution of tert-butylmagnesium
chloride in THF was added dropwise. DMPU (0.9 mL) was added and the mixture was stirred at
room temperature for 10 min. A solution of reagent R3 (181 mg, 0.404 mmol) in THF (1 mL) was
added and the resulting mixture was stirred at room temperature overnigh. The reaction was
quenched with 0.5M hydrochloric acid (1 .5 mL) and diluted with ethyl acetate (10 mL). The
organic layer was dried (Na2SO4), filtered and concentrated. The product was isolated using C-
18 preparative HPLC without separating the two phosphorus diastereomers which gave the title
compound as a 3:1 mixture of P-diastereomers (42 mg, 22%).
64
Claims (41)
1. A method for preparing a compound of Formula la or lb: O | o R4o//l/ RÖ N r/.P \ ”MP l \O Base O . ä I \O Base R5\N O d 7 c O O 7 R R OR4 7 R24 R 24 R R .ßÛÜ/RC Rzs R1 RQQ Ri R6:O Rd R22 Rz Formula Ia Formu|a lb or a pharmaceutically acceptable salt or acid thereof; wherein: each F21, RZ, RV, RH, R” or R” is independen?y H, oRtt, NR11R12, c(o)NR“R12,-oc(o)NR“R“2, c(o)oR“, oc(o)oR“, s(o)nRa , s(o)2NR“R”, M3, cN, halogen, (C1-C8)a|ky|, (C3-C8)carbocyc|y|, (C4-C8)carbocyc|y|a|ky|, (C2-C8)a|keny|, (C2- C8)a|kyny| or ary|(C C8)a|ky|; or any two R1 , Rz , R7 , R” , R” or R24 on adjacent carbon atoms when taken together are - O(CO)O- or -O(CR"R12)O- or when taken together with the ring carbon atoms to which they are attached form a double bond; each Base is independently a naturally occurring or modified purine or pyrimidine base linked to the furanose ring through a carbon or nitrogen atom; each n is independently 0, 1, or 2; each Ra, R4 or RB is independently (C1-C8)a|ky|, (C2-Cß)a|keny|, (C2-C8)a|kyny|, (C3- C8)carbocyc|y|, (C4-C8)carbocyc|y|a|ky|, ary|(C1-C8)alky|, heterocyclyl(C1-C8)a|ky|, (C6- C20)ary|, (C2-C20)heterocyc|y| or heteroaryl; each R° or Rd is independently H, (C1-C8)a|ky|, (C2-C8)a|keny|, (C2-C8)a|kyny|, (C3- C8)carbocyc|y|, (C4-C8)carbocyc|y|a|ky|, ary|(C1-C8)alky|, heterocyclyl(C1-C8)a|ky|, (C6- C20)ary|, heterocyclyl or heteroaryl; each Rs is independently H, (C1-Cß)a|ky|, (C2-C8)alkeny|, (C2-C8)a|kyny|, (C3-C8)carbocyc|y|, (C4-C8)carbocyc|y|a|ky|, ary|(C1-C8)a|ky|, heterocyc|y|(C1-C8)a|ky|, (C6-C20)ary|, heterocyclyl or heteroaryl; each Rtt of R12is independen?y H, (c1-c8)a|ky|,(cz-cgaikenyi, (cz-cgaikynyi, (C3- C8)carbocyc|y|, (C4-C8)carbocyc|y|a|ky|, ary|(C1-C8)alky|, heterocyclyl(C1-C8)a|ky|, (C6- C20)ary|, heterocyclyl, heteroaryl, -C(=O)(C1-C8)a|ky|, -S(O)n(C1-C8)a|ky|, or R“ and R” taken together with a nitrogen to which they are both attached form a 3 to 7 membered 65 M337 prio-lb heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O-, -S(O),- or -NRa-; and wherein each (C1-C8)a|kyl, (C2-C8)alkenyl, (C2-C8)a|kynyl, (C3-C8)carbocyclyl, (C4- C8)carbocycly|alkyl, aryl(C1-C8)a|kyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl ofeach R°, Rd, Rl, R2, R22, R23, R24, R4, RS, RS, RV, R” or R12is, independen?y, optionally substituted with one or more halo, hydroxy, CN, Ng, N(Ra)2, NH(Ra), NH2, N02, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(R'““)2, OC(O)NH(R'““), OC(O)NH2, C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)Ra, S(O),.Ra S(O)2N(Ra)2, S(O)2NH(Ra), S(O)2NH2, ORa or Ra; said method comprising : (a) providing a compound of Formula ll HO Base R23 Rl Formula ll and (b) treating the compound of Formula ll with a compound of Formula Illa and a base o RS Formula Illa thereby forming a compound of Formula la, or (c) treating the compound of Formula ll with a compound of Formula lllb and a base o FIF Ra Nl/'n o P\ Rd zR° o] s-Ar \ R4 Formula lllb thereby forming a compound of Formula lb; wherein: each Ar is (Cß-CZO) aryl or a 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, N02, (C1-C8)ha|oa|ky|, CN, Ng, N(Ra)2, 66 M337 prio-lb C(O)N(Ra)2, OC(O)N(Ra)2, C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)R'°“, S(O),,Ra, S(O)2N(Ra)2, ORa or Ra with the proviso that Ar is different from R4.
2. The method of claim 1 wherein Formula la is Formula IV a, Formula lb is Formula IVb and Formula ll is Formula V: o R5 o | 0 R4o / RK NH” /I/n._P/\ O a, P\ 5 l O Base d 2,0 [4 O O Base R\N 0 R R OR R24HW WWR7 Û R24uw ..||IIR7 Rze, 31 '”""R° RB R1 É R6_O Rd Ršz Éz R22 RZ Formula IVa Formula IVb HO O Base R24uu- '*I|||R7 R23 :_ _: R1 R2=2 ERZ FormulaV
3. The method of claim 1 or 2 wherein Base is selected from the group consisting of: RS F? í/s _. ixzï/šN åxfaàxš/sçN ggr/gå, \_ h X;\ i Vi /ë > alá/W" R” ïW//Waff MARç É/ *N #29 Nim, j __ MEN , RB Rs Rs l , t k /]\\N \ t W *X2 N i ' /i i \N/'§\O \ï,/^\R,_, »MW , -"-"- and Nfëw' wherein: each X1 is independently N or CR1°; each X2 is independently NR11, O, or S(O),.; each Rs is independently hamgen, NRttRtä N(R“)oR“, NR11NR“R12, M3, No, N02, cHo, cN, -cH(=NR“), -CH=NNHR“, -cH=N(oR“), -cH(oR“)2, -c(=o)NR“R12, -c(=s)NR“R12, -c(o)oR“, (c1-c8)a|i C20)ary|, heterocyclyl, heteroaryl, -C(=O)(C1-C8)a|ky|, -S(O),,(C1-C8)a|ky|, ary|(C1-C8)a|ky|, OR” or SR11; each n is independently 0, 1, or 2; 67 M337 prio-lb each RQ or R1° is independently H, halogen, NRltR?, N(R“)oR“, NR11NR“R12, M3, No, N02, cHo, CN, -CH(=NR“), -cH=NHNR“, -oH=N(oR“), -cH(oR“)2, -o(=o)NR“R12, - C(=S)NR”R12,-C(=O)OR”, R”, OR” or SR”; each R” or R” is independently H, (C1- C8)a|ky|, (C2-C8)a|keny|, (C2-C8)a|kynyl, (C3-C8)carbocyc|y|, (C4-C8)carbocyc|y|a|ky|, ary|(C1- C8)alky|, heterocyclyl(C1-Cg)alkyl, (C6-C20)aryl, heterocyclyl, heteroaryl, -C(=O)(C1- C8)a|kyl, -S(O),.(C1-C8)alkyl or R” and R” taken together With a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O-, -S(O)n- or -NRa-; wherein each (C1-C8)a|kyl, (C2-C8)alkenyl, (C2-C8)alkyny|, (C3-C8)carbocyclyl, (C4- C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl of each R°, Rd, R1, R2, R22, R23, R24, R4, Rs, Re, R7, RB, RQ, R1°, R” or R” is, independently, optionally substituted with one or more halo, hydroxy, CN, Ng, N(Ra)¿NH(Ra), NH2, N02, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(Ra)2, OC(O)NH(Ra), OC(O)NH2, C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)Ra, S(O),,Ra , S(O)2N(Ra)2, S(O)2NH(Ra), S(O)2NH2, ORa or Ra.
The method of any one of claims 1-3 wherein Base is selected from the group consisting of: NH O NH? NH NH Ä 2 N N 11k 2 H i 2 / “r/ “N 4.» f" *NH .f/ \ " *N ff ~/ \*N Nr~~ “N K/ (f z i i // i f \ f \ . .fi \ /\ f/K .\" \ -fL \ »Ei f* i \\\\ «'\ fi T W" N" \ ” NHR *ßí/ *NH? N" *N/ ' NJ” H NH , , n /O ~~ f/*š N /f “Wí \ N /Ilëí/ “QN /Éïwí/ ÄN /N“\~ / \\\N \\\\ _ J f \\\/ß\ I (i Sx ?/?í <\ N '_ i N\\\ (Ä f” NV \N f \ \ 'f \ T' \\Ná NH; NH, ;¿\\\.Y_/-”Ä\\_.¿N N I: fj-'ïçN ”N\ :IL /fš \\,,,il\ /Ä i “W ~ and NW» NHÉ o o 'š\ F- HgCt l:\ F N XIONHZ í- N \ i NH :F ï ï a/go x fi» .Nvvvvc ..~\a^^.vx .nAÅn/ux. .f-.fvšnz-.m .i . 68 M337 prio-lb Ni-iz o
5. The method of any one of claims 1-3 wherein Formula la is Formula Vla, Formula lb is Formula Vlb and Formula ll is Formula Vll: Ra RB Formula Vla Formula Vlb RE Formula Vll I\) RQ
6. The method of any one of claims 1 -3 wherein Formula la is Formula Xla, Formula lb is Formula Xlb and Formula ll is Formula Xll: Formula Xla Formula Xlb 69 M337 prio-lb Formula XII wherein: each R1 is independently H, halogen, optionally substituted (C1-Cg)alkyl, optionally substituted (C2-C8)alkenyl or optionally substituted (C2-C8)alkynyl; each Rz is independently halogen or OR11; each Rs is H; and each R” is OR”.
The method of any one of claims 1-3 wherein Formula la is Formula Xllla, Formula lb is Formula Xlllb and Formula ll is Formula XIV: Rß Ra O R5 X14< X1~< 6 i ° / \ 4 ° / \ R\ Nm // R o,,,,, // N O ' IP\O Nà< ÜP\O N Rd /IRC OR4 O O HN" IIIIR7 O Huun- 'IIIHRY O 1 -.,, H R RKO ”Rc H R" R22 §2 Rd Ršz ïaz Formula Xllla Formula Xlllb wherein: each R1 is independently H, halogen, optionally substituted (C1-C8)a|ky|, optionally substituted (C2-C8)alkenyl or optionally substituted (C2-C8)a|kynyl; each RZ is independently halogen or OR11; each Rs is H; and each R” is OR”.
The method of any one of claims 1-7 wherein R1 is H, halogen, optionally substituted (C1- C8)alkyl, optionally substituted (C2-C8)alkenyl or optionally substituted (C2-C8)alkynyl.
The method of any one of claims 1-8 wherein R1 is H, CHg, F or Cl. 70
10.
11.
12.
13.
14.
15. M337 prio-lb The method of any one of claims 1-8 wherein R1 is CH3, or Cl, and R2 is F or Cl. The method of any one of claims 1-10 wherein each R5, R23 and R24 is H. The method of any one of claims 1-11 wherein one of R° or Rd is H and the other of R° or Rd is optionally substituted (c1-c8)a|ky|. The method of any one of claims 1-12 wherein RB is optionally substituted (C1-C8)a|ky| or optionally substituted (C3-C8)cycloalkyl. The method of any one of claims 1-13 wherein Ra is NR11R12 or OR". The method of any one of claims 1-14 wherein RQ is H or NR11R12.
16. The method of any one of claims 1-15 wherein when Ra or RQ is OR" or NR11R12 then each R” and R” of said OR” of NR11R12 is H.
17. The method of any one of claims 1-16 wherein Rs is NH2 and RQ is H.
18 The method of any one of claims 1-16 wherein Rs is OH and RQ is H.
19. The method of any one of claims 1-18 wherein R4 is optionally substituted (C6-C20)ary|.
20. The method of any one of claims 1-19 further comprising a method of preparing a compound of Formula Illa or Formula llllb o ||R5 0 FI! e O R6\ Nx io R\ Nm i ° 'f ~P\ O 'f Ä Rd zR° (f s-Ar Rd /R° 0\ S-Af \R4 R4 Formula Illa Or Formula lllb wherein: each Ra, R4 or RB is independently (C1-C8)a|ky|, (C2-Cg)a|keny|, (C2-Cg)a|kyny|, (C3- C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6- C20)ary|, heterocyclyl or heteroaryl;
21. M337 prio-lb each R° or Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3- C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6- C20)aryl, (C2C20)heterocyclyl or heteroaryl; each Rö is independently H, (C1-Cg)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl; wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4- C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alky|, (C6-C20)aryl, heterocyclyl or heteroaryl of each R°, Rd, R4, R5 or RB is, independently, optionally substituted with one or more halo, hydroxy, CN, Ng, N(Ra)2; NH(Ra), NH2, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(R'°“)2, OC(O)NH(Ra), OC(O)NH2, C(O)OR'°“, OC(O)ORa, S(O),.Ra, S(O)2N(Ra)2, s(o)2N|-l(Ra), s(o)2NH2, oRa or Ra; and each Ar is (C6-C2) aryl or a 5 to 20 membered or heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, N02, (C1-C8)haloalky| CN, Ng, N(Ra)2, C(O)N(Ra)2, OC(O)N(Ra)2, C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)Ra, S(O),1Ra S(O)2N(Ra)2, ORa or Ra with the proviso that Ar is different from R4; said method comprising: (d) providing a diastereomeric compound of Formula Vlll 6 R\ Formula Vlll and (e) dissolving the compound of Formula Vlll in a suitable solvent and inducing crystallization by cooling the solution; thereby forming a pure diastereomer of Formula lla or Formula lllb. The method of claim 20 further comprising a method of preparing a compound of Formula Vlll 72 M337 prio-lb Formula V||| wherein: each Ra, R4 or RB is independently (C1-C8)a|ky|, (C2-C8)a|keny|, (C2-Cg)a|kyny|, (C3- C8)carbocyclyl, (C4-C8)carbocyclylalky|, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyI, (C6- C2o)aryI, heterocyclyl or heteroaryl; each R° or Rd is independently H, (C1-Cg)alkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)a|kyl, (C6-C20)ary|, heterocyclyl or heteroaryl; each Rs is independently H, (C1-Cß)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryI(C1-C8)a|kyI, heterocyclyl(C1-Cg)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl; wherein each (C1-C8)a|kyl, (C2-C8)alkenyl, (C2-C8)alkynyI, (C3-C8)carbocyclyl, (C4- C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alky|, (C6-C20)ary|, heterocyclyl or heteroaryl of each R°, Rd, R4, Rs or RB is, independently, optionally substituted with one or more halo, hydroxy, CN, Ng, N(Ra)2 NH(Ra), NH2, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(R“)2, OC(O)NH(Ra), OC(O)NH2, C(O)OR““, OC(O)ORa, S(O)nRa S(O)2N(Ra)2, S(O)2NH(Ra), S(O)2NH2, ORa or Ra; and each Ar is (CG-Cm) aryl or 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, N02, (C1-C8)ha|oalky| CN, N3, N(Ra)2, C(O)N(Ra)2, OC(O)N(R'““)2, C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)Ra, S(O),.Ra, S(O)2N(Ra)2, ORa or Ra With the proviso that Ar is different from R4; said method comprising: (f) providing a chirally pure amino acid ester of Formula IX or a salt thereof O R5 I Rà NH Giv, Rd RC Formula IX I (g) treating the compound of Formula IX with a compound of Formula X in the presence of a base 73
22. M337 prio-lb Formula X wherein each X3 is halogen; and (h) treating the resulting mixture with ArSH; thereby forming a compound of Formula VIII. A method of preparing a compound of Formula Illa or Formula lllb o F|e5 0 lf 6 O 6 O R\O N///,,P\y Rd RC \S_Ar Rd Rc O\ sïÅl' R4 R4 Formula Illa Formula Illb or or a salt or ester thereof, wherein: each Ra, R4 or RS is independently (C1-Cg)alkyl, (C2-C8)a|keny|, (C2-C8)a|kynyl, (C3- Cg)carbocyclyl, (C4-Cg)carbocyclylalkyl, aryl(C1-Cg)alkyl, heterocyclyl(C1-C8)alkyI, (C6- C20)aryI, heterocyclyl or heteroaryl; each R° or Rd is independently H, (C1-Cg)alkyl, (C2-C8)aIkenyI, (C2-C8)aIkynyI, (C3- C8)carbocycIyI, (C4-Cg)carbocyclylalkyl, aryl(C1-Cg)alkyl, heterocyclyl(C1-C)alkyl, (C6- C20)ary|, heterocyclyl or heteroaryl; each Rs is independently H, (C1-Cß)alkyl, (C2-C8)a|kenyI, (C2-C8)a|kynyI, (C3-C8)carbocycIyI, (C4-Cg)carbocyclylalkyl, aryl(C1-Cg)alkyl, heterocyclyl(C1-Ca)alkyl, (C6-C20)aryI, heterocyclyl or heteroaryl; wherein each (C1-C6)aIkyI, (C2-C8)aIkenyI, (C2-C8)aIkynyI, (C3-C8)carbocycIyI, (C4- Cg)carbocyclylalkyl, aryl(C1-Cg)alkyl, heterocyclyl(C1-Cg)alkyl, (C6-C20)ary|, heterocyclyl or heteroaryl of each R°, Rd, R4, Rs or RB is, independently, optionally substituted with one or more halo, hydroxy, CN, Ng, N(Ra)2; NH(Ra), NH2, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(Ra)2, OC(O)NH(Ra), OC(O)NH2, C(O)ORa, OC(O)ORa, S(O),,Ra _ S(O)2N(Ra)2, s(o)2NH(Ra), s(o)2NH2, oRa or Ra; and each Ar is (C6-C20)aryI or 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, N02, (C1-Cg)haloalkyl CN, N3, N(Ra)2, C(O)N(Ra)2, OC(O)N(Ra)2, C(O)OR'““, OC(O)ORa, C(O)Ra, OC(O)Ra, S(O),.Ra , S(O)2N(Ra)2, ORa or Ra With the proviso that Ar is different from R4; 74 M337 prio-lb said method comprising: (d) providing a diastereomeric compound of Formula Vlll T5 R6\ N O O \ PJ dac/\_ R RO\S Ar R4 Formula Vlll and (e) dissolving the compound of Formula Vlll in a suitable solvent and inducing crystallization by cooling the solution; thereby forming a pure diastereomer of Formula Illa or Formula lllb.
23. The method of claim 22 further comprising a method of preparing a compound of Formula Vlll o Pias 6 O R\O N\P% d /\_ R R o\ s Ar R4 Formula Vlll or a salt or ester thereof, wherein each Ra, R4 or RB is independently (C1-C8)alky|, (C2-Cg)alkenyl, (C2-Cg)a|kynyl, (C3- C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6- C20)ary|, heterocyclyl or heteroaryl; each R” or Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3- C8)carbocyclyl, (C4-C8)carbocyclylalky|, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6- C20)aryl, heterocyclyl or heteroaryl; each Rs is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl; wherein each (C1-C8)a|ky|, (C2-C8)alkeny|, (C2-C8)alkyny|, (C3-C8)carbocycly|, (C4- C8)carbocyclyla|kyl, aryl(C1-C8)a|kyl, heterocyclyl(C1-C8)a|ky|, (C6-C20)ary|, heterocyclyl or heteroaryl of each R°, Rd, R4, Rs or RB is, independently, optionally substituted with one or 75
24. M337 prio-lb more halo, hydroxy, CN, Ng, N(Ra)2, NH(Ra), NH2, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(Ra)2, OC(O)NH(Ra), OC(O)NH2, C(O)ORa, OC(O)ORa, S(O),,Ra S(O)2N(Ra)2, S(O)2NH(Ra), S(O)2NH2, ORa or Ra; and each Ar is (CG-Cm) aryl or a 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, N02, (C1-C8)haloalkyl CN, N3, N(Ra)2) C(O)N(Ra)2, OC(O)N(R"°')2, C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)Ra, S(O),.Ra , S(O)2N(Ra)2, ORa or Ra With the proviso that Ar is different from R4; said method comprising: (f) providing a chirally pure amino acid ester of Formula IX or a salt thereof | RíoÄg/NH Rd '?RC Formula IX (g) treating the compound of Formula IX with a compound of Formula X in the presence of a base wherein each X3 is halogen; and (h) treating the resulting mixture with ArSH; thereby forming a compound of Formula Vlll. The method of any one of claims 20-23 wherein the compound Formula Illa or Formula lllb is ° if ° is o R6\ Nx y R6\ N,,,,_ yo o .z __P\ o IP\ Rd "R° o: s-Ar Rd °R° o\ s-Ar R4 R4 Formula Illa Or F0rmu|a |||b or a salt or ester thereof; wherein: each Ra, R4 or RB is independently (C1-C8)a|ky|, (C2-C8)a|keny|, (C2-Cg)a|kyny|, (C3- C8)carbocyclyl, (C4-C8)carbocyclylalky|, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6- 76
25. M337 prio-lb C20)aryl, heterocyclyl or heteroaryl; each R° or Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3- C8)carbocyclyl, (C4-C8)carbocyclylalky|, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6- C2o)ary|, heterocyclyl or heteroaryl; each Rs is independently H, (C1-C8)alkyl, (C2-C8)a|kenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl; wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4- C8)carbocyclylalky|, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (Cs-C20)aryl, heterocyclyl or heteroaryl of each R°, Rd, R4, R5 or RB is, independently, optionally substituted with one or more halo, hydrOXy, CN, Ng, N(Ra)2, NH(Ra), NH2, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(Ra)2, OC(O)NH(Ra), OC(O)NH2, C(O)ORa, OC(O)ORa, S(O),.Ra _ S(O)2N(Ra)2, s(o)2NH(Ra), s(o)2NH2, oRa or Ra; and each Ar is (CG-Cm) aryl or a 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, N02, (C1-C8)haloalkyl CN, N3, N(Ra)2; C(O)N(Ra)2, OC(O)N(Ra)2, C(O)ORa, OC(O)OR'“*, C(O)Ra, OC(O)Ra, S(O),.Ra , S(O)2N(Ra)2, ORa or Ra With the proviso that Ar is different from R4. The method of any one of claims 20-24 wherein Rs is H and one of R° or Rd is H.
26. The method of any one of claims 20-25 wherein RB is optionally substituted (C1-Cg)alkyl or optionally substituted (C3-C8)cycloalkyl, and R4 is optionally substituted (C6-C20)aryl.
27. The method of any one of claims 20-26 wherein R4 is optionally substituted phenyl. 28. 29. 30.
The method of any one of claims 20-27 wherein one of R° or Rd is H and the other of R° or Rd is cHs.
The method of any one of claims 20-28 wherein Ar is optionally substituted phenyl.
The method of any one of claims 20-29 wherein the chirality at the carbon directly attached to R°and Rd is s.
_ The method of any one of claims 20-30 wherein the chirality at the carbon directly attached to R°and Rd is R. 77 M337 prio-lb
32. The method of any one of claims 20-31 Wherein the compound of formula Illa or |||b is selected from the group consisting of O >n||l| Z Ohï?lo / _ (D Q |||| O>'Ü_O wow Û -|||l| n|lll -O c| \s' i “c| c| >'Ü \/Ow(\Nr-\S CI QOWN \S O ”Û O Û O Cl Cl \ z* -O (D/ _ Q \ O-:UIO w/ Q c| c| = o = o o š 'Fl o š 'PI WN“¿\S c| WN* |\s c| H o H o O Û O Û c| c| Ö 78 M337 prio-lb I F F F F C F F F F F F F F F F F F F F F F F F S E: S _|_| S S S | \ F S \ \ O|P.|O \ \ OHPÅO OHPÅO \ OHPÅO OHPÅO \ \ \ NH \ v OHP|O NH NH NH NH U ___... NH ___... ___... ___... ___... O ___... O O O O O O O o O O I F F F F C F F F F F F F F F F F F F F F F F F S E: S E: S S S | \ F s | \ \ OIDLIO ¶ ¶ O\D|...._o OHDLZZO f OHPÉZO OHD|__.._O É f f NH f f OnDkzzO NH NH NH NH r ___... NH ___... ___... ___... ___... O ___... O O O O O O O O O O 79 M337 prio-lb F F F F F F E o : O O I! ? -- W Nfšïs F N\'P\S F i H ö z H g : O \(>F : O \(>F F F F F F F E O : O O F IF! o F IF! KY WNIÉ\S F /Y WN\-|\S F Ö Ho O \(>F 0 \íšp ; or salts or hydrates thereof.
33. A compound of the formula VIII Formula VIII wherein: each Ra, R4 or RB is independently (C1-Cg)alkyl, (C2-C8)aIkeny|, (C2-C8)aIkyny|, (C3- C8)carbocycIyI, (C4-Cg)carbocyclylalkyl, aryI(C1-C8)aIkyI, heterocyclyl(C1-C8)aIkyI, (C6- C20)aryI, heterocyclyl or heteroaryl; each R° or Rd is independently H, (C1-Cg)alkyl, (C2-C8)aIkenyI, (C2-C8)aIkynyI, (C3- C8)carbocycIyI, (C4-Cg)carbocyclylalkyl, aryI(C1-C8)aIkyI, heterocyclyl(C1-C8)aIkyI, (C6- C20)aryI, heterocyclyl or heteroaryl; each Rs is independently H, (C1-Cß)alkyl, (C2-C8)a|keny|, (C2-C8)aIkynyI, (C3-C8)carbocyc|y|, (C4-Cg)carbocyclylalkyl, aryI(C1-C8)aIkyI, heterocycIyI(C1-C8)aIkyI, (C6-C20)aryI, heterocyclyl or heteroaryl; wherein each (C1-Cg)alkyl, (C2-C8)aIkenyI, (C2-C8)aIkynyI, (C3-C8)carbocycIyI, (C4- C8)carbocycIyIaIkyI, aryI(C1-C8)aIkyI, heterocycIyI(C1-C8)aIkyI, (C6-C20)aryI, heterocyclyl or heteroaryl of each R°, Rd, R4, R5 or RB is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(Ra)2; NH(Ra), NH2, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(Ra)2, OC(O)NH(Ra), OC(O)NH2, C(O)ORa, OC(O)ORa, S(O)nRa, S(O)2N(R'"°')2, S(O)2NH(Ra), S(O)2NH2, ORa or Ra; and 80 M337 prio-lb each Ar is (C6-C20)aryl or a 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, N02, (C1-C8)ha|oalky| CN, N3, N(Ra)2, C(O)N(R“)2, OC(O)N(R'““)2, C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)R'““, S(O),.Ra S(O)2N(Ra)2, ORa or Ra with the proviso that Ar is different from R4: or a salt, hydrate or N-oxide thereof.
34. A diastereomer of the compound of claim 33 with the stereochemistry depicted in Formula Illa: Formula Illa
35. A diastereomer of the compound of claim 33 with the stereochemistry depicted in Formula lllb: Formula lllb
36. The diastereomer or compound of any one of claims 33-35, wherein R5 is H and one of R° orRd is H.
37. The diastereomer or compound of any one of claims 33-36, wherein Re is optionally substituted (C1-C8)alkyl or optionally substituted (C3-C8)cycloalkyl. 38. The diastereomer or compound of claim 37, wherein Rs is methyl, ethyl, 1-methylbutyl, 2- ethylbutyl, cyclopentyl or preferably isopropyl.
38. The diastereomer or compound of any one of claims 33-37, wherein R4 is phenyl.
39. The diastereomer or compound of any one of claims 33-38, wherein one of R° and Rd is H and the other one is CH3. 81 M337 prio-lb
40. The diastereomer or compound of claim 39, wherein the stereochemistry at the chiral center to which R°and Rd are directly attached is S.
41. The diastereomer or compound of any one of claims 33-39, wherein Ar is 3,5- dichlorophenyl or pentafluorophenyl. 82
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
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| SE1451080A SE1451080A1 (sv) | 2014-09-16 | 2014-09-16 | Medivir AB, Box 1086, 141 22 Huddinge, SE |
| CN201580061238.8A CN107108676A (zh) | 2014-09-15 | 2015-09-11 | 用于制备非对映异构纯的磷酰胺酯前药的方法 |
| PCT/EP2015/070876 WO2016041877A1 (en) | 2014-09-15 | 2015-09-11 | Methods for the preparation of diastereomerically pure phosphoramidate prodrugs |
| US15/511,096 US10118941B2 (en) | 2014-09-15 | 2015-09-11 | Methods for the preparation of diastereomerically pure phosphoramidate prodrugs |
| EP15763562.4A EP3194414A1 (en) | 2014-09-15 | 2015-09-11 | Methods for the preparation of diastereomerically pure phosphoramidate prodrugs |
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| SE1451080A SE1451080A1 (sv) | 2014-09-16 | 2014-09-16 | Medivir AB, Box 1086, 141 22 Huddinge, SE |
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