U.S. patent application number 14/341426 was filed with the patent office on 2015-01-29 for therapeutically active compounds and their methods of use.
This patent application is currently assigned to AGIOS PHARMACEUTICALS, INC. The applicant listed for this patent is Zhenwei Cai, Dawei Cui, Rene M. Lemieux, Janeta Popovici-Muller, Jeremy Travins, Ding Zhou. Invention is credited to Zhenwei Cai, Dawei Cui, Rene M. Lemieux, Janeta Popovici-Muller, Jeremy Travins, Ding Zhou.
Application Number | 20150031627 14/341426 |
Document ID | / |
Family ID | 52391005 |
Filed Date | 2015-01-29 |
United States Patent
Application |
20150031627 |
Kind Code |
A1 |
Lemieux; Rene M. ; et
al. |
January 29, 2015 |
THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
Abstract
Provided are methods of treating a cancer characterized by the
presence of a mutant allele of IDH1/2 comprising administering to a
subject in need thereof a compound described here.
Inventors: |
Lemieux; Rene M.;
(Charlestown, MA) ; Popovici-Muller; Janeta;
(Windham, NH) ; Travins; Jeremy; (Southborough,
MA) ; Cai; Zhenwei; (Belle Mead, NJ) ; Cui;
Dawei; (Shanghai, CN) ; Zhou; Ding; (Shanghai,
CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Lemieux; Rene M.
Popovici-Muller; Janeta
Travins; Jeremy
Cai; Zhenwei
Cui; Dawei
Zhou; Ding |
Charlestown
Windham
Southborough
Belle Mead
Shanghai
Shanghai |
MA
NH
MA
NJ |
US
US
US
US
CN
CN |
|
|
Assignee: |
AGIOS PHARMACEUTICALS, INC
Cambridge
MA
|
Family ID: |
52391005 |
Appl. No.: |
14/341426 |
Filed: |
July 25, 2014 |
Current U.S.
Class: |
514/19.6 ;
514/19.3; 544/122; 544/329; 544/332; 544/336; 544/96; 546/143;
546/256; 546/278.4; 548/195; 548/537 |
Current CPC
Class: |
A61K 38/05 20130101;
A61K 45/06 20130101; C07K 5/06191 20130101; A61K 38/00 20130101;
A61K 38/07 20130101 |
Class at
Publication: |
514/19.6 ;
548/537; 514/19.3; 544/332; 546/278.4; 546/143; 544/329; 544/336;
548/195; 544/122; 546/256; 544/96 |
International
Class: |
A61K 38/00 20060101
A61K038/00; C07K 5/078 20060101 C07K005/078 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 25, 2013 |
CN |
PCT/CN2013/080105 |
Jul 24, 2014 |
CN |
PCT/CN2014/082869 |
Claims
1. A compound of formula I or a pharmaceutically acceptable salt,
tautomer, isotopologue or hydrate thereof, wherein: ##STR00474##
R.sup.1 is optionally substituted C.sub.4-C.sub.6 carbocyclyl; each
R.sup.2 and R.sup.3 is independently selected from optionally
substituted aryl or optionally substituted heteroaryl; R.sup.4 is
alkyl, optionally substituted aryl, optionally substituted
heteroaryl, optionally substituted aralkyl, or optionally
substituted heteroaralkyl; ring A is 4-6 membered non-aromatic ring
having 0-1 additional heteroatoms selected from N, O or S, wherein
ring A is optionally substituted with one or two R.sup.5 groups;
each R.sup.5 is independently halo; --CF.sub.3; --CN; --OR.sup.6;
--N(R.sup.6).sub.2; --C(O)C.sub.1-C.sub.4 alkyl; C.sub.1-C.sub.4
haloalkyl; C.sub.1-C.sub.4 alkyl optionally substituted with
--OR.sup.6 or --N(R.sup.6).sub.2; --O--C.sub.1-C.sub.4 alkyl
optionally substituted with halo, --OR.sup.6 or --N(R.sup.6).sub.2;
--SO.sub.2N(R.sup.6).sub.2; --SO.sub.2(C.sub.1-C.sub.4 alkyl);
--NR.sup.6SO.sub.2R.sup.6; C.sub.3-C.sub.5 carbocyclyl optionally
substituted with one or two R.sup.6 groups; --O--(C.sub.3-C.sub.6
carbocyclyl optionally substituted with one or two R.sup.6 groups);
5-6 membered heteroaryl; --C.sub.1-C.sub.4
alkyl-C(O)O--C.sub.1-C.sub.4 alkyl; or --C(O)O--C.sub.1-C.sub.4
alkyl; or each R.sup.6 is independently H or C.sub.1-C.sub.3
alkyl.
2. The compound of claim 1, wherein: R.sup.1 is C.sub.4-C.sub.6
carbocyclyl optionally substituted with one to three R.sup.7
groups; each R.sup.2 and R.sup.3 is independently selected from
aryl or heteroaryl, wherein said aryl or heteroaryl is
independently optionally substituted with one to three R.sup.7
groups; R.sup.4 is alkyl, aryl, heteroaryl, aralkyl, or
heteroaralkyl, wherein said aryl, heteroaryl, aralkyl, and
heteroaralkyl are each independently optionally substituted with
one to three R.sup.7 groups; ring A is 4-6 membered non-aromatic
ring having 0-1 additional heteroatoms selected from N, O or S,
wherein ring A is optionally substituted with one or two R.sup.5
groups; each R.sup.5 and R.sup.7 is independently halo; --CF.sub.3;
--CN; --OR.sup.6; --N(R.sup.6).sub.2; --C(O)C.sub.1-C.sub.4 alkyl;
C.sub.1-C.sub.4 haloalkyl; C.sub.1-C.sub.4 alkyl optionally
substituted with --OR.sup.6 or --N(R.sup.6).sub.2;
--O--C.sub.1-C.sub.4 alkyl optionally substituted with halo,
--OR.sup.6 or --N(R.sup.6).sub.2; --SO.sub.2N(R.sup.6).sub.2;
--S(O)--C.sub.1-4 alkyl; --SO.sub.2 (C.sub.1-C.sub.4 alkyl);
--NR.sup.6SO.sub.2R.sup.6; C.sub.3-C.sub.5 carbocyclyl optionally
substituted with one or two R.sup.6 groups; --O--(C.sub.3-C.sub.6
carbocyclyl optionally substituted with one or two R.sup.6 groups);
5-6 membered heteroaryl; --C.sub.1-C.sub.4
alkyl-C(O)O--C.sub.1-C.sub.4 alkyl; or --C(O)O--C.sub.1-C.sub.4
alkyl; or each R.sup.6 is independently H or C.sub.1-C.sub.4
alkyl.
3. The compound of claim 1 or 2, wherein each R.sup.2 and R.sup.3
is independently aryl optionally substituted with one to three
R.sup.7 groups.
4. The compound of claim 1 having formula II-a, ##STR00475##
wherein R.sup.10 is CR.sup.11 or N; and R.sup.11 is --F,
--SO.sub.2NH.sub.2, --SO.sub.2CH.sub.3, --S(O)CH.sub.3, --CN,
methoxy, --OCH.sub.2OH, --CH.sub.2OH, --SO.sub.2N(CH.sub.3).sub.2,
--SO.sub.2NHCH.sub.3, --NHSO.sub.2CH.sub.3, --CH.sub.2CH.sub.2OH,
--N(CH.sub.3).sub.2, t-butyl, cyclopropyl, --C(OH)(CH.sub.3).sub.2,
--OCF.sub.3, --OCHF.sub.2, --O-cyclopropyl, -1-methyl-cyclopropyl,
or pyrazolyl.
5. The compound of claim 1 or 2, wherein R.sup.1 is C.sub.4 or
C.sub.6 cycloalkyl optionally substituted with one to two R.sup.7
groups and R.sup.7 associated with R.sup.1 is halo.
6. The compound of claim 5, wherein R.sup.1 is ##STR00476##
7. The compound of claim 5, wherein ring A is: ##STR00477## wherein
##STR00478## denotes ring A's attachment to the amide moiety of
formula and ##STR00479## denotes ring A's attachment to R.sup.4;
and each member of ring A is optionally substituted with one or two
R.sup.5 groups.
8. The compound of claim 7, wherein ring A is: ##STR00480##
9. The compound of claim 7, wherein R.sup.4 is aryl or heteroaryl,
each aryl or heteroaryl is optionally substituted with one to three
R.sup.7 groups.
10. The compound of claim 9, wherein R.sup.4 is: ##STR00481##
wherein each member of R.sup.4 is optionally substituted with one
or two R.sup.7 groups and each R.sup.7 is independently F, Cl,
methyl, CF.sub.3, CN, OMe, or N(R.sup.6).sub.2.
11. The compound of claim 10, wherein R.sup.4 is: ##STR00482##
wherein R.sup.100 is H, methyl, C.sub.1, CF.sub.3, CN, OCH.sub.3,
or N(R.sup.6).sub.2 and R.sup.101 is H, F or methyl.
12. The compound is selected from any one of compounds from Table
1.
13. A pharmaceutical composition comprising a compound of claim 1;
and a pharmaceutically acceptable carrier.
14. The composition of claim 13, further comprising a second
therapeutic agent useful in the treatment of cancer.
15. A method of treating a cancer characterized by the presence of
an IDH1 mutation, wherein the IDH1 mutation results in a new
ability of the enzyme to catalyze the NAPH-dependent reduction of
.alpha.-ketoglutarate to R(-)-2-hydroxyglutarate in a patient,
comprising the step of administering to the patient in need thereof
a composition of claim 13.
16. The method of claim 15, wherein the IDH1 mutation is an IDH1
R132H or R132C mutation.
17. The method of claim 15, wherein the cancer is selected from
glioma (glioblastoma), acute myelogenous leukemia, melanoma,
non-small cell lung cancer (NSCLC), cholangiocarcinomas,
chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative
neoplasm (MPN), colon cancer in a patient.
18. The method of claim 17, further comprising administering to the
patient in need thereof a second therapeutic agent useful in the
treatment of cancer.
Description
CLAIM OF PRIORITY
[0001] This application claims priority from International
Application Serial No. PCT/CN2014/082869 filed Jul. 24, 2014, and
International Application Serial No. PCT/CN2013/080105 filed Jul.
25, 2013, each of which is incorporated herein by reference in its
entirety.
BACKGROUND OF INVENTION
[0002] Isocitrate dehydrogenases (IDHs) catalyze the oxidative
decarboxylation of isocitrate to 2-oxoglutarate (i.e.,
.alpha.-ketoglutarate). These enzymes belong to two distinct
subclasses, one of which utilizes NAD(+) as the electron acceptor
and the other NADP(+). Five isocitrate dehydrogenases have been
reported: three NAD(+)-dependent isocitrate dehydrogenases, which
localize to the mitochondrial matrix, and two NADP(+)-dependent
isocitrate dehydrogenases, one of which is mitochondrial and the
other predominantly cytosolic. Each NADP(+)-dependent isozyme is a
homodimer.
[0003] IDH1 (isocitrate dehydrogenase 1 (NADP+), cytosolic) is also
known as IDH; IDP; IDCD; IDPC or PICD. The protein encoded by this
gene is the NADP(+)-dependent isocitrate dehydrogenase found in the
cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal
targeting signal sequence. The presence of this enzyme in
peroxisomes suggests roles in the regeneration of NADPH for
intraperoxisomal reductions, such as the conversion of
2,4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal
reactions that consume 2-oxoglutarate, namely the
alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves
a significant role in cytoplasmic NADPH production.
[0004] The human IDH1 gene encodes a protein of 414 amino acids.
The nucleotide and amino acid sequences for human IDH1 can be found
as GenBank entries NM.sub.--005896.2 and NP.sub.--005887.2
respectively. The nucleotide and amino acid sequences for IDH1 are
also described in, e.g., Nekrutenko et al., Mol. Biol. Evol.
15:1674-1684 (1998); Geisbrecht et al., J. Biol. Chem.
274:30527-30533 (1999); Wiemann et al., Genome Res. 11:422-435
(2001); The MGC Project Team, Genome Res. 14:2121-2127 (2004);
Lubec et al., Submitted (December 2008) to UniProtKB; Kullmann et
al., Submitted (June 1996) to the EMBL/GenBank/DDBJ databases; and
Sjoeblom et al., Science 314:268-274 (2006).
[0005] Non-mutant, e.g., wild type, IDH1 catalyzes the oxidative
decarboxylation of isocitrate to .alpha.-ketoglutarate thereby
reducing NAD.sup.+ (NADP.sup.+) to NADH (NADPH), e.g., in the
forward reaction:
Isocitrate+NAD.sup.+(NADP.sup.+).fwdarw..alpha.-KG+CO.sub.2+NADH(NADPH)+-
H.sup.+.
[0006] It has been discovered that mutations of IDH1 present in
certain cancer cells result in a new ability of the enzyme to
catalyze the NAPH-dependent reduction of .alpha.-ketoglutarate to
R(-)-2-hydroxy glutarate (2HG). The production of 2HG is believed
to contribute to the formation and progression of cancer (Dang, L
et al, Nature 2009, 462:739-44).
[0007] The inhibition of mutant IDH1 and its neoactivity is
therefore a potential therapeutic treatment for cancer.
Accordingly, there is an ongoing need for inhibitors of IDH1
mutants having alpha hydroxyl neoactivity.
SUMMARY OF INVENTION
[0008] Described herein are methods of treating a cancer
characterized by the presence of a mutant allele of IDH1 or IDH2.
The methods comprise the step of administering to a subject in need
thereof a compound of formula I, or a pharmaceutically acceptable
salt, tautomer, isotopologue or hydrate thereof, wherein:
##STR00001##
[0009] R.sup.1 is optionally substituted C.sub.4-C.sub.6
carbocyclyl;
[0010] each R.sup.2 and R.sup.3 is independently selected from
optionally substituted aryl or optionally substituted
heteroaryl;
[0011] R.sup.4 is alkyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted aralkyl, or
optionally substituted heteroaralkyl;
[0012] ring A is 4-6 membered non-aromatic ring having 0-1
additional heteroatoms selected from N, O or S, wherein ring A is
optionally substituted with one or two R.sup.5 groups;
[0013] each R.sup.5 is independently halo; --CF.sub.3; --CN;
--OR.sup.6; --N(R.sup.6).sub.2; --C(O)C.sub.1-C.sub.4 alkyl;
C.sub.1-C.sub.4 haloalkyl; C.sub.1-C.sub.4 alkyl optionally
substituted with --OR.sup.6 or --N(R.sup.6).sub.2;
--O--C.sub.1-C.sub.4 alkyl optionally substituted with halo,
--OR.sup.6 or --N(R.sup.6).sub.2; --SO.sub.2N(R.sup.6).sub.2;
--SO.sub.2 (C.sub.1-C.sub.4 alkyl); --NR.sup.6SO.sub.2R.sup.6;
C.sub.3-C.sub.5 carbocyclyl optionally substituted with one or two
R.sup.6 groups; --O--(C.sub.3-C.sub.6 carbocyclyl optionally
substituted with one or two R.sup.6 groups); 5-6 membered
heteroaryl; --C.sub.1-C.sub.4 alkyl-C(O)O--C.sub.1-C.sub.4 alkyl;
or --C(O)O--C.sub.1-C.sub.4 alkyl; or
[0014] each R.sup.6 is independently H or C.sub.1-C.sub.3
alkyl.
[0015] The compound of formula I inhibits mutant IDH1/2,
particularly mutant IDH1 having alpha hydroxyl neoactivity. Also
described herein are pharmaceutical compositions comprising a
compound of formula I.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The details of construction and the arrangement of
components set forth in the following description or illustrated in
the drawings are not meant to be limiting. Other embodiments and
different ways to practice the invention are expressly included.
Also, the phraseology and terminology used herein is for the
purpose of description and should not be regarded as limiting. The
use of "including," "comprising," or "having," "containing",
"involving", and variations thereof herein, is meant to encompass
the items listed thereafter and equivalents thereof as well as
additional items.
DEFINITIONS
[0017] The term "halo" or "halogen" refers to any radical of
fluorine, chlorine, bromine or iodine.
[0018] The term "alkyl" refers to a hydrocarbon chain that may be a
straight chain or branched chain, containing the indicated number
of carbon atoms. For example, C.sub.1-C.sub.12 alkyl indicates that
the group may have from 1 to 12 (inclusive) carbon atoms in it. The
term "haloalkyl" refers to an alkyl in which one or more hydrogen
atoms are replaced by halo, and includes alkyl moieties in which
all hydrogens have been replaced by halo (e.g., perfluoroalkyl).
The terms "arylalkyl" or "aralkyl" refer to an alkyl moiety in
which an alkyl hydrogen atom is replaced by an aryl group.
Arylalkyl or aralkyl includes groups in which more than one
hydrogen atom has been replaced by an aryl group. Examples of
"arylalkyl" or "aralkyl" include benzyl, 2-phenylethyl,
3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups. The
terms "heteroarylalkyl" or "heteroaralkyl" refer to an alkyl moiety
in which an alkyl hydrogen atom is replaced by a heteroaryl group.
Heteroarylalkyl or heteroaralkyl includes groups in which more than
one hydrogen atom has been replaced by a heteroaryl group.
[0019] The term "alkylene" refers to a divalent alkyl, e.g.,
--CH.sub.2--, --CH.sub.2CH.sub.2--, and
--CH.sub.2CH.sub.2CH.sub.2--.
[0020] The term "alkenyl" refers to a straight or branched
hydrocarbon chain containing 2-12 carbon atoms and having one or
more double bonds. Examples of alkenyl groups include, but are not
limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl
groups. One of the double bond carbons may optionally be the point
of attachment of the alkenyl substituent. The term "alkynyl" refers
to a straight or branched hydrocarbon chain containing 2-12 carbon
atoms and characterized in having one or more triple bonds.
Examples of alkynyl groups include, but are not limited to,
ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons
may optionally be the point of attachment of the alkynyl
substituent.
[0021] The term "alkoxy" refers to an --O-alkyl radical. The term
"haloalkoxy" refers to an alkoxy in which one or more hydrogen
atoms are replaced by halo, and includes alkoxy moieties in which
all hydrogens have been replaced by halo (e.g.,
perfluoroalkoxy).
[0022] The term "carbocyclyl" refers to a monocyclic, bicyclic or
tricyclic, hydrocarbon ring system that is not fully aromatic,
wherein any ring atom capable of substitution can be substituted by
one or more substituents. A carbocyclyl can be fully or partially
saturated. A bicyclic or tricylic carbocyclyl may contain one (in
the case of a bicycle) or up to two (in the case of a tricycle)
aromatic rings, as long as at least one ring in the carbocyclyl is
non-aromatic. Unless otherwise specified, any ring atom capable of
substitution in a carbocyclyl can be substituted by one or more
substituents.
[0023] The term "aryl" refers to a fully aromatic monocyclic,
bicyclic, or tricyclic hydrocarbon ring system. Examples of aryl
moieties are phenyl, naphthyl, and anthracenyl. Unless otherwise
specified, any ring atom in an aryl can be substituted by one or
more substituents.
[0024] The term "cycloalkyl" as employed herein refers to a
saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon
group. Unless otherwise specified, any ring atom can be substituted
by one or more substituents. The cycloalkyl groups can contain
fused rings. Fused rings are rings that share a common carbon atom.
Examples of cycloalkyl moieties include, but are not limited to,
cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and
norbornyl. Unless otherwise specified, any ring atom can be
substituted by one or more substituents.
[0025] The term "heterocyclyl" refers to a monocyclic, bicyclic or
tricyclic, ring structure that is not fully aromatic and includes
one to four heteroatoms independently selected from N, O, or S in
one or more of the rings. A heterocyclyl can be fully or partially
saturated. A bicyclic or tricylic heterocyclyl may contain one (in
the case of a bicycle) or up to two (in the case of a tricycle)
aromatic rings, as long as at least one ring in the heterocyclyl is
non-aromatic. Unless otherwise specified, any ring atom capable of
substitution in a heterocyclyl can be substituted by one or more
substituents. Heterocyclyl groups include, for example, thiophene,
thianthrene, furan, pyran, isobenzofuran, chromene, xanthene,
phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole,
pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole,
indole, indazole, purine, quinolizine, isoquinoline, quinoline,
phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,
pteridine, carbazole, carboline, phenanthridine, acridine,
pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine,
furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole,
piperidine, piperazine, morpholine, lactones, lactams such as
azetidinones and pyrrolidinones, sultams, sultones, and the
like.
[0026] The term "heteroaryl" refers to a monocyclic, bicyclic, or
tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6
heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said
heteroatoms independently selected from O, N, or S, wherein each
ring in a heteroaryl is fully aromatic. Unless otherwise specified,
any ring atom capable of substitution in a heteroaryl can be
substituted by one or more substituents. The terms "hetaralkyl" and
"heteroaralkyl", as used herein, refers to an alkyl group
substituted with a heteroaryl group. The ring heteroatoms of the
compounds provided herein include N--O, S(O), and S(O).sub.2.
[0027] The term "substituted" refers to the replacement of a
hydrogen atom with another moiety. Typical substituents include
alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12
straight or branched chain alkyl), cycloalkyl, haloalkyl (e.g.,
perfluoroalkyl such as CF.sub.3), aryl, heteroaryl, aralkyl,
heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl,
heterocycloalkenyl, alkoxy, haloalkoxy (e.g., perfluoroalkoxy such
as OCF.sub.3), halo, hydroxy, carboxy, carboxylate, cyano, nitro,
amino, alkyl amino, SO.sub.3H, sulfate, phosphate, methylenedioxy
(--O--CH.sub.2--O-- wherein oxygens are attached to vicinal atoms),
ethylenedioxy, oxo (not a substituent on heteroaryl), thioxo (e.g.,
C.dbd.S) (not a substituent on heteroaryl), imino (alkyl, aryl,
aralkyl), S(O).sub.nalkyl (where n is 0-2), S(O).sub.n aryl (where
n is 0-2), S(O).sub.n heteroaryl (where n is 0-2), S(O).sub.n
heterocyclyl (where n is 0-2), amine (mono-, di-, alkyl,
cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, and
combinations thereof), ester (alkyl, aralkyl, heteroaralkyl, aryl,
heteroaryl), amide (mono-, di-, alkyl, aralkyl, heteroaralkyl,
aryl, heteroaryl, and combinations thereof), sulfonamide (mono-,
di-, alkyl, aralkyl, heteroaralkyl, and combinations thereof). In
one aspect, the substituents on a group are independently any one
single, or any subset of the aforementioned substituents. In
another aspect, a substituent may itself be substituted with any
one of the above substituents.
[0028] The term "tautomer" refers to each of two or more isomers of
a compound (e.g., a compound described herein) that exist together
in equilibrium, and are readily interchangeable by migration of a
hydrogen atom or proton, accompanied by a switch of a single bond
and an adjacent double bond.
[0029] As used herein, the term "elevated levels of 2HG" means 10%,
20% 30%, 50%, 75%, 100%, 200%, 500% or more 2HG than is present in
a subject that does not carry a mutant IDH1 or IDH2 allele. The
term "elevated levels of 2HG" may refer to the amount of 2HG within
a cell, within a tumor, within an organ comprising a tumor, or
within a bodily fluid.
[0030] The term "bodily fluid" includes one or more of amniotic
fluid surrounding a fetus, aqueous humour, blood (e.g., blood
plasma), serum, Cerebrospinal fluid, cerumen, chyme, Cowper's
fluid, female ejaculate, interstitial fluid, lymph, breast milk,
mucus (e.g., nasal drainage or phlegm), pleural fluid, pus, saliva,
sebum, semen, serum, sweat, tears, urine, vaginal secretion, or
vomit.
[0031] As used herein, the terms "inhibit" or "prevent" include
both complete and partial inhibition and prevention. An inhibitor
may completely or partially inhibit.
[0032] The term "treat" means decrease, suppress, attenuate,
diminish, arrest, or stabilize the development or progression of a
cancer (e.g., a cancer delineated herein), lessen the severity of
the cancer or improve the symptoms associated with the cancer.
[0033] As used herein, an amount of a compound effective to treat a
disorder, or a "therapeutically effective amount" refers to an
amount of the compound which is effective, upon single or multiple
dose administration to a subject, in treating a cell, or in curing,
alleviating, relieving or improving a subject with a disorder
beyond that expected in the absence of such treatment.
[0034] As used herein, the term "subject" is intended to include
human and non-human animals. Exemplary human subjects include a
human patient having a disorder, e.g., a disorder described herein
or a normal subject. The term "non-human animals" of the invention
includes all vertebrates, e.g., non-mammals (such as chickens,
amphibians, reptiles) and mammals, such as non-human primates,
domesticated and/or agriculturally useful animals, e.g., sheep,
dog, cat, cow, pig, etc.
Compounds
[0035] Provided is a compound having formula I or a
pharmaceutically acceptable salt, tautomer, isotopologue or hydrate
thereof, wherein:
##STR00002##
[0036] R.sup.1 is optionally substituted C.sub.4-C.sub.6
carbocyclyl;
[0037] each R.sup.2 and R.sup.3 is independently selected from
optionally substituted aryl or optionally substituted
heteroaryl;
[0038] R.sup.4 is alkyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted aralkyl, or
optionally substituted heteroaralkyl;
[0039] ring A is 4-6 membered non-aromatic ring having 0-1
additional heteroatoms selected from N, O or S, wherein ring A is
optionally substituted with one or two R.sup.5 groups;
[0040] each R.sup.5 is independently halo; --CF.sub.3; --CN;
--OR.sup.6; --N(R.sup.6).sub.2; --C(O)C.sub.1-C.sub.4 alkyl;
C.sub.1-C.sub.4 haloalkyl; C.sub.1-C.sub.4 alkyl optionally
substituted with --OR.sup.6 or --N(R.sup.6).sub.2;
--O--C.sub.1-C.sub.4 alkyl optionally substituted with halo,
--OR.sup.6 or --N(R.sup.6).sub.2; --SO.sub.2N(R.sup.6).sub.2;
--SO.sub.2(C.sub.1-C.sub.4 alkyl); --NR.sup.6SO.sub.2R.sup.6;
C.sub.3-C.sub.5 carbocyclyl optionally substituted with one or two
R.sup.6 groups; --O--(C.sub.3-C.sub.6 carbocyclyl optionally
substituted with one or two R.sup.6 groups); 5-6 membered
heteroaryl; --C.sub.1-C.sub.4 alkyl-C(O)O--C.sub.1-C.sub.4 alkyl;
or --C(O)O--C.sub.1-C.sub.4 alkyl; or
[0041] each R.sup.6 is independently H or C.sub.1-C.sub.3
alkyl.
[0042] Provided is also a compound having formula I or a
pharmaceutically acceptable salt or hydrate thereof, wherein:
##STR00003##
[0043] R.sup.1 is optionally substituted C.sub.4-C.sub.6
carbocyclyl;
[0044] each R.sup.2 and R.sup.3 is independently selected from
optionally substituted aryl or optionally substituted
heteroaryl;
[0045] R.sup.4 is alkyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted aralkyl, or
optionally substituted heteroaralkyl;
[0046] ring A is 4-6 membered non-aromatic ring having 0-1
additional heteroatoms selected from N, O or S, wherein ring A is
optionally substituted with one or two R.sup.5 groups;
[0047] each R.sup.5 is independently halo, --CF.sub.3, --CN,
--OR.sup.6, --N(R.sup.6).sub.2, --C(O)CH.sub.3; C.sub.1-C.sub.3
haloalkyl, C.sub.1-C.sub.3 alkyl optionally substituted with
--OR.sup.6 or --N(R.sup.6).sub.2; or
[0048] each R.sup.6 is independently H or C.sub.1-C.sub.3
alkyl.
[0049] Provided is also a compound having formula I or a
pharmaceutically acceptable salt, tautomer, isotopologue or hydrate
thereof, wherein:
##STR00004##
[0050] R.sup.1 is C.sub.4-C.sub.6 carbocyclyl optionally
substituted with one to three R.sup.7 groups;
[0051] each R.sup.2 and R.sup.3 is independently selected from aryl
or heteroaryl, wherein said aryl or heteroaryl is independently
optionally substituted with one to three R.sup.7 groups;
[0052] R.sup.4 is alkyl, aryl, heteroaryl, aralkyl, or
heteroaralkyl, wherein said aryl, heteroaryl, aralkyl, and
heteroaralkyl are each independently optionally substituted with
one to three R.sup.7 groups;
[0053] ring A is 4-6 membered non-aromatic ring having 0-1
additional heteroatoms selected from N, O or S, wherein ring A is
optionally substituted with one or two R.sup.5 groups;
[0054] each R.sup.5 and R.sup.7 is independently halo; --CF.sub.3;
--CN; --OR.sup.6; --N(R.sup.6).sub.2; --C(O)C.sub.1-C.sub.4 alkyl;
C.sub.1-C.sub.4 haloalkyl; C.sub.1-C.sub.4 alkyl optionally
substituted with --OR.sup.6 or --N(R.sup.6).sub.2;
--O--C.sub.1-C.sub.4 alkyl optionally substituted with halo,
--OR.sup.6 or --N(R.sup.6).sub.2; --SO.sub.2N(R.sup.6).sub.2;
--SO.sub.2(C.sub.1-C.sub.4 alkyl); --S(O)--C.sub.1-4 alkyl,
--NR.sup.6SO.sub.2R.sup.6; C.sub.3-C.sub.5 carbocyclyl optionally
substituted with one or two R.sup.6 groups; --O--(C.sub.3-C.sub.6
carbocyclyl optionally substituted with one or two R.sup.6 groups);
5-6 membered heteroaryl; --C.sub.1-C.sub.4
alkyl-C(O)O--C.sub.1-C.sub.4 alkyl; or --C(O)O--C.sub.1-C.sub.4
alkyl; or
[0055] each R.sup.6 is independently H or C.sub.1-C.sub.4
alkyl.
[0056] Provided is also a compound having formula I or a
pharmaceutically acceptable salt, tautomer, isotopologue or hydrate
thereof, wherein:
##STR00005##
[0057] R.sup.1 is C.sub.4-C.sub.6 carbocyclyl optionally
substituted with one to three R.sup.7 groups;
[0058] each R.sup.2 and R.sup.3 is independently selected from aryl
or heteroaryl, wherein said aryl or heteroaryl is independently
optionally substituted with one to three R.sup.7 groups;
[0059] R.sup.4 is alkyl, aryl, heteroaryl, aralkyl, or
heteroaralkyl, wherein said aryl, heteroaryl, aralkyl, and
heteroaralkyl are each independently optionally substituted with
one to three R.sup.7 groups;
[0060] ring A is 4-6 membered non-aromatic ring having 0-1
additional heteroatoms selected from N, O or S, wherein ring A is
optionally substituted with one or two R.sup.5 groups;
[0061] each R.sup.5 and R.sup.7 is independently halo, --CF.sub.3,
--CN, --OR.sup.6, --N(R.sup.6).sub.2, --C(O)CH.sub.3;
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl optionally
substituted with OR.sup.6 or --N(R.sup.6).sub.2; or
[0062] each R.sup.6 is independently H or C.sub.1-C.sub.3
alkyl.
[0063] In one embodiment, R.sup.1 is optionally substituted
C.sub.4-C.sub.6 cycloalkyl. In one aspect of this embodiment,
R.sup.1 is C.sub.4-C.sub.6 cycloalkyl optionally substituted with
one to three R.sup.7 groups. In another aspect of this embodiment,
R.sup.1 is C.sub.4, C.sub.5, or C.sub.6 cycloalkyl optionally
substituted with one to two R.sup.7 groups and R.sup.7 is halo. In
another aspect of this embodiment, R.sup.1 is C.sub.4 or C.sub.6
cycloalkyl optionally substituted with one to two R.sup.7 groups
and R.sup.7 is halo. In yet another aspect of this embodiment,
R.sup.1 is
##STR00006##
In yet another aspect of this embodiment, R.sup.1 is
##STR00007##
[0064] In another embodiment, R.sup.2 is optionally substituted
aryl. In one aspect of this embodiment, R.sup.2 is aryl optionally
substituted with one to three R.sup.7 groups. In another aspect of
this embodiment, R.sup.2 is phenyl optionally substituted with one
to two R.sup.7 groups and R.sup.7 is --Cl.
[0065] In another embodiment, R.sup.3 is optionally substituted
aryl or optionally substituted aryl heteroaryl. In one aspect of
this embodiment, R.sup.3 is optionally substituted heteroaryl. In
another aspect of this embodiment, R.sup.3 is heteroaryl optionally
substituted with one to three R.sup.7 group. In yet another aspect
of this embodiment, R.sup.3 is pyridinyl, indazolyl,
benzoimidazolyl, indolyl, or N-methylindolyl, wherein each R.sup.3
is optionally substituted with one R.sup.7 wherein R.sup.7 is F. In
another aspect of this embodiment, R.sup.3 is optionally
substituted aryl. In another aspect of this embodiment, R.sup.3 is
aryl optionally substituted with one to three R.sup.7 groups. In
yet another aspect of this embodiment, R.sup.3 is phenyl optionally
substituted with one R.sup.7 wherein R.sup.7 is --F. In yet another
aspect of this embodiment, R.sup.3 is phenyl optionally substituted
with one or two R.sup.7s wherein each R.sup.7 is independently
halo; --CN; --N(R.sup.6).sub.2; C.sub.1-C.sub.4 alkyl optionally
substituted with --OR.sup.6; --O--C.sub.1-C.sub.4 alkyl optionally
substituted with halo, or --OR.sup.6; --SO.sub.2N(R.sup.6).sub.2;
--SO.sub.2 (C.sub.1-C.sub.4 alkyl); --S(O)--C.sub.1-4 alkyl,
--NR.sup.6SO.sub.2R.sup.6; C.sub.3-C.sub.5 carbocyclyl optionally
substituted with one R.sup.6; --O--(C.sub.3-C.sub.6 carbocyclyl);
5-membered heteroaryl. In yet another aspect of this embodiment,
R.sup.3 is phenyl optionally substituted with one or two R.sup.7s
wherein each R.sup.7 is independently --F, --SO.sub.2NH.sub.2,
--SO.sub.2CH.sub.3, --S(O)CH.sub.3, --CN, methoxy, --OCH.sub.2OH,
--CH.sub.2OH, --SO.sub.2N(CH.sub.3).sub.2, --SO.sub.2NHCH.sub.3,
--NHSO.sub.2CH.sub.3, --CH.sub.2CH.sub.2OH, --N(CH.sub.3).sub.2,
t-butyl, cyclopropyl, --C(OH)(CH.sub.3).sub.2, --OCF.sub.3,
--OCHF.sub.2, --O-cyclopropyl, -1-methyl-cyclopropyl, or
pyrazolyl.
[0066] In another embodiment, R.sup.4 is optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
aralkyl, or optionally substituted heteroaralkyl. In one aspect of
this embodiment, R.sup.4 is aryl, heteroaryl, aralkyl, or
heteroaralkyl, wherein said aryl, heteroaryl, aralkyl, and
heteroaralkyl are each independently optionally substituted with
one to three R.sup.7 groups. In another aspect of this embodiment,
R.sup.4 is aryl or heteroaryl, each aryl or heteroaryl is
optionally substituted with one to three R.sup.7 groups. In another
aspect of this embodiment, R.sup.4 is 6-membered aryl or 5-6
membered heteroaryl, wherein said aryl or heteroaryl is optionally
substituted with one to three R.sup.7 groups. In yet another aspect
of this embodiment, R.sup.4 is:
##STR00008##
wherein each member of R.sup.4 is optionally substituted with one
or two R.sup.7 groups and each R.sup.7 is independently F, Cl,
methyl, CF.sub.3, CN, OMe, or N(R.sup.6).sub.2. In yet another
aspect of this embodiment, R.sup.4 is:
##STR00009##
wherein each R.sup.100 is independently H, methyl, F, Cl, CF.sub.3,
CN, OCH.sub.3, or N(R.sup.6).sub.2. In yet another aspect of this
embodiment, R.sup.4 is:
##STR00010##
wherein R.sup.100 is H, methyl, F, C.sub.1, CF.sub.3, CN,
OCH.sub.3, or N(R.sup.6).sub.2. In yet another embodiment, R.sup.4
is:
##STR00011##
wherein R.sup.100 is H, methyl, C.sub.1, CF.sub.3, CN, OCH.sub.3,
or N(R.sup.6).sub.2 and R.sup.101 is H, F or methyl.
[0067] In another embodiment, ring A is
##STR00012##
wherein
##STR00013##
denotes ring A's attachment to the amide moiety of formula and
##STR00014##
denotes ring A's attachment to R.sup.4; and each member of ring A
is optionally substituted with one or two R.sup.5 groups. In
another embodiment, ring A is
##STR00015##
wherein
##STR00016##
denotes ring A's attachment to the amide moiety of formula and
##STR00017##
denotes ring A's attachment to R.sup.4; and each member of ring A
is optionally substituted with one or two R.sup.5 groups. In one
aspect of this embodiment, each R.sup.5 is independently halo;
--OR.sup.6; --C(O)C.sub.1-C.sub.4 alkyl; C.sub.1-C.sub.4 alkyl
optionally substituted with --OR.sup.6; --C.sub.3-C.sub.5
carbocyclyl optionally substituted with one or two R.sup.6 groups;
--C.sub.1-C.sub.4 alkyl-C(O)O--C.sub.1-C.sub.4 alkyl; or
--C(O)O--C.sub.1-C.sub.4 alkyl. In one aspect of this embodiment,
each R.sup.5 is independently --OH, --F, --CH.sub.2CH.sub.2OH,
--CH.sub.2C(O)OCH.sub.2CH.sub.3, --C(O)O-t-butyl, cyclopropyl,
methyl or --C(O)CH.sub.3. In one aspect of this embodiment, each
R.sup.5 is independently methyl or --C(O)CH.sub.3. In another
aspect of this embodiment, ring A is:
##STR00018##
In another aspect of this embodiment, ring A is:
##STR00019##
[0068] Provided is also a compound having formula II or a
pharmaceutically acceptable salt or hydrate thereof, wherein
R.sup.1, R.sup.2, R.sup.3, ring A and R.sup.4 are as defined in
formula I or any one of the above embodiments.
##STR00020##
[0069] Provided is also a compound having formula II-a or a
pharmaceutically acceptable salt or hydrate thereof, wherein
R.sup.1, R.sup.4, ring A and R.sup.7 are as defined in formula I or
any one of the above embodiments.
##STR00021##
[0070] Provided is also a compound having formula II-a-1 or a
pharmaceutically acceptable salt or hydrate thereof, wherein
R.sup.1, R.sup.4, ring A and R.sup.7 are as defined in formula I or
any one of the above embodiments and R.sup.10 is CR.sup.11 or N
wherein R.sup.11 is --F, --SO.sub.2NH.sub.2, --SO.sub.2CH.sub.3,
--CN, methoxy, --OCH.sub.2OH, --CH.sub.2OH,
--SO.sub.2N(CH.sub.3).sub.2, --SO.sub.2NHCH.sub.3,
--NHSO.sub.2CH.sub.3, --CH.sub.2CH.sub.2OH, --N(CH.sub.3).sub.2,
t-butyl, cyclopropyl, --C(OH)(CH.sub.3).sub.2, --OCF.sub.3,
--OCHF.sub.2, --O-cyclopropyl, -1-methyl-cyclopropyl, or
pyrazolyl.
##STR00022##
[0071] Provided is also a compound having formula II-b or a
pharmaceutically acceptable salt or hydrate thereof, wherein
R.sup.1, R.sup.4, and ring A are as defined in formula I or any one
of the above embodiments; R.sup.7' is H or Cl; and R.sup.10 is
CR.sup.11 or N wherein R.sup.11 is --F, --SO.sub.2NH.sub.2,
--SO.sub.2CH.sub.3, --CN, methoxy, --OCH.sub.2OH, --CH.sub.2OH,
--SO.sub.2N(CH.sub.3).sub.2, --SO.sub.2NHCH.sub.3,
--NHSO.sub.2CH.sub.3, --CH.sub.2CH.sub.2OH, --N(CH.sub.3).sub.2,
t-butyl, cyclopropyl, --C(OH)(CH.sub.3).sub.2, --OCF.sub.3,
--OCHF.sub.2, --O-cyclopropyl, -1-methyl-cyclopropyl, or
pyrazolyl.
##STR00023##
[0072] Provided is also a compound having formula II-b-1 or a
pharmaceutically acceptable salt or hydrate thereof, wherein
R.sup.1, R.sup.4, and ring A are as defined in formula I or any one
of the above embodiments and R.sup.7 is H or Cl.
##STR00024##
[0073] In another embodiment of formula II, II-a, II-a-1, II-b, or
II-b-1, [0074] R.sup.1 is:
[0074] ##STR00025## [0075] R.sup.4 is:
##STR00026##
[0075] wherein R.sup.100 is H, methyl, C.sub.1, CF.sub.3, CN,
OCH.sub.3, or N(R.sup.6).sub.2 and R.sup.101 is H, F or methyl;
[0076] ring A is:
##STR00027##
[0077] Further embodiments provided herein include combinations of
one or more of the particular embodiments set forth above.
[0078] In another embodiment, exemplary compounds of formula I are
depicted below in Table 1.
TABLE-US-00001 Cpd No. Structure 1 ##STR00028## 2 ##STR00029## 3
##STR00030## 4 ##STR00031## 5 ##STR00032## 6 ##STR00033## 7
##STR00034## 8 ##STR00035## 9 ##STR00036## 10 ##STR00037## 11
##STR00038## 12 ##STR00039## 13 ##STR00040## 14 ##STR00041## 15
##STR00042## 16 ##STR00043## 17 ##STR00044## 18 ##STR00045## 19
##STR00046## 20 ##STR00047## 21 ##STR00048## 22 ##STR00049## 23
##STR00050## 24 ##STR00051## 25 ##STR00052## 26 ##STR00053## 27
##STR00054## 28 ##STR00055## 29 ##STR00056## 30 ##STR00057## 31
##STR00058## 32 ##STR00059## 33 ##STR00060## 34 ##STR00061## 35
##STR00062## 36 ##STR00063## 37 ##STR00064## 38 ##STR00065## 39
##STR00066## 40 ##STR00067## 41 ##STR00068## 42 ##STR00069## 43
##STR00070## 44 ##STR00071## 45 ##STR00072## 46 ##STR00073## 47
##STR00074## 48 ##STR00075## 49 ##STR00076## 50 ##STR00077## 51
##STR00078## 52 ##STR00079## 53 ##STR00080## 54 ##STR00081## 55
##STR00082## 56 ##STR00083## 57 ##STR00084## 58 ##STR00085## 59
##STR00086## 60 ##STR00087## 61 ##STR00088## 62 ##STR00089## 63
##STR00090## 64 ##STR00091## 65 ##STR00092## 66 ##STR00093## 67
##STR00094## 68 ##STR00095## 69 ##STR00096## 70 ##STR00097## 71
##STR00098## 72 ##STR00099## 73 ##STR00100## 74 ##STR00101## 75
##STR00102## 76 ##STR00103## 77 ##STR00104## 78 ##STR00105## 79
##STR00106## 80 ##STR00107## 81 ##STR00108## 82 ##STR00109## 83
##STR00110## 84 ##STR00111## 85 ##STR00112## 86 ##STR00113## 87
##STR00114## 88 ##STR00115## 89 ##STR00116## 90 ##STR00117## 91
##STR00118## 92 ##STR00119## 93 ##STR00120## 94 ##STR00121## 95
##STR00122## 96 ##STR00123## 97 ##STR00124## 98 ##STR00125## 99
##STR00126## 100 ##STR00127## 101 ##STR00128## 102 ##STR00129## 103
##STR00130## 104 ##STR00131## 105 ##STR00132## 106 ##STR00133## 107
##STR00134## 108 ##STR00135## 109 ##STR00136## 110 ##STR00137## 111
##STR00138## 112 ##STR00139## 113 ##STR00140## 114 ##STR00141## 115
##STR00142## 116 ##STR00143## 117 ##STR00144## 118 ##STR00145## 119
##STR00146## 120 ##STR00147## 121 ##STR00148## 122 ##STR00149## 123
##STR00150##
124 ##STR00151## 125 ##STR00152## 126 ##STR00153## 127 ##STR00154##
128 ##STR00155## 129 ##STR00156## 130 ##STR00157## 131 ##STR00158##
132 ##STR00159## 133 ##STR00160## 134 ##STR00161## 135 ##STR00162##
136 ##STR00163## 137 ##STR00164## 138 ##STR00165## 139 ##STR00166##
140 ##STR00167## 141 ##STR00168## 142 ##STR00169## 143 ##STR00170##
144 ##STR00171## 145 ##STR00172## 146 ##STR00173## 147 ##STR00174##
148 ##STR00175## 149 ##STR00176## 150 ##STR00177## 151 ##STR00178##
152 ##STR00179## 153 ##STR00180## 154 ##STR00181## 155 ##STR00182##
156 ##STR00183## 157 ##STR00184## 158 ##STR00185## 159 ##STR00186##
160 ##STR00187## 161 ##STR00188## 162 ##STR00189## 163 ##STR00190##
164 ##STR00191## 165 ##STR00192## 166 ##STR00193## 167 ##STR00194##
168 ##STR00195## 169 ##STR00196## 170 ##STR00197## 171 ##STR00198##
172 ##STR00199## 173 ##STR00200## 174 ##STR00201## 175 ##STR00202##
176 ##STR00203## 177 ##STR00204## 178 ##STR00205## 179 ##STR00206##
180 ##STR00207## 181 ##STR00208## 182 ##STR00209## 183 ##STR00210##
184 ##STR00211## 185 ##STR00212## 186 ##STR00213## 187 ##STR00214##
188 ##STR00215## 189 ##STR00216## 190 ##STR00217## 191 ##STR00218##
192 ##STR00219## 193 ##STR00220## 194 ##STR00221## 195 ##STR00222##
196 ##STR00223## 197 ##STR00224## 198 ##STR00225## 199 ##STR00226##
200 ##STR00227## 201 ##STR00228## 202 ##STR00229## 203 ##STR00230##
204 ##STR00231## 205 ##STR00232## 206 ##STR00233## 207 ##STR00234##
208 ##STR00235## 209 ##STR00236## 210 ##STR00237## 211 ##STR00238##
212 ##STR00239##
[0079] Included herein are also methods for making compounds of
Formula I or a compound of any one of the embodiments described
herein comprising reacting R.sup.1NC with R.sup.2CHO,
R.sup.3NH.sub.2 and
##STR00240##
wherein R.sup.4' is H or R.sup.4 and R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and ring A as defined in Formula I or in any of the
embodiments described herein. In one aspect of the preceding
methods, R.sup.4 is alkyl.
[0080] Also included herein are methods for making compounds of
Formula I or a compound of any one of the embodiments described
herein comprising (1) reacting R.sup.1NC with R.sup.2CHO,
R.sup.3NH.sub.2 and
##STR00241##
to give
##STR00242##
and (2) reacting
##STR00243##
with R.sup.4-halide to give
##STR00244##
wherein R.sup.4
[0081] optionally substituted aryl or optionally substituted
heteroaryl; and R.sup.1, R.sup.2, R.sup.3, R.sup.4 and ring A as
defined in Formula I or in any of the embodiments described herein.
In one aspect of the preceding methods, R.sup.4 is aryl or
heteroaryl, each independently substituted with one to three
R.sup.7 groups. In another aspect of the preceding method, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and ring A are
as defined in any of the embodiments herein.
[0082] The compounds of this invention may contain one or more
asymmetric centers and thus occur as racemates, racemic mixtures,
scalemic mixtures, and diastereomeric mixtures, as well as single
enantiomers or individual stereoisomers that are substantially free
from another possible enantiomer or stereoisomer. The term
"substantially free of other stereoisomers" as used herein means a
preparation enriched in a compound having a selected
stereochemistry at one or more selected stereocenters by at least
about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or
99%. The term "enriched" means that at least the designated
percentage of a preparation is the compound having a selected
stereochemistry at one or more selected stereocenters. Methods of
obtaining or synthesizing an individual enantiomer or stereoisomer
for a given compound are known in the art and may be applied as
practicable to final compounds or to starting material or
intermediates.
[0083] In one embodiment, the compound is enriched in a specific
stereoisomer by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%,
95%, 96%, 97%, 98%, or 99%.
[0084] The compounds of formula I, II, II-a, II-a-1, II-b or II-b-1
may also comprise one or more isotopic substitutions. For example,
H may be in any isotopic form, including .sup.1H, .sup.2H (D or
deuterium), and .sup.3H (T or tritium); C may be in any isotopic
form, including .sup.11C, .sup.12C, .sup.13C, and .sup.14C; N may
be in any isotopic form, including .sup.13N, .sup.14N and .sup.15N;
O may be in any isotopic form, including .sup.15O, .sup.16O and
.sup.18O; F may be in any isotopic form, including .sup.18F; and
the like. For example, the compound is enriched in a specific
isotopic form of H, C, N, O and/or F by at least about 60%, 65%,
70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
[0085] Unless otherwise indicated when a disclosed compound is
named or depicted by a structure without specifying the
stereochemistry and has one or more chiral centers, it is
understood to represent all possible stereoisomers of the
compound.
[0086] The compounds of this invention may also be represented in
multiple tautomeric forms, in such instances, the invention
expressly includes all tautomeric forms of the compounds described
herein, even though only a single tautomeric form may be
represented (e.g., alkylation of a ring system may result in
alkylation at multiple sites, the invention expressly includes all
such reaction products). All such isomeric forms of such compounds
are expressly included in the present invention.
[0087] Compounds described herein may be prepared following
procedures detailed in the examples and other analogous methods
known to one skilled in the art. Compounds produced by any of the
schemes set forth below may be further modified (e.g., through the
addition of substituents to rings, etc.) to produce additional
compounds. The specific approaches and compounds shown herein are
not intended to be limiting. The suitability of a chemical group in
a compound structure for use in the synthesis of another compound
is within the knowledge of one of ordinary skill in the art.
Synthetic chemistry transformations and protecting group
methodologies (protection and deprotection) useful in synthesizing
the applicable compounds are known in the art and include, for
example, those described in Larock R, Comprehensive Organic
Transformations, VCH Publishers (1989); Greene, T W et al.,
Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley
and Sons (1999); Fieser, L et al., Fieser and Fieser's Reagents for
Organic Synthesis, John Wiley and Sons (1994); and Paquette, L,
ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and
Sons (1995) and subsequent editions thereof.
[0088] Combinations of substituents and variables envisioned by
this invention are only those that result in the formation of
stable compounds.
[0089] It may be convenient or desirable to prepare, purify, and/or
handle a corresponding salt of the active compound, for example, a
pharmaceutically acceptable salt. Examples of pharmaceutically
acceptable salts are discussed in Berge et al., 1977,
"Pharmaceutically Acceptable Salts." J. Pharm. Sci. Vol. 66, pp.
1-19.
[0090] For example, if the compound is anionic, or has a functional
group which may be anionic (e.g., --COOH may be --COO.sup.-), then
a salt may be formed with a suitable cation. Examples of suitable
inorganic cations include, but are not limited to, alkali metal
ions such as Na.sup.+ and K.sup.+, alkaline earth cations such as
Ca.sup.2+ and Mg.sup.2+, and other cations such as Al.sup.3+.
Examples of suitable organic cations include, but are not limited
to, ammonium ion (i.e., NH.sub.4.sup.+) and substituted ammonium
ions (e.g., NH.sub.3R.sup.+, NH.sub.2R.sup.2+, NHR.sup.3+,
NR.sup.4+). Examples of some suitable substituted ammonium ions are
those derived from: ethylamine, diethylamine, dicyclohexylamine,
triethylamine, butylamine, ethylenediamine, ethanolamine,
diethanolamine, piperazine, benzylamine, phenylbenzylamine,
choline, meglumine, and tromethamine, as well as amino acids, such
as lysine and arginine. An example of a common quaternary ammonium
ion is N(CH.sub.3).sub.4.sup.+.
[0091] If the compound is cationic, or has a functional group that
may be cationic (e.g., --NH.sub.2 may be --NH.sub.3.sup.+), then a
salt may be formed with a suitable anion. Examples of suitable
inorganic anions include, but are not limited to, those derived
from the following inorganic acids: hydrochloric, hydrobromic,
hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and
phosphorous.
[0092] Examples of suitable organic anions include, but are not
limited to, those derived from the following organic acids:
2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic,
camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic,
ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic,
glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic,
lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic,
oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic,
phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic,
sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of
suitable polymeric organic anions include, but are not limited to,
those derived from the following polymeric acids: tannic acid,
carboxymethyl cellulose.
[0093] Unless otherwise specified, a reference to a particular
compound also includes salt forms thereof.
Compositions and Routes of Administration
[0094] The compounds utilized in the methods described herein may
be formulated together with a pharmaceutically acceptable carrier
or adjuvant into pharmaceutically acceptable compositions prior to
be administered to a subject. In another embodiment, such
pharmaceutically acceptable compositions further comprise
additional therapeutic agents in amounts effective for achieving a
modulation of disease or disease symptoms, including those
described herein.
[0095] The term "pharmaceutically acceptable carrier or adjuvant"
refers to a carrier or adjuvant that may be administered to a
subject, together with a compound of this invention, and which does
not destroy the pharmacological activity thereof and is nontoxic
when administered in doses sufficient to deliver a therapeutic
amount of the compound.
[0096] Pharmaceutically acceptable carriers, adjuvants and vehicles
that may be used in the pharmaceutical compositions of this
invention include, but are not limited to, ion exchangers, alumina,
aluminum stearate, lecithin, self-emulsifying drug delivery systems
(SEDDS) such as d-.alpha.-tocopherol polyethyleneglycol 1000
succinate, surfactants used in pharmaceutical dosage forms such as
Tweens or other similar polymeric delivery matrices, serum
proteins, such as human serum albumin, buffer substances such as
phosphates, glycine, sorbic acid, potassium sorbate, partial
glyceride mixtures of saturated vegetable fatty acids, water, salts
or electrolytes, such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, cellulose-based substances, polyethylene glycol,
sodium carboxymethylcellulose, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, polyethylene glycol
and wool fat. Cyclodextrins such as .alpha.-, .beta.-, and
.gamma.-cyclodextrin, or chemically modified derivatives such as
hydroxyalkylcyclodextrins, including 2- and
3-hydroxypropyl-.beta.-cyclodextrins, or other solubilized
derivatives may also be advantageously used to enhance delivery of
compounds of the formulae described herein.
[0097] The pharmaceutical compositions of this invention may be
administered orally, parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir, preferably by oral administration or administration by
injection. The pharmaceutical compositions of this invention may
contain any conventional non-toxic pharmaceutically-acceptable
carriers, adjuvants or vehicles. In some cases, the pH of the
formulation may be adjusted with pharmaceutically acceptable acids,
bases or buffers to enhance the stability of the formulated
compound or its delivery form. The term parenteral as used herein
includes subcutaneous, intracutaneous, intravenous, intramuscular,
intraarticular, intraarterial, intrasynovial, intrasternal,
intrathecal, intralesional and intracranial injection or infusion
techniques.
[0098] The pharmaceutical compositions may be in the form of a
sterile injectable preparation, for example, as a sterile
injectable aqueous or oleaginous suspension. This suspension may be
formulated according to techniques known in the art using suitable
dispersing or wetting agents (such as, for example, Tween 80) and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are mannitol, water, Ringer's
solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose, any bland fixed oil may be
employed including synthetic mono- or diglycerides. Fatty acids,
such as oleic acid and its glyceride derivatives are useful in the
preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil solutions
or suspensions may also contain a long-chain alcohol diluent or
dispersant, or carboxymethyl cellulose or similar dispersing agents
which are commonly used in the formulation of pharmaceutically
acceptable dosage forms such as emulsions and or suspensions. Other
commonly used surfactants such as Tweens or Spans and/or other
similar emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for the
purposes of formulation.
[0099] The pharmaceutical compositions of this invention may be
orally administered in any orally acceptable dosage form including,
but not limited to, capsules, tablets, emulsions and aqueous
suspensions, dispersions and solutions. In the case of tablets for
oral use, carriers which are commonly used include lactose and corn
starch. Lubricating agents, such as magnesium stearate, are also
typically added. For oral administration in a capsule form, useful
diluents include lactose and dried corn starch. When aqueous
suspensions and/or emulsions are administered orally, the active
ingredient may be suspended or dissolved in an oily phase is
combined with emulsifying and/or suspending agents. If desired,
certain sweetening and/or flavoring and/or coloring agents may be
added.
[0100] The pharmaceutical compositions of this invention may also
be administered in the form of suppositories for rectal
administration. These compositions can be prepared by mixing a
compound of this invention with a suitable non-irritating excipient
which is solid at room temperature but liquid at the rectal
temperature and therefore will melt in the rectum to release the
active components. Such materials include, but are not limited to,
cocoa butter, beeswax and polyethylene glycols.
[0101] Topical administration of the pharmaceutical compositions of
this invention is useful when the desired treatment involves areas
or organs readily accessible by topical application. For
application topically to the skin, the pharmaceutical composition
should be formulated with a suitable ointment containing the active
components suspended or dissolved in a carrier. Carriers for
topical administration of the compounds of this invention include,
but are not limited to, mineral oil, liquid petroleum, white
petroleum, propylene glycol, polyoxyethylene polyoxypropylene
compound, emulsifying wax and water. Alternatively, the
pharmaceutical composition can be formulated with a suitable lotion
or cream containing the active compound suspended or dissolved in a
carrier with suitable emulsifying agents. Suitable carriers
include, but are not limited to, mineral oil, sorbitan
monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,
2-octyldodecanol, benzyl alcohol and water. The pharmaceutical
compositions of this invention may also be topically applied to the
lower intestinal tract by rectal suppository formulation or in a
suitable enema formulation. Topically-transdermal patches are also
included in this invention.
[0102] The pharmaceutical compositions of this invention may be
administered by nasal aerosol or inhalation. Such compositions are
prepared according to techniques well-known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons,
and/or other solubilizing or dispersing agents known in the
art.
When the compositions of this invention comprise a combination of a
compound of the formulae described herein and one or more
additional therapeutic or prophylactic agents, both the compound
and the additional agent should be present at dosage levels of
between about 1 to 100%, and more preferably between about 5 to 95%
of the dosage normally administered in a monotherapy regimen. The
additional agents may be administered separately, as part of a
multiple dose regimen, from the compounds of this invention.
Alternatively, those agents may be part of a single dosage form,
mixed together with the compounds of this invention in a single
composition.
[0103] The compounds described herein can, for example, be
administered by injection, intravenously, intraarterially,
subdermally, intraperitoneally, intramuscularly, or subcutaneously;
or orally, buccally, nasally, transmucosally, topically, in an
ophthalmic preparation, or by inhalation, with a dosage ranging
from about 0.5 to about 100 mg/kg of body weight, alternatively
dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or
according to the requirements of the particular drug. The methods
herein contemplate administration of an effective amount of
compound or compound composition to achieve the desired or stated
effect. Typically, the pharmaceutical compositions of this
invention will be administered from about 1 to about 6 times per
day or alternatively, as a continuous infusion. Such administration
can be used as a chronic or acute therapy. The amount of active
ingredient that may be combined with the carrier materials to
produce a single dosage form will vary depending upon the host
treated and the particular mode of administration. A typical
preparation will contain from about 5% to about 95% active compound
(w/w). Alternatively, such preparations contain from about 20% to
about 80% active compound.
[0104] Lower or higher doses than those recited above may be
required. Specific dosage and treatment regimens for any particular
subject will depend upon a variety of factors, including the
activity of the specific compound employed, the age, body weight,
general health status, sex, diet, time of administration, rate of
excretion, drug combination, the severity and course of the
disease, condition or symptoms, the subject's disposition to the
disease, condition or symptoms, and the judgment of the treating
physician.
[0105] Upon improvement of a subject's condition, a maintenance
dose of a compound, composition or combination of this invention
may be administered, if necessary. Subsequently, the dosage or
frequency of administration, or both, may be reduced, as a function
of the symptoms, to a level at which the improved condition is
retained when the symptoms have been alleviated to the desired
level. Subjects may, however, require intermittent treatment on a
long-term basis upon any recurrence of disease symptoms.
[0106] The pharmaceutical compositions described above comprising a
compound of formula I, II, II-a, II-a-1, II-b, or II-b-1 or a
compound described in any one of the embodiments herein, may
further comprise another therapeutic agent useful for treating
cancer.
Methods of Use
[0107] Provided is a method for inhibiting a mutant IDH1 or IDH2
activity comprising contacting a subject in need thereof with a
compound (including its tautomers and/or isotopologues) of
structural formula I, II, II-a, II-a-1, II-b, or II-b-1 or a
compound described in any one of the embodiments herein, or a
pharmaceutically acceptable salt thereof. In one embodiment, the
cancer to be treated is characterized by a mutant allele of IDH1 or
IDH2 wherein the IDH1 or IDH2 mutation results in a new ability of
the enzyme to catalyze the NAPH-dependent reduction of
.alpha.-ketoglutarate to R(-)-2-hydroxyglutarate in a subject. In
one aspect of this embodiment, the mutant IDH1 has an R132X
mutation. In one aspect of this embodiment, the R132X mutation is
selected from R132H, R132C, R132L, R132V, R132S and R132G. In
another aspect, the R132X mutation is R132H or R132C. In yet
another aspect, the R132X mutation is R132H.
[0108] Also provided are methods of treating a cancer characterized
by the presence of a mutant allele of IDH1 comprising the step of
administering to subject in need thereof (a) a compound of formula
I, II, II-a, II-a-1, II-b, or II-b-1, or a compound described in
any one of the embodiments herein, or a pharmaceutically acceptable
salt thereof, or (b) a pharmaceutical composition comprising (a)
and a pharmaceutically acceptable carrier.
[0109] In one embodiment, the cancer to be treated is characterized
by a mutant allele of IDH1 wherein the IDH1 mutation results in a
new ability of the enzyme to catalyze the NAPH-dependent reduction
of .alpha.-ketoglutarate to R(-)-2-hydroxyglutarate in a patient.
In one aspect of this embodiment, the IDH1 mutation is an R132X
mutation. In another aspect of this embodiment, the R132X mutation
is selected from R132H, R132C, R132L, R132V, R132S and R132G. In
another aspect, the R132X mutation is R132H or R132C. A cancer can
be analyzed by sequencing cell samples to determine the presence
and specific nature of (e.g., the changed amino acid present at) a
mutation at amino acid 132 of IDH1.
[0110] Without being bound by theory, applicants believe that
mutant alleles of IDH1 wherein the IDH1 mutation results in a new
ability of the enzyme to catalyze the NAPH-dependent reduction of
.alpha.-ketoglutarate to R(-)-2-hydroxyglutarate, and in particular
R132H mutations of IDH1, characterize a subset of all types of
cancers, without regard to their cellular nature or location in the
body. Thus, the compounds and methods of this invention are useful
to treat any type of cancer that is characterized by the presence
of a mutant allele of IDH1 imparting such activity and in
particular an IDH1 R132H or R132C mutation.
[0111] In one aspect of this embodiment, the efficacy of cancer
treatment is monitored by measuring the levels of 2HG in the
subject. Typically levels of 2HG are measured prior to treatment,
wherein an elevated level is indicated for the use of the compound
of formula I, II, II-a, II-a-1, II-b, or II-b-1 or a compound
described in any one of the embodiments described herein to treat
the cancer. Once the elevated levels are established, the level of
2HG is determined during the course of and/or following termination
of treatment to establish efficacy. In certain embodiments, the
level of 2HG is only determined during the course of and/or
following termination of treatment. A reduction of 2HG levels
during the course of treatment and following treatment is
indicative of efficacy. Similarly, a determination that 2HG levels
are not elevated during the course of or following treatment is
also indicative of efficacy. Typically, the these 2HG measurements
will be utilized together with other well-known determinations of
efficacy of cancer treatment, such as reduction in number and size
of tumors and/or other cancer-associated lesions, improvement in
the general health of the subject, and alterations in other
biomarkers that are associated with cancer treatment efficacy.
[0112] 2HG can be detected in a sample by LC/MS. The sample is
mixed 80:20 with methanol, and centrifuged at 3,000 rpm for 20
minutes at 4 degrees Celsius. The resulting supernatant can be
collected and stored at -80 degrees Celsius prior to LC-MS/MS to
assess 2-hydroxyglutarate levels. A variety of different liquid
chromatography (LC) separation methods can be used. Each method can
be coupled by negative electrospray ionization (ESI, -3.0 kV) to
triple-quadrupole mass spectrometers operating in multiple reaction
monitoring (MRM) mode, with MS parameters optimized on infused
metabolite standard solutions. Metabolites can be separated by
reversed phase chromatography using 10 mM tributyl-amine as an ion
pairing agent in the aqueous mobile phase, according to a variant
of a previously reported method (Luo et al. J Chromatogr A 1147,
153-64, 2007). One method allows resolution of TCA metabolites:
t=0, 50% B; t=5, 95% B; t=7, 95% B; t=8, 0% B, where B refers to an
organic mobile phase of 100% methanol. Another method is specific
for 2-hydroxyglutarate, running a fast linear gradient from 50%-95%
B (buffers as defined above) over 5 minutes. A Synergi Hydro-RP,
100 mm.times.2 mm, 2.1 .mu.m particle size (Phenomonex) can be used
as the column, as described above. Metabolites can be quantified by
comparison of peak areas with pure metabolite standards at known
concentration. Metabolite flux studies from .sup.13C-glutamine can
be performed as described, e.g., in Munger et al. Nat Biotechnol
26, 1179-86, 2008.
[0113] In one embodiment 2HG is directly evaluated.
[0114] In another embodiment a derivative of 2HG formed in process
of performing the analytic method is evaluated. By way of example
such a derivative can be a derivative formed in MS analysis.
Derivatives can include a salt adduct, e.g., a Na adduct, a
hydration variant, or a hydration variant which is also a salt
adduct, e.g., a Na adduct, e.g., as formed in MS analysis.
[0115] In another embodiment a metabolic derivative of 2HG is
evaluated. Examples include species that build up or are elevated,
or reduced, as a result of the presence of 2HG, such as glutarate
or glutamate that will be correlated to 2HG, e.g., R-2HG.
[0116] Exemplary 2HG derivatives include dehydrated derivatives
such as the compounds provided below or a salt adduct thereof:
##STR00245##
[0117] In one embodiment the cancer is a tumor wherein at least 30,
40, 50, 60, 70, 80 or 90% of the tumor cells carry an IDH1
mutation, and in particular an IDH1 R132H or R132C mutation, at the
time of diagnosis or treatment.
[0118] IDH1 R132X mutations are known to occur in certain types of
cancers as indicated in Table 2, below.
TABLE-US-00002 TABLE 2 IDH mutations associated with certain
cancers IDH1 R132X Cancer Type Mutation Tumor Type brain tumors
R132H primary tumor R132C primary tumor R132S primary tumor R132G
primary tumor R132L primary tumor R132V primary tumor fibrosarcoma
R132C HT1080 fibrosarcoma cell line Acute Myeloid Leukemia R132H
primary tumor (AML) R132G primary tumor R132C primary tumor
Prostate cancer R132H primary tumor R132C primary tumor Acute
lymphoblastic leukemia R132C primary tumor (ALL) paragangliomas
R132C primary tumor
[0119] IDH1 R132H mutations have been identified in glioblastoma,
acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung
cancer, cholangiocarcinomas, chondrosarcoma, myelodysplastic
syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer,
and angio-immunoblastic non-Hodgkin's lymphoma (NHL). Accordingly,
in one embodiment, the methods described herein are used to treat
glioma (glioblastoma), acute myelogenous leukemia, sarcoma,
melanoma, non-small cell lung cancer (NSCLC) or
cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes
(MDS), myeloproliferative neoplasm (MPN), colon cancer, or
angio-immunoblastic non-Hodgkin's lymphoma (NHL) in a patient.
[0120] Accordingly in one embodiment, the cancer is a cancer
selected from any one of the cancer types listed in Table 2, and
the IDH R132X mutation is one or more of the IDH1 R132X mutations
listed in Table 2 for that particular cancer type.
[0121] In another embodiment, the methods described herein are used
to treat glioma (glioblastoma), acute myelogenous leukemia,
sarcoma, melanoma, non-small cell lung cancer (NSCLC),
cholangiocarcinomas (e.g., intrahepatic cholangiocarcinoma (IHCC)),
chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative
neoplasm (MPN), prostate cancer, chronic myelomonocytic leukemia
(CMML), B-acute lymphoblastic leukemias (B-ALL), B-acute
lymphoblastic leukemias (B-ALL), myeloid sarcoma, multiple myeloma,
lymphoma colon cancer, or angio-immunoblastic non-Hodgkin's
lymphoma (NHL) in a patient. In another embodiment, the cancer to
be treated is an advanced hematologic malignancy selected from
lymphoma (e.g., Non-Hodgkin lymphoma (NHL) such B-cell lymphoma
(e.g., Burkitt lymphoma, chronic lymphocytic leukemia/small
lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma,
follicular lymphoma, immunoblastic large cell lymphoma, precursor
B-lymphoblastic lymphoma, and mantle cell lymphoma) and T-cell
lymphoma (e.g., mycosis fungoides, anaplastic large cell lymphoma,
and precursor T-lymphoblastic lymphoma).
[0122] Also provided are methods of treating a disease selected
from Maffucci syndrome and Ollier disease, characterized by the
presence of a mutant allele of IDH1 comprising the step of
administering to subject in need thereof (a) a compound of Formula
I, II, II-a, II-a-1, II-b, or II-b-1 or a compound described in any
one of the embodiments herein, or a pharmaceutically acceptable
salt thereof, or (b) a pharmaceutical composition comprising (a)
and a pharmaceutically acceptable carrier.
[0123] Treatment methods described herein can additionally comprise
various evaluation steps prior to and/or following treatment with a
compound of formula I, II, II-a, II-a-1, II-b, or II-b-1 or a
compound described in any one of the embodiments described
herein.
[0124] In one embodiment, prior to and/or after treatment with a
compound of Structural formula I, II, II-a, II-a-1, II-b, or II-b-1
or a compound described in any one of the embodiments described
herein, the method further comprises the step of evaluating the
growth, size, weight, invasiveness, stage and/or other phenotype of
the cancer.
[0125] In one embodiment, prior to and/or after treatment with a
compound of formula I, II, II-a, II-a-1, II-b, or II-b-1 or a
compound described in any one of the embodiments described herein,
the method further comprises the step of evaluating the IDH1
genotype of the cancer. This may be achieved by ordinary methods in
the art, such as DNA sequencing, immuno analysis, and/or evaluation
of the presence, distribution or level of 2HG.
[0126] In one embodiment, prior to and/or after treatment with a
compound of formula I, II, II-a, II-a-1, II-b, or II-b-1 or a
compound described in any one of the embodiments described herein,
the method further comprises the step of determining the 2HG level
in the subject. This may be achieved by spectroscopic analysis,
e.g., magnetic resonance-based analysis, e.g., MRI and/or MRS
measurement, sample analysis of bodily fluid, such as serum or
spinal cord fluid analysis, or by analysis of surgical material,
e.g., by mass-spectroscopy.
Combination Therapies
[0127] In some embodiments, the methods described herein comprise
the additional step of co-administering to a subject in need
thereof a second therapy e.g., an additional cancer therapeutic
agent or an additional cancer treatment. Exemplary additional
cancer therapeutic agents include for example, chemotherapy,
targeted therapy, antibody therapies, immunotherapy, and hormonal
therapy. Additional cancer treatments include, for example:
surgery, and radiation therapy. Examples of each of these
treatments are provided below.
[0128] The term "co-administering" as used herein with respect to
an additional cancer therapeutic agents means that the additional
cancer therapeutic agent may be administered together with a
compound of this invention as part of a single dosage form (such as
a composition of this invention comprising a compound of the
invention and an second therapeutic agent as described above) or as
separate, multiple dosage forms. Alternatively, the additional
cancer therapeutic agent may be administered prior to,
consecutively with, or following the administration of a compound
of this invention. In such combination therapy treatment, both the
compounds of this invention and the second therapeutic agent(s) are
administered by conventional methods. The administration of a
composition of this invention, comprising both a compound of the
invention and a second therapeutic agent, to a subject does not
preclude the separate administration of that same therapeutic
agent, any other second therapeutic agent or any compound of this
invention to said subject at another time during a course of
treatment. The term "co-administering" as used herein with respect
to an additional cancer treatment means that the additional cancer
treatment may occur prior to, consecutively with, concurrently with
or following the administration of a compound of this
invention.
[0129] In some embodiments, the additional cancer therapeutic agent
is a chemotherapy agent. Examples of chemotherapeutic agents used
in cancer therapy include, for example, antimetabolites (e.g.,
folic acid, purine, and pyrimidine derivatives), alkylating agents
(e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates,
hydrazines, triazenes, aziridines, spindle poison, cytotoxic
agents, topoisomerase inhibitors and others) and hypomethylating
agents (e.g., decitabine (5-aza-deoxycytidine), zebularine,
isothiocyanates, azacitidine (5-azacytidine,
5-fluoro-2'-deoxycytidine, 5,6-dihydro-5-azacytidine and others).
Exemplary agents include Aclarubicin, Actinomycin, Alitretinoin,
Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin,
Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan,
Belotecan, Bexarotene, bendamustine, Bleomycin, Bortezomib,
Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone,
Carmofur, Carmustine, Celecoxib, Chlorambucil, Chlormethine,
Cisplatin, Cladribine, Clofarabine, Crisantaspase,
Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin,
Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin,
Efaproxiral, Elesclomol, Elsamitrucin, Enocitabine, Epirubicin,
Estramustine, Etoglucid, Etoposide, Floxuridine, Fludarabine,
Fluorouracil (5FU), Fotemustine, Gemcitabine, Gliadel implants,
Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan,
Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomal
doxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine,
Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine,
Mesna, Methotrexate, Methyl aminolevulinate, Mitobronitol,
Mitoguazone, Mitotane, Mitomycin, Mitoxantrone, Nedaplatin,
Nimustine, Oblimersen, Omacetaxine, Ortataxel, Oxaliplatin,
Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin, Pirarubicin,
Pixantrone, Plicamycin, Porfimer sodium, Prednimustine,
Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine,
Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin,
Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide,
Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine,
Tioguanine, Tipifarnib, Topotecan, Trabectedin, Triaziquone,
Triethylenemelamine, Triplatin, Tretinoin, Treosulfan,
Trofosfamide, Uramustine, Valrubicin, Verteporfin, Vinblastine,
Vincristine, Vindesine, Vinflunine, Vinorelbine, Vorinostat,
Zorubicin, and other cytostatic or cytotoxic agents described
herein.
[0130] Because some drugs work better together than alone, two or
more drugs are often given at the same time. Often, two or more
chemotherapy agents are used as combination chemotherapy.
[0131] In some embodiments, the additional cancer therapeutic agent
is a differentiation agent. Such differentiation agent includes
retinoids (such as all-trans-retinoic acid (ATRA), 9-cis retinoic
acid, 13-cis-retinoic acid (13-cRA) and 4-hydroxy-phenretinamide
(4-HPR)); arsenic trioxide; histone deacetylase inhibitors HDACs
(such as azacytidine (Vidaza) and butyrates (e.g., sodium
phenylbutyrate)); hybrid polar compounds (such as hexamethylene
bisacetamide ((HMBA)); vitamin D; and cytokines (such as
colony-stimulating factors including G-CSF and GM-CSF, and
interferons).
[0132] In some embodiments the additional cancer therapeutic agent
is a targeted therapy agent. Targeted therapy constitutes the use
of agents specific for the deregulated proteins of cancer cells.
Small molecule targeted therapy drugs are generally inhibitors of
enzymatic domains on mutated, overexpressed, or otherwise critical
proteins within the cancer cell. Prominent examples are the
tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib,
dasatinib, erlotinib, imatinib, gefitinib, lapatinib, Lestaurtinib,
Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandetanib, and
also cyclin-dependent kinase inhibitors such as Alvocidib and
Seliciclib. Monoclonal antibody therapy is another strategy in
which the therapeutic agent is an antibody which specifically binds
to a protein on the surface of the cancer cells. Examples include
the anti-HER2/neu antibody trastuzumab (HERCEPTIN.RTM.) typically
used in breast cancer, and the anti-CD20 antibody rituximab and
Tositumomab typically used in a variety of B-cell malignancies.
Other exemplary antibodies include Cetuximab, Panitumumab,
Trastuzumab, Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab.
Exemplary fusion proteins include Aflibercept and Denileukin
diftitox. In some embodiments, the targeted therapy can be used in
combination with a compound described herein, e.g., a biguanide
such as metformin or phenformin, preferably phenformin.
[0133] Targeted therapy can also involve small peptides as "homing
devices" which can bind to cell surface receptors or affected
extracellular matrix surrounding the tumor. Radionuclides which are
attached to these peptides (e.g., RGDs) eventually kill the cancer
cell if the nuclide decays in the vicinity of the cell. An example
of such therapy includes BEXXAR.RTM..
[0134] In some embodiments, the additional cancer therapeutic agent
is an immunotherapy agent. Cancer immunotherapy refers to a diverse
set of therapeutic strategies designed to induce the subject's own
immune system to fight the tumor. Contemporary methods for
generating an immune response against tumors include intravesicular
BCG immunotherapy for superficial bladder cancer, and use of
interferons and other cytokines to induce an immune response in
renal cell carcinoma and melanoma subjects.
[0135] Allogeneic hematopoietic stem cell transplantation can be
considered a form of immunotherapy, since the donor's immune cells
will often attack the tumor in a graft-versus-tumor effect. In some
embodiments, the immunotherapy agents can be used in combination
with a compound or composition described herein.
[0136] In some embodiments, the additional cancer therapeutic agent
is a hormonal therapy agent. The growth of some cancers can be
inhibited by providing or blocking certain hormones. Common
examples of hormone-sensitive tumors include certain types of
breast and prostate cancers. Removing or blocking estrogen or
testosterone is often an important additional treatment. In certain
cancers, administration of hormone agonists, such as progestogens
may be therapeutically beneficial. In some embodiments, the
hormonal therapy agents can be used in combination with a compound
or a composition described herein.
[0137] Other possible additional therapeutic modalities include
imatinib, gene therapy, peptide and dendritic cell vaccines,
synthetic chlorotoxins, and radiolabeled drugs and antibodies.
EXAMPLES
[0138] The chemical name of each compound described below is
generated by ChemBioOffice software.
TABLE-US-00003 DCM = dichloromethane TEA = triethylamine DPPA =
diphenylphosphoryl azide TPA = trifluoroacetic acid DIPEA =
N,N-Diisopropyiethylamine TFAA = trifluoroacetic anhydride
General Procedures for the Preparation of
1,1-difluoro-3-isocyanocyclobutane
Method A:
##STR00246##
[0139] Step A: Tert-butyl 3-oxocyclobutylcarbamate
[0140] To a solution of 3-oxocyclobutanecarboxylic acid (10 g, 88
mmol) in dry DCM (60 mL) at 0.degree. C., SOCl.sub.2 (20 mL) was
added dropwise. The mixture was heated to reflux for 1.5 h and then
evaporated in vacuo. The resulting mixture was co-evaporated twice
with toluene (2.times.8 mL) and the residue was dissolved in
acetone (30 mL), followed by adding dropwise to a solution of
NaN.sub.3 (12 g, 185.0 mmol) in H.sub.2O (35 mL) at 0.degree. C.
After addition, the mixture was stirred for another 1 h and then
quenched with ice (110 g). The resulting mixture was extracted with
Et.sub.2O (2.times.100 mL). Combined organic layers were washed
with brine, dried over anhydrous Mg.sub.2SO.sub.4 and concentrated
to about 15 mL solution. Toluene (2.times.30 mL) was added into the
residue and the mixture was co-evaporated twice to remove Et.sub.2O
(about 30 mL solution left each time to avoid explosion). The
resulting toluene solution was heated to 90.degree. C. until the
evolution of N.sub.2 ceased. Next, 40 mL of t-BuOH was added into
the reaction mixture and the resulting mixture was stirred
overnight at 90.degree. C. The mixture was cooled and concentrated.
The residue was purified by column chromatography using petroleum
ether/EtOAc (V:V, 7:1 to 5:1) as eluent to afford the desired
product as a white solid. MS: 186.1 (M+1).sup.+.
Step B: Tert-butyl 3,3-difluorocyclobutylcarbamate
[0141] To a solution of tert-butyl-3-oxocyclo-butylcarbamate (2.56
g, 111.07 mmol) in dry DCM (190 mL), DAST (diethylaminosulfur
trifluoride) (41.0 mL, 222.14 mmol) was added dropwise at 0.degree.
C. under the atmosphere of N.sub.2. The mixture was then allowed to
warm up to r.t and stirred overnight. The resulting mixture was
slowly added into a pre-cooled saturated aq. NaHCO.sub.3 solution
and extracted with DCM (3.times.200 mL). Combined organic layers
were washed with brine, dried over anhydrous MgSO.sub.4, and
concentrated in vacuo. The residue was purified by column
chromatography using petroleum ether/EtOAc (V:V, 15:1) as eluent to
afford the desired product. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 4.79 (s, 1H), 4.07 (s, 1H), 2.98 (s, 2H), 2.58-2.29 (m,
2H), 1.46 (s, 9H). MS: 208.1 (M+1).sup.+.
Step C: N-(3,3-difluorocyclobutyl)formamide
[0142] To a solution of MeOH (170 mL) and CH.sub.3COCl (65 mL),
tert-butyl 3,3-difluoro-cyclobutylcarbamate (12.1 g, 58.42 mmol)
was added in one portion dropwise at 0.degree. C. The reaction
mixture was stirred at 0.degree. C. for 20 min, and then allowed to
warm up to r.t and stirred for another 1.5 h. The reaction mixture
was concentrated and dissolved in H.sub.2O (200 mL). The resulting
mixture was extracted by Et.sub.2O (150 mL) and the aqueous layer
was adjusted to pH=11 with solid Na.sub.2CO.sub.3 and extracted by
DCM (2.times.150 mL). The combined organic layers were dried over
anhydrous MgSO.sub.4, filtered and concentrated in vacuo using a
cold-water bath (<20.degree. C.). The residue was dissolved in
HCOOEt (90 mL), and transferred into a sealed pressure tube. This
reaction mixture was heated to 80.degree. C. and stirred overnight.
The solvent was removed, and the residue was purified by column
chromatography using petroleum ether/EtOAc (V:V, 1:1 to 1:3) as
eluent to afford the desired product. MS: 136.1 (M+1).sup.+.
Step D: 1,1-Difluoro-3-isocyanocyclobutane
[0143] To a solution of N-(3,3-difluorocyclobutyl)-formamide (2.0
g, 14.81 mmol) and PPh.sub.3 (4.27 g, 16.29 mmol) in DCM (35 mL)
were added CCl.sub.4 (1.43 mL, 14.81 mmol) and TEA (2.06 mL, 14.81
mmol). The reaction mixture was stirred at 45.degree. C. overnight
under a N.sub.2 atmosphere. The resulting mixture was evaporated in
vacuo at 0.degree. C. The residue was suspended in Et.sub.2O (25
mL) at 0.degree. C. for 30 min and then filtered. The filtrate was
evaporated to about 5 mL at 0.degree. C. under reduced pressure.
The residue was purified by column chromatography using Et.sub.2O
as eluent to afford the desired product which was used directly in
the next step.
Method B:
##STR00247##
[0144] Step A: Benzyl 3-oxocyclobutanecarboxylate
[0145] A mixture of 3-oxocyclobutanecarboxylic acid (5 g, 44 mmol),
potassium carbonate (12 g, 88 mmol) and benzyl bromide (11.2 g, 66
mmol) in acetone (50 mL) was refluxed for 16 h. The solvent was
then removed under reduced pressure and the residue was partitioned
between ethyl acetate and water. Combined organic layers were dried
over anhydrous MgSO.sub.4, filtered and concentrated. The residue
was purified with silica gel chromatography eluting with a gradient
of 100% hexane to 96% hexane/EtOAc to give the desired compound.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.45-7.27 (m, 5H), 5.19
(s, 2H), 3.55-3.36 (m, 2H), 3.33-3.11 (m, 3H).
Step B: Benzyl 3,3-difluorocyclobutanecarboxylate
[0146] To a solution of benzyl 3-oxocyclobutanecarboxylate (1.23 g,
6.03 mmol) in DCM (35 mL) was added DAST (0.8 mL, 6.03 mmol)
dropwise under nitrogen. The mixture was stirred at room
temperature for 16 h and then diluted with DCM. After successive
washes with saturated sodium bicarbonate, 1N aq. hydrochloride
acid, and brine, the organic layer was dried over anhydrous sodium
sulfate, filtered and concentrated. The crude product was purified
by silica gel chromatography with 93% hexane/EtOAc as eluent to
give the desired compound as an oil. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.47-7.27 (m, 5H), 5.16 (s, 2H), 3.09-2.95 (m,
1H), 2.90-2.60 (m, 4H).
Step C: 3,3-Difluorocyclobutanecarboxylic acid
[0147] Benzyl 3,3-difluorocyclobutanecarboxylate (0.84 g, 3.72 mol)
was dissolved in ethanol (40 mL), and approximately 0.02 g
palladium on activated carbon was added. The mixture was stirred at
room temperature for 12 h under the atmosphere of H.sub.2 and then
filtered through a pad of Celite. The filtrates were concentrated
and dried in vacuo to give the desired compound. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 3.16-2.55 (m, 5H).
Step D: Tert-butyl 3,3-difluorocyclobutylcarbamate
[0148] Benzyl 3,3-difluorocyclobutanecarboxylic acid (3.7 g, 27.3
mmol), DPPA (7.87 g, 27 mmol) and TEA (2.87 g, 28.4 mmol) were
dissolved in t-BuOH (25 mL). The mixture was refluxed for 5 h and
then diluted with ethyl acetate (about 200 mL). The organic phase
was washed twice with 5% citric acid and saturated sodium hydrogen
carbonate respectively, dried over anhydrous Mg.sub.2SO.sub.4 and
evaporated under reduced pressure. The residue was purified by
silica gel chromatography with 50% hexane/EtOAc to give the desired
product. MS: 208.1 (M+1).sup.+.
Step E: 3,3-Difluorocyclobutanamine hydrochloride
[0149] To a cold solution of MeOH (170 mL) and CH.sub.3COCl (65 mL)
was added tert-butyl 3,3-difluorocyclobutylcarbamate (12.1 g, 58.4
mmol) dropwise at 0.degree. C. After completion of the addition,
the mixture was stirred at 0.degree. C. for 20 min and then allowed
to warm up to room temperature. The reaction mixture was stirred
for another 1.5 h and then concentrated to give the crude product
which was precipitated in ether to give the desired product as a
white solid. MS: 108.1 (M+1).sup.+.
Step F: N-(3,3-difluorocyclobutyl)formamide
[0150] The mixture of 3,3-difluorocyclobutanamine hydrochloride
(6.5 g, 60.7 mmol) and TEA (3 eq) in HCOOEt (90 mL) was stirred at
80.degree. C. overnight in a sealed pressure tube. The solvent was
removed in vacuo and the residue was purified by column
chromatography with 50% petroleum ether/EtOAc to 25% petroleum
ether/EtOAc to give the desired product. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.54 (s, 1H), 8.01-7.89 (m, 1H), 4.16-3.84
(m, 1H), 3.06-2.73 (m, 2H), 2.72-2.33 (m, 2H). MS: 136.1
(M+1).sup.+.
Step G: 1,1-Difluoro-3-isocyanocyclobutane
[0151] The compound was synthesized as outlined in step D of method
A set forth above.
General Procedures for the Preparation of
1-fluoro-3-isocyanocyclobutane
##STR00248##
Step A: Tert-butyl 3-hydroxycyclobutylcarbamate
[0152] To a solution of tert-butyl 3-oxocyclobutylcarbamate (2 g,
10.8 mmol, 2 eq) in EtOH (20 mL) was added NaBH.sub.4 (204 mg, 1
eq) at 0.degree. C. The mixture was then allowed to warm to room
temperature and stirred for 30 min. The mixture was concentrated in
vacuo and the residue was purified by column chromatography using
petroleum ether/EtOAc (V:V, 2:1 to pure EtOAc) as eluent to afford
the desired product as a white solid. MS: 188.1 (M+1).sup.+.
Step B: Tert-butyl 3-fluorocyclobutylcarbamate
[0153] To a solution tert-butyl 3-hydroxycyclobutyl carbamate (1 g,
5.35 mmol) in dry DCM (20 mL) at -70.degree. C. was added DAST
dropwise (1 g, 0.85 mL, 1.17 eq) under the atmosphere of N.sub.2.
The mixture was then slowly warmed to room temperature and stirred
overnight. The resulting mixture was washed with diluted aq.
NaHCO.sub.3. The organic layer was dried over anhydrous
Mg.sub.2SO.sub.4 and concentrated. The residue was purified by
flash chromatography using petroleum ether/EtOAc (V:V, 20:1 to 2:1)
as eluent to afford a white solid as the desired product. MS: 190.1
(M+1).sup.+.
Step C: 3-Fluorocyclobutanamine
[0154] The compound was synthesized as outlined in step E of method
A set forth above.
Step D: N-(3-fluorocyclobutyl)formamide
[0155] The compound was synthesized as outlined in step F of method
A set forth above. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.10
(s, 1H), 5.94-5.89 (brs, 1H), 5.32-5.25 (m, 0.5H), 5.18-5.11 (m,
0.5H), 4.63-4.42 (m, 1H), 2.76-2.62 (m, 2H), 2.44-2.31 (m, 2H).
Step E: 1-Fluoro-3-isocyanocyclobutane
[0156] The compound was synthesized via the general procedure as
the step G in method A set forth above.
General Procedures for the Preparation of
1,1-difluoro-4-isocyanocyclohexane
##STR00249##
Step A: Tert-butyl 4-hydroxycyclohexylcarbamate
[0157] To a solution of 4-aminocyclohexanol (23 g, 0.2 mol) and
Et.sub.3N (60 g, 0.6 mol) in THF (230 mL) was added (Boc).sub.2O
(87 g, 0.4 mol). The resulting solution was stirred at room
temperature overnight. The solvent was removed under reduced
pressure and the residue was extracted with EtOAc (3.times.200 mL).
The combined organic layers were washed with water (2.times.200 mL)
and brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by column chromatography on
silica gel using DCM/MeOH (V:V, 20:1) to afford the desired product
as a white solid. MS: 216.2 (M+1).sup.+.
Step B: Tert-butyl 4-oxocyclohexylcarbamate
[0158] To a solution of tert-butyl 4-hydroxycyclohexyl-carbamate
(10.0 g, 46.5 mmol) in DCM (100 mL) was added Dess-Martin
periodinane (39.4 g, 92.9 mmol) portionwise. The resulting solution
was stirred at room temperature overnight, quenched with aq.
Na.sub.2S.sub.2O.sub.3 solution and extracted with DCM (3.times.100
mL). The combined organic layers were washed with water
(2.times.100 mL) and brine (100 mL), dried over anhydrous
Na.sub.2SO.sub.4, and concentrated. The residue was purified by
column chromatography on silica gel using petroleum ether/EtOAc
(V:V, 10:1) to afford desired product as a white solid.
Step C: Tert-butyl 4,4-difluorocyclohexylcarbamate
[0159] To a solution of tert-butyl 4-oxocyclo-hexylcarbamate (2.13
g, 10 mmol) in dry DCM (25 mL) was added DAST (2.58 g, 16 mmol)
dropwise at -5.degree. C. under nitrogen. After addition, the
reaction mixture was stirred at r.t overnight. The reaction mixture
was poured into ice water slowly and extracted with DCM
(3.times.100 mL). The combined organic layers were washed with 2 N
aq. NaHCO.sub.3 and brine, dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue was purified by
column chromatography using petroleum ether/EtOAc (V:V, 5:1) as
eluent to afford a mixture of the title compound (.about.70%) and
the byproduct tert-butyl 4-fluorocyclohex-3-enylcarbamate
(.about.30%) as a light-yellow solid.
[0160] To the above mixtures (2.52 g, 10.7 mmol) in DCM (25 mL) was
added m-CPBA (2.20 g, 12.9 mmol) portionwise at 0.degree. C. while
keeping the internal temperature below 5.degree. C. After addition,
the reaction mixture was stirred at room temperature overnight. To
the reaction mixture was added saturated aq. Na.sub.2S.sub.2O.sub.3
(8.0 mL) at 0.degree. C. The resulting mixture was stirred at
0.degree. C. for 40 min, and then extracted by DCM (3.times.5.0
mL). The combined organic layers were washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, and evaporated in vacuo. The residue
was used directly in the next step without further
purification.
[0161] To the above residue in MeOH (15 mL) was added NaBH.sub.4
(0.202 g, 5.35 mmol) at 0.degree. C. The reaction mixture was
stirred at room temperature overnight. Water (0.38 g) was added
dropwise to quench the reaction at 0.degree. C. The resulting
mixture was stirred at 0.degree. C. for 30 min, and concentrated in
vacuo. The residue was purified by column chromatography using DCM
as eluent to afford the pure compound as a white solid. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 4.46 (s, 1H), 3.59 (s, 1H),
2.25-1.69 (m, 6H), 1.61-1.20 (m, 11H). MS: 236.2 (M+1).sup.+.
Step D: 4,4-Difluorocyclohexanamine hydrochloride
[0162] A mixture of tert-butyl 4,4-difluorocyclo-hexylcarbamate
(6.0 g, 25.5 mmol) and 6 N HCl/MeOH (60 mL) was stirred at room
temperature for 2 h. The reaction mixture was concentrated to give
the crude product which was directly used in next step without
further purification. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.
4.89 (s, 2H), 3.32-3.26 (m, 1H), 2.14-2.01 (m, 4H), 2.02-1.85 (m,
2H), 1.74-1.65 (m, 2H). MS: 136.1 (M+1).sup.+.
Step E: N-(4,4-difluorocyclohexyl)formamide
[0163] A mixture of 4,4-difluorocyclohexanamine
[0164] (crude 3.4 g, 25.2 mmol), TEA (3 eq) and ethyl formate (35
mL) was stirred at 110.degree. C. overnight in a sealed tank. The
solvent was removed and the residue was purified by column
chromatography using DCM/MeOH (V:V, 10:1) as eluent to afford the
desired product. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.14
(s, 1H), 5.98 (s, 1H), 3.93 (m, 1H), 2.54-2.19 (m, 1H), 2.15-1.39
(m, 7H). MS: 164.1 (M+1).sup.+.
Step F: 1,1-Difluoro-4-isocyanocyclohexane
[0165] A mixture of N-(4,4-difluorocyclohexyl)-formamide (2.5 g,
15.3 mmol), PPh.sub.3 (4.4 g, 16.8 mmol), CCl.sub.4 (2.3 g, 15.1
mmol), Et.sub.3N (1.5 g, 14.9 mmol) and DCM (50 mL) was heated to
45.degree. C. and stirred overnight. The resulting mixture was
evaporated in vacuo and the residue was suspended in Et.sub.2O (125
mL) at 0.degree. C. The filtrate was concentrated and the residue
was purified by column chromatography on silica gel eluting with
Et.sub.2O to afford the desired product as a yellow oil which was
used directly in the next step.
General Procedures for the Preparation of
2-(3-aminophenoxy)ethanol
##STR00250##
Step A: 2-(3-Nitrophenoxy)ethanol
[0166] A suspension of 3-nitrophenol (1 g, 7.2 mmol),
2-bromoethanol (1.2 g, 9.6 mmol) and K.sub.2CO.sub.3 (2 g, 14.4
mmol) in MeCN (12 mL) was stirred at 90.degree. C. overnight. The
precipitate was collected by filtration to give the first batch of
product. The filtrate was concentrated and the residue was purified
by column chromatography to afford another batch of the desired
product as a yellow solid.
Step B: 2-(3-Aminophenoxy)ethanol
[0167] To a solution of 2-(3-nitrophenoxy)ethanol (500 mg, 2.7
mmol) and NH.sub.4Cl (720 mg, 13.5 mmol) in EtOH (10 mL) was added
iron powder (900 mg, 16.2 mmol) at room temperature. The reaction
was then stirred at 90.degree. C. for 2 hr and subsequently cooled.
The mixture was filtered and the filtrate was concentrated. The
resulting residue was purified by column chromatography to afford
the desired product as a yellow solid. MS: 154.1 (M+1).sup.+.
General Procedures for the Preparation of
3-(1H-pyrazol-4-yl)aniline
##STR00251##
Step A: Tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate
[0168] To a solution of
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500
mg, 2.57 mmol) and (Boc).sub.2O (672 mg, 3.08 mmol) in DMF (1.0 mL)
was added DMAP (63 mg, 0.52 mmol) in one portion. The mixture was
stirred at room temperature overnight, and then partitioned between
EtOAc and saturated aq. NH.sub.4Cl. The organic layer was
separated, washed with brine, dried over anhydrous
Na.sub.2SO.sub.4, and concentrated to afford the crude product.
Step B: 4-(3-Nitrophenyl)-1H-pyrazole
[0169] To a solution of tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate
(300 mg, 0.82 mmol), 1-bromo-3-nitrobenzene (137 mg, 0.68 mmol) and
Na.sub.2CO.sub.3 (216 mg, 2.04 mmol) in DME/H.sub.2O (5 mL/1 mL)
under N.sub.2, was added Pd(PPh.sub.3).sub.2Cl.sub.2 (24 mg, 0.034
mmol). The mixture was stirred at 85.degree. C. overnight, and then
quenched with H.sub.2O. The resulting mixture was extracted with
EtOAc (3.times.25 mL). The organic layer was separated, washed with
brine, dried over anhydrous Na.sub.2SO.sub.4, and concentrated. The
resulting residue was purified by column chromatography to afford
the desired product. MS: 190.2 (M+1).sup.+.
Step C: 3-(1H-pyrazol-4-yl)aniline
[0170] Iron powder (296 mg, 5.30 mmol) was added to a solution of
4-(3-nitrophenyl)-1H-pyrazole (200 mg, 1.06 mmol) in AcOH/EtOH (2
mL/3 mL). The reaction mixture was stirred at 90.degree. C. for 2
hr and then cooled to room temperature. The reaction mixture was
filtered through Celite. The filter cake was washed with H.sub.2O.
The filtrate was neutralized with 1 N NaOH to pH=8 and extracted
with EtOAc (3.times.30 mL). The combined organic layers were washed
with brine, dried over anhydrous Na.sub.2SO.sub.4, and
concentrated. The resulting residue was purified by column
chromatography to afford the desired product. MS: 160.2
(M+1).sup.+.
General Procedures for the Preparation of
2-(3-aminophenyl)propan-2-ol
##STR00252##
Step A: Ethyl 3-(dibenzylamino)benzoate 2
[0171] To a solution of ethyl 3-aminobenzoate (2 g, 0.012 mmol) and
Et.sub.3N (5.26 mL, 0.036 mmol) in CH.sub.3CN (30 mL), was added
BnBr (4.32 mL, 0.036 mmol) in one portion. The reaction mixture was
heated to reflux for 18 hr and then cooled to room temperature. The
mixture was concentrated to dryness in vacuo and the residue was
purified by column chromatography (PE:EtOAc=10:1 as eluent) to
afford the desired product as a white solid. MS: 346.1
(M+1).sup.+.
Step B: 2-(3-(dibenzylamino)phenyl)propan-2-ol
[0172] To a solution of ethyl 3-(dibenzylamino)benzoate (1.85 g,
5.58 mmol) in anhydrous THF (15 mL) at 0.degree. C. under nitrogen
atmosphere was added MeMgBr (3 M sol. in THF, 5.58 mL, 16.7 mmol)
dropwise over 30 min. The reaction was stirred at room temperature
overnight and quenched by addition of saturated NH.sub.4Cl. The
resulting mixture was extracted with ethyl acetate (3.times.50 mL).
The combined organic layers were washed with NaHCO.sub.3, water and
brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and then
concentrated to dryness. The residue was purified by column
chromatography (PE:EtOAc=2:1 as eluent) to afford the desired
product as a colorless oil. MS: 332.1 (M+1).sup.+.
Step C: 2-(3-aminophenyl)propan-2-ol
[0173] To a solution of 2-(3-(dibenzylamino)phenyl)propan-2-ol (268
mg, 0.81 mmol) in MeOH (5 mL) was added 10% Pd/C (27 mg) in one
portion. The reaction mixture was hydrogenated at room temperature
overnight under hydrogen atmosphere. The catalyst was filtered off
through Celite and the filtrate was concentrated to dryness. The
residue was purified by column chromatography (PE:EtOAc=1:2 as
eluent) to afford the desired product as a yellow solid. MS: 152.1
(M+1).sup.+.
General Procedures for the Preparation of
2-(3-amino-5-fluorophenyl)propan-2-ol
##STR00253##
Step A. Methyl 3-fluoro-5-nitrobenzoate
[0174] Thionyl chloride (488 mg, 4.1 mmol) was added dropwise to a
solution of 3-fluoro-5-nitrobenzoic acid (500 mg, 2.7 mmol) in dry
methanol (10 mL) at 0.degree. C. under nitrogen atmosphere. The
reaction was warmed to room temperature and stirred for 6 hr. The
reaction mixture was concentrated under reduced pressure to obtain
the corresponding methyl ester hydrochloride as a waxy solid which
was used directly in the next step. MS: 200 (M+1).sup.+.
Step B. Methyl 3-amino-5-fluorobenzoate
[0175] To a solution of methyl 3-fluoro-5-nitrobenzoate (400 mg, 2
mmol) in ethanol (10 mL) was added iron powder (560 mg, 10 mmol)
and ammonium chloride (540 mg, 10 mmol) in one portion. The
reaction mixture was stirred at 80.degree. C. for 1 hr. After
cooling the reaction, the mixture was filtered through Celite. The
filtrate was concentrated under reduced pressure to give the
desired product. MS: 170 (M+1).sup.+.
Step C. Methyl 3-(dibenzylamino)-5-fluorobenzoate
[0176] To a solution of methyl 3-amino-5-fluorobenzoate (440 mg,
2.6 mmol) in dry DMF (10 mL) was added NaH (187 mg, 7.8 mmol)
portionwise, followed by addition of benzyl bromide (1.1 g, 6.5
mmol). The reaction mixture was stirred at 40.degree. C. for 16 hr
and concentrated. The resulting residue was purified by column
chromatography to give the desired product. MS: 350
(M+1).sup.+.
Step D. 2-(3-(Dibenzylamino)-5-fluorophenyl)propan-2-ol
[0177] Methylmagnesium bromide (1 M in THF, 2.4 mL, 2.4 mmol) was
dissolved in THF (5 mL) and placed in an ice-water bath. Methyl
3-(dibenzylamino)-5-fluorobenzoate (280 mg, 0.8 mmol) in THF (5 mL)
was then slowly added to the reaction mixture. This mixture was
stirred for 3 hr while maintaining an internal temperature range
between 15 to 25.degree. C. Then the mixture was cooled to
0.degree. C. and treated with ammonium chloride solution, then
extracted with ethyl acetate (3.times.30 mL). The combined organic
layers were dried over anhydrous Na.sub.2SO.sub.4, and concentrated
in vacuo. The residue was purified by column chromatography on
silica gel to give the desired product. MS: 350 (M+1).sup.+.
Step E. 2-(3-Amino-5-fluorophenyl)propan-2-ol
[0178] To a solution of
2-(3-(dibenzylamino)-5-fluorophenyl)propan-2-ol (150 mg, 0.43 mmol)
in ethanol (5 mL) was added 10% Pd/C (15 mg) under a hydrogen
atmosphere. The reaction mixture was stirred at room temperature
for 16 hr. The suspension was then filtered through Celite and the
filtrate was concentrated in vacuo. The residue was purified by
column chromatography to give the desired product. MS: 170
(M+1).sup.+.
General Procedures for the Preparation of ethyl
1-(3-aminophenyl)cyclopropanol
##STR00254##
Step A. Ethyl 3-(dibenzylamino)benzoate
[0179] To a solution of ethyl 3-aminobenzoate (2 g, 0.012 mmol) and
Et.sub.3N (5.26 mL, 0.036 mmol) in CH.sub.3CN (30 mL) was added
BnBr (4.32 mL, 0.036 mmol) in one portion. The reaction mixture was
heated to reflux for 18 h and cooled down to room temperature. The
mixture was concentrated in vacuo and the resulting residue was
purified by column chromatography to afford the desired product as
a white solid. MS: 346.1 (M+1).sup.+.
Step B. 1-(3-(Dibenzylamino)phenyl)cyclopropanol
[0180] To a solution of ethyl 3-(dibenzylamino)benzoate (1.85 g,
5.58 mmol) in anhydrous THF (20 mL) at room temperature under
N.sub.2 was added titanium tetraisopropoxide (0.25 mL, 0.84 mmol)
dropwise over 10 min. After one hour of stirring, EtMgBr (THF
solution, 4.1 mL, 12.3 mmol) was added dropwise over 30 min. The
reaction mixture was stirred at room temperature for 3 h. The
resulting mixture was quenched by addition of saturated aq.
NH.sub.4Cl, and extracted with ethyl acetate (3.times.50 mL). The
combined organic layers were washed with NaHCO.sub.3, water and
brine, dried over anhydrous Na.sub.2SO.sub.4, and concentrated in
vacuo. The residue was purified by column chromatography
(PE:EtOAc=5:1 as eluent) to afford the desired product as a
colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.33-7.28
(m, 5H), 7.25-7.18 (m, 5H), 7.11 (t, J=8.0 Hz, 1H), 6.80-6.75 (m,
1H), 6.61-6.56 (m, 2H), 4.65 (s, 4H), 1.17-1.13 (m, 2H), 0.93-0.90
(m, 2H). MS: 330.1 (M+1).sup.+.
Step C. Ethyl 1-(3-aminophenyl)cyclopropanol
[0181] To a solution of 1-(3-(dibenzylamino)phenyl)cyclopropanol
(1.8 g, 5.45 mmol) in MeOH (10 mL) at room temperature was added
10% Pd/C (200 mg) in one portion. The reaction mixture was stirred
at room temperature under a hydrogen atmosphere overnight. The
suspension was filtered through Celite, and the filtrate was
concentrated in vacuo. The residue was purified by column
chromatography (PE:EtOAc=2:1 as eluent) to afford the desired
product as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 7.10 (t, J=7.8 Hz, 1H), 6.69 (t, J=2.0 Hz, 1H), 6.63-6.60
(m, 1H), 6.56-6.53 (m, 1H), 1.22-1.19 (m, 2H), 1.01-0.98 (m, 2H).
MS: 150.1 (M+1).sup.+.
General Procedures for the Preparation of
3-fluoro-5-(methylthio)aniline
##STR00255##
Step A. (3-Fluoro-5-nitrophenyl)(methyl)sulfane
[0182] A solution of 3-fluoro-5-nitroaniline (200 mg, 1.28 mmol),
1,2-dimethyldisulfane (121 mg, 1.29 mmol) and CH.sub.3CN (3 mL) was
stirred at 30.degree. C. Neat isoamyl nitrite (150 mg, 1.28 mmol)
was slowly added via syringe over 5 min. The reaction mixture was
slowly heated to reflux over 10 min and maintained at a gentle
reflux until N.sub.2 evolution ceased (30-60 min). The reaction
mixture was cooled and the solvent was removed in vacuo to afford a
dark oil. The resulting oil was purified by column chromatography
to give the desired product as a pale yellow solid.
Step B: 3-Fluoro-5-(methylthio)aniline
[0183] To a solution of (3-fluoro-5-nitrophenyl)(methyl)sulfane (90
mg, 0.48 mmol) in MeOH (10 mL) was added 10% Pd/C (9 mg) in one
portion. The resulting mixture was purged with H.sub.2 three times
and stirred at room temperature for 1 h. The suspension was
filtered through Celite, and the filter cake was washed with MeOH
(5 mL). The filtrate was concentrated in vacuo to afford the
desired product which was used directly in next step. MS: 158.0
(M+1).sup.+.
General Procedure for the Preparation of
(S)-2-oxo-1,3-oxazinane-4-carboxylic acid
##STR00256##
[0184] To a mixture of (S)-2-amino-4-hydroxybutanoic acid (10 g,
84.0 mmol) and 250 mL of aq. NaOH (2 mol/L, 20.4 g, 510 mmol) at
0.degree. C. was added a solution of triphosgene in dioxane (25.3 g
in 125 mL dioxane) dropwise over 1 h. The internal temperature was
kept below 5.degree. C. during the addition. The mixture was then
stirred at room temperature for 2 days. The reaction mixture was
then concentrated in vacuo, followed by addition of 200 mL of
CH.sub.3CN. The resulting mixture was then heated to 60.degree. C.
and stirred vigorously for 0.5 h. The hot mixture was filtered
immediately. The filtrate was then concentrated to 100 mL and the
desired product was precipitated out. The crude product was
collected by filtration and used directly in the next step without
further purification. MS: 146.0 (M+1).sup.+.
General Procedure for the Preparation of
(S)-4-(tert-butoxycarbonyl)-6-oxopiperazine-2-carboxylic acid
##STR00257##
Step A: (S)-3-Amino-2-(((benzyloxy)carbonyl)amino)propanoic
acid
[0185] To a mixture of
(S)-4-amino-2-(((benzyloxy)carbonyl)amino)-4-oxobutanoic acid (3 g,
11.3 mmol) in MeCN (20 mL), EtOAc (20 mL) and H.sub.2O (10 mL), was
added PIAD (4.38 g, 13.5 mmol) in one portion. The reaction mixture
was stirred at room temperature overnight. The resulting mixture
was filtered, and the filtrate was concentrated in vacuo to afford
the desired product. MS: 239.1 (M+1).sup.+.
Step B: (S)-Methyl 3-amino-2-(((benzyloxy)carbonyl)amino)propanoate
hydrochloride
[0186] To a stirred solution of MeOH (50 mL) was added SOCl.sub.2
(5 mL) dropwise at 0.degree. C. The resulting mixture was stirred
at 0.degree. C. for 0.5 h before
(S)-3-amino-2-(((benzyloxy)carbonyl)amino) propanoic acid (2.6 g,
10 mmol) was added. Then the reaction mixture was stirred at room
temperature overnight and concentrated in vacuo to afford the
desired product. MS: 253.1 (M+1).sup.+.
Step C: (S)-Methyl
3-((2-(benzyloxy)-2-oxoethyl)amino)-2-(((benzyloxy)carbonyl)amino)pro-pan-
eate
[0187] To a solution of (S)-methyl
3-amino-2-(((benzyloxy)carbonyl)amino)propanoate hydrochloride (2.6
g, 0.01 mol) in THF (40 mL) was added DIPEA (4.0 g, 0.03 mol) at
0.degree. C. The mixture was stirred at 0.degree. C. for 5 min,
followed by addition of benzyl 2-bromoacetate (4.7 g, 0.02 mol).
Then the mixture was allowed to warm to room temperature and
stirred overnight. The reaction mixture was quenched by addition of
H.sub.2O and then extracted with EtOAc (3.times.40 mL). The
combined organic layers were washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, and concentrated. The resulting residue
was purified by column chromatography to afford the desired
product. MS: 401.2 (M+1).sup.+.
Step D: (S)-Methyl
3-((2-(benzyloxy)-2-oxoethyl)(tert-butoxycarbonyl)amino)-2-(((benzyloxy)
carbonyl)amino)propanoate
[0188] To a solution of (S)-methyl
3-((2-(benzyloxy)-2-oxoethyl)amino)-2-(((benzyloxy)carbonyl)amino)propano-
ate (3.0 g, 7.5 mmol) in THF (40 mL) was added DIPEA (2.9 g, 22.5
mmol) at 0.degree. C. The mixture was stirred at 0.degree. C. for 5
min followed by addition of di-tert-butyl dicarbonate (3.27 g, 15
mmol). Then the mixture was allowed to warm to room temperature and
stirred overnight. After quenching with a saturated. NaHCO.sub.3
solution, the resulting mixture was extracted with EtOAc
(3.times.60 mL) and concentrated. The resulting residue was
purified by column chromatography to afford the desired product.
MS: 501.2 (M+1).sup.+.
Step E:
(S)-2-((2-Amino-3-methoxy-3-oxopropyl)(tert-butoxycarbonyl)amino)a-
cetic acid
[0189] To a solution of (S)-methyl
3-((2-(benzyloxy)-2-oxoethyl)(tert-butoxycarbonyl)amino)-2-(((benzyl-oxy)-
carbonyl)amino)propanoate (2.5 g, 5 mmol) in MeOH (30 mL) was added
10% Pd/C (250 mg). The mixture was stirred under hydrogen
atmosphere at room temperature overnight. The resulting suspension
was filtered through Celite, and the filtrate was concentrated in
vacuo to afford the desired product. MS: 277.1 (M+1).sup.+.
Step E: (S)-1-tent-Butyl 3-methyl
5-oxopiperazine-1,3-dicarboxylate
[0190] To a solution of
(S)-2-((2-amino-3-methoxy-3-oxopropyl)(tert-butoxycarbonyl)amino)acetic
acid (1.2 g, 4 mmol) in DCM (100 mL) was added DCC (1.34 g, 6 mmol)
at 5.degree. C. The mixture was stirred at 10.degree. C. for 4 h
followed by addition of Et.sub.3N (0.88 g, 8 mmol). The resulting
mixture was stirred at room temperature for 18 h and then
concentrated. The residue was added to EtOAc (20 mL) and the
precipitate was filtered. The filtrate was concentrated and the
residue was purified by column chromatography to afford the desired
product. MS: 259.1 (M+1).sup.+.
Step F: (S)-4-(tent-Butoxycarbonyl)-6-oxopiperazine-2-carboxylic
acid
[0191] To a mixture of (S)-1-tert-butyl 3-methyl
5-oxopiperazine-1,3-dicarboxylate (500 mg, 1.9 mmol) in MeOH (20
mL) and THF (20 mL) was added a solution of LiOH.H.sub.2O (159 mg,
3.8 mmol) in H.sub.2O (10 mL) at 0.degree. C. The mixture was
stirred at room temperature for 2 h and then partitioned between
EtOAc (25 mL) and H.sub.2O. The aqueous layer was acidified with 2N
HCl to pH 3-4 and then extracted with EtOAc (3.times.20 mL). The
combined organic layers were washed with brine, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated to afford the desired
product which was used directly in the next reaction. MS: 245.1
(M+1).sup.+.
General Procedure for the Preparation of
2-bromopyrimidine-4-carbonitrile
##STR00258##
Step A: 2-Hydroxy-4-carboxyaldehyde oxime
[0192] 2-Hydroxy-4-methylpyrimidine hydrochloride
[0193] (25.0 g 171 mmol) and sodium nitrate (17.7 mg, 260 mmol)
were slowly added to 200 mL of 50% acetic acid at 0.degree. C. The
reaction mixture was stirred at room temperature for 3 h. The
resulting suspension and the solids were filtered, washed with
water and dried to afford the desired product. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 12.42 (s, 1H), 11.89 (s, 1H), 7.92 (d,
J=6.4 Hz, 1H), 7.75 (s, 1H), 6.43 (d, J=6.4 Hz, 1H). MS: 140.0
(M+1).sup.+.
Step B: 2-Bromopyrimidine-4-carbonitrile
[0194] A mixture of 2-hydroxy-4-carboxyaldehyde oxime (9 g, 28.8
mmol), tetrabutyl ammonium bromide (10 g, 71.9 mmol) and phosphorus
pentoxide (2 g, 14.4 mmol) in toluene (300 mL) was stirred at
120.degree. C. for 2 h. The resulting mixture was filtered and the
filtrate was concentrated. The resulting residue was purified by
column chromatography to give the desired compound as a yellow
solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.82 (d, J=4.8
Hz, 1H), 7.66 (d, J=4.8 Hz, 1H). MS: 185.0 (M+1).sup.+.
General Synthetic Procedures for Making Compounds of Formula I:
##STR00259##
[0195] General Procedures for the UGI Reaction:
[0196] A mixture of aldehyde (3.5 mmol) and aniline (3.5 mmol) in
MeOH (8 mL) was stirred at room temperature for 30 min. Then the
acid (3.5 mmol) was added and the reaction mixture was stirred for
another 30 min, followed by addition of the isocyanide (3.5 mmol).
The resulting mixture was then stirred at room temperature
overnight and quenched with H.sub.2O. The resulting mixture was
partitioned between EtOAc and H.sub.2O. The organic layer was
washed with brine, dried over anhydrous Na.sub.2SO.sub.4, and then
concentrated. The resulting residue was purified by a standard
method to afford the desired product.
General Procedures for the Buchwald Reaction:
[0197] A mixture of amine (0.30 mmol), aryl bromide (0.30 mmol),
Cs.sub.2CO.sub.3 (129 mg, 0.39 mmol), Pd.sub.2(dba).sub.3 (18 mg,
0.02 mmol) and Xant-Phos (9.4 mg, 0.02 mmol) in 1,4-dioxane (10 mL)
was stirred under N.sub.2 at 80.degree. C. overnight. After
filtration, the filtrate was concentrated in vacuo and the residue
was purified by a standard method to give the desired products.
Example 1
Preparation of (S)-methyl
1-methyl-5-oxopyrrolidine-2-carboxylate
[0198] Compound 2 was prepared according to the following scheme,
using the following protocol.
##STR00260##
Step A: (S)-Methyl 1-methyl-5-oxopyrrolidine-2-carboxylate
[0199] To a mixture of (S)-5-oxopyro-lidine-2-carboxylic acid (5.0
g, 38.8 mmol) in DMF (50 mL) were added anhydrous K.sub.2CO.sub.3
(16 g, 116 mmol) and iodomethane (16.4 g, 116 mmol) at room
temperature The resulting mixture was warmed to 40.degree. C.,
stirred for 24 h and concentrated in vacuo. The residue was
precipitated with EtOAc (80 mL) and filtered. The filter cake was
washed with EtOAc (2.times.10 mL). The combined filtrates were
concentrated and the residue was purified by column chromatography
on silica gel to give the desired product. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 4.18-4.11 (m, 1H), 3.70 (s, 3H), 2.87 (s, 3H),
2.56-2.29 (m, 3H), 2.16-2.04 (m, 1H). MS: 158.1 (M+1).sup.+.
Step B: (S)-1-Methyl-5-oxopyrrolidine-2-carboxylic acid
[0200] To a solution of (S)-methyl
1-methyl-5-oxopyrrolidine-2-carboxylate (0.6 g, 3.8 mmol) in MeOH
(6 mL) were added THF (2 mL), H.sub.2O (2 mL) and NaOH (0.45 g,
11.4 mmol) at room temperature The resulting mixture was stirred at
room temperature for 18 h and then acidified with 2 N HCl to pH=3-4
at 0.degree. C. The mixture was extracted with EtOAc (3.times.30
mL), the combined organic layers were dried over anhydrous
Na.sub.2SO.sub.4 and concentrated to give the crude product as a
yellow solid (0.8 g) which was used directly in the next step. MS:
142.1 (M-1).sup.-.
Step C: Compound 2
[0201] 2-Chlorobenzaldehyde (117 mg, 0.83 mmol), 3-fluoroaniline
(92.5 mg, 0.83 mmol), crude
(S)-1-methyl-5-oxopyrrolidine-2-carboxylic acid (200 mg, .about.60%
purity, 0.83 mmol) and 1,1-difluoro-3-isocyanocyclobutane (119 mg,
90% purity, 1.0 mmol) were used in the UGI reaction to give the
desired product (diastereomeric mixture). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.52 (d, J=4.9 Hz, 0.2H), 8.16 (m, 0.3H),
7.87-7.47 (m, 2H), 7.42-7.31 (m, 1H), 7.25-7.11 (m, 2H), 7.08-6.89
(m, 3.3H), 6.74 (d, J=6.0 Hz, 0.7H), 6.57 (m, 2H), 4.42-4.26 (m,
1.3H), 4.20-4.08 (m, 0.5H), 4.00 (m, 1H), 3.00 (m, 2H), 2.74 (m,
3H), 2.63-1.82 (m, 6H). MS: 494.1 (M+1).sup.+.
Example 2
Preparation of
(S)--N-(1-(2-chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoethyl)--
N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide
[0202] Compounds 3 and 4 were prepared according to the following
scheme, using the following protocol.
##STR00261##
Step A.
(S)--N-(1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-ox-
oethyl)-N-(3-fluoro-phenyl)-5-oxopyrrolidine-2-carboxamide
[0203] 3-Fluoroaniline (86 mg, 0.78 mmol), 2-chlorobenzaldehyde
(109 mg, 0.78 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (100
mg, 0.78 mmol) and 1,1-difluoro-4-isocyanocyclohexane (135 mg, 0.91
mmol) were used in the UGI reaction to give the desired product.
MS: 508.1 (M+1).sup.+.
Step B.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)--
2-oxoethyl)-N-(3-fluorophenyl)-5-oxo-1-(pyrimidin-2-yl)pyrrolidine-2-carbo-
xamide and
(S)--N--((R)-1-(2-chlorophenyl)-2-((4,4-difluorocyclohexyl)amin-
o)-2-oxoethyl)-N-(3-fluorophenyl)-5-oxo-1-(pyrimidin-2-yl)pyrrolidine-2-ca-
rboxamide
[0204] A mixture of
(S)--N-(1-(2-chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoethyl)--
N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide (100 mg, 0.20
mmol), 2-bromopyrimidine (47 mg, 0.30 mmol), Cs.sub.2CO.sub.3 (129
mg, 0.39 mmol), Pd.sub.2(dba).sub.3 (18 mg, 0.02 mmol) and
Xant-Phos (9.4 mg, 0.02 mmol) in 1,4-dioxane (10 mL) was stirred
under N.sub.2 at 80.degree. C. overnight. After filtration, the
filtrate was concentrated in vacuo and the residue was purified by
a standard method to give the desired products.
(S)--N--((S)-1-(2-chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-N-(3-fluoro-phenyl)-5-oxo-1-(pyrimidin-2-yl)pyrrolidine-2-carboxamide.
Compound 4
[0205] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.71 (d, J=4.8
Hz, 2H), 7.75 (m, 1H), 7.33 (m, 2H), 7.18 (m, 1H), 7.09-6.87 (m,
5H), 6.47 (s, 1H), 5.61 (d, J=7.6 Hz, 1H), 4.86 (d, J=6.6 Hz, 1H),
3.98 (m, 1H), 3.01-2.84 (m, 2H), 2.58 (m, 1H), 2.30-2.20 (m, 1H),
1.93 (m, 7H), 1.47 (m, 2H); MS: 586.2 (M+1).sup.+.
(S)--N--((R)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-N-(3-fluorophenyl)-5-oxo-1-(pyrimidin-2-yl)pyrrolidine-2-carboxamide.
Compound 3
[0206] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.75 (dd, J=4.8,
2.0 Hz, 2H), 7.40 (d, J=7.8 Hz, 1H), 7.23 (s, 3H), 7.08 (dt,
J=11.3, 6.3 Hz, 3H), 6.99 (d, J=3.7 Hz, 1H), 6.27 (s, 1H),
6.13-5.92 (m, 1H), 5.02 (m, 1H), 4.76 (m, 1H), 3.92 (m, 1H), 2.88
(m, 1H), 2.67-2.46 (m, 1H), 2.44-2.19 (m, 2H), 2.00 (m, 8H). MS:
586.1 (M+1).sup.+.
[0207] The following analogs were synthesized via the procedures
set forth above, using the appropriate aldehyde, amine, carboxylic
acid, isocyanide and halo-substituted-aromatic ring or
heteroaromatic ring using the reagents and solvents set forth above
or similar reagents and solvents thereof, and purified via standard
methods.
##STR00262##
[0208] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.75 (d, J=4.8
Hz, 2H), 7.35 (m, 3H), 7.25-6.81 (m, 5H), 6.28 (s, 1H), 5.84 (d,
J=7.5 Hz, 1H), 4.76 (m, 1H), 3.98-3.59 (m, 1H), 2.92 (m, 1H), 2.58
(m, 1H), 2.35-2.20 (m, 1H), 2.07 (m, 1H), 1.83 (m, 2H), 1.57 (m,
4H), 1.46-1.17 (m, 4H). MS: 550.2 (M+1).sup.+.
##STR00263##
[0209] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.73 (m, 2H),
7.80 (s, 1H), 7.35 (s, 1H), 7.23-6.72 (m, 6H), 6.47 (s, 1H), 5.49
(d, J=7.7 Hz, 1H), 4.87 (d, J=6.6 Hz, 1H), 4.74-4.42 (m, 1H), 3.86
(d, J=8.0 Hz, 1H), 3.19-2.77 (m, 1H), 2.56 (m, 1H), 2.44-2.21 (m,
1H), 2.13-1.73 (m, 4H), 1.60 (s, 2H), 1.26 (m, 4H). MS: 550.2
(M+1).sup.+.
##STR00264##
[0210] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.69 (s, 2H),
7.76 (s, 1H), 7.49-6.68 (m, 7H), 6.44 (s, 1H), 6.19 (s, 1H), 4.93
(m, 3H), 2.23 (m, 8H). MS: 540.1 (M+1).sup.+.
##STR00265##
[0211] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.81 (d, J=4.9
Hz, 1H), 8.66 (d, J=2.7 Hz, 1H), 8.04-7.79 (m, 1H), 7.49-7.31 (m,
1H), 7.13-6.92 (m, 6H), 6.60 (m, 1H), 6.25-5.95 (m, 1H), 5.68 (m,
1H), 4.73 (dd, J=16.0, 6.9 Hz, 1H), 4.39 (m, 1H), 2.98 (m, 3H),
2.53 (m, 4H), 2.14-1.93 (m, 1H). MS: 592.1 (M+1).sup.+.
##STR00266##
[0212] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.46-8.32 (m,
1.7H), 7.78-7.61 (m, 1.5H), 7.39 (m, 1.5H), 7.23 (m, 1.6H),
7.13-6.88 (m, 4H), 6.40 (m, 1H), 6.11 (m, 1H), 5.01-4.77 (m, 1H),
4.26 (m, 1H), 3.51 (d, J=5.5 Hz, 0.3H), 3.13-2.75 (m, 3H),
2.61-2.22 (m, 3H), 2.17-1.90 (m, 1H). MS: 557.1 (M+1).sup.+.
##STR00267##
[0213] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.56 (m, 2H),
8.16 (s, 1.3H), 7.74 (s, 1H), 7.36 (s, 2.6H), 7.19 (s, 1H),
7.12-6.82 (m, 3H), 6.52 (m, 2H), 6.19 (m, 1H), 4.65-4.48 (m, 1H),
4.26 (m, 1.3H), 3.90-3.82 (m, 0.3H), 2.87 (m, 3H), 2.64-1.98 (m,
6H). MS: 557.1 (M+1).sup.+.
##STR00268##
[0214] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.98 (m, 1H),
7.65 (m, 2H), 7.44-7.30 (m, 2H), 7.03 (m, 6H), 6.51 (m, 1H), 6.36
(s, 1H), 5.12 (d, J=6.3 Hz, 1H), 4.33 (s, 1H), 3.97 (s, 3H),
3.10-2.63 (m, 3H), 2.60-2.00 (m, 5H). MS: 587.1 (M+1).sup.+.
##STR00269##
[0215] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.32 (m, 1H),
8.05 (t, J=8.6 Hz, 1H), 7.69 (s, 1H), 7.45-7.30 (m, 1H), 7.25-6.78
(m, 6H), 6.38 (m, 2H), 4.88 (m, 1H), 4.33 (s, 1H), 3.89 (s, 3H),
3.11-2.72 (m, 3H), 2.66-2.29 (m, 3H), 2.23-1.86 (m, 2H). MS: 587.1
(M+1).sup.+.
##STR00270##
[0216] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.93 (m, 1H),
7.56 (m, 2H), 7.21 (m, 3H), 7.10-6.87 (m, 3H), 6.42 (m, 3H), 5.04
(m, 1H), 4.25 (m, 1H), 3.97 (d, J=6.1 Hz, 3H), 3.10-2.69 (m, 3H),
2.60-2.15 (m, 4H), 2.12-1.87 (m, 1H). MS: 587.2 (M+1).sup.+.
##STR00271##
[0217] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.19 (m, 1H),
7.79-7.33 (m, 3H), 7.28-7.06 (m, 4H), 7.06-6.83 (m, 4H), 6.47-6.32
(m, 2H), 5.09-4.91 (m, 1H), 4.25 (m, 1H), 3.09-2.60 (m, 4H), 2.57
(s, 3H), 2.53-1.99 (m, 5H). MS: 571.0 (M+1).sup.+.
##STR00272##
[0218] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.26 (d, J=8.5
Hz, 1H), 8.15 (s, 1H), 7.64 (s, 1H), 7.48 (m, 1H), 7.32 (d, J=7.5
Hz, 1H), 7.14 (m, 2H), 7.04-6.83 (m, 3H), 6.40 (s, 1H), 6.04 (s,
1H), 4.89 (m, 1H), 4.31 (s, 1H), 2.89 (m, 3H), 2.48 (m, 2H),
2.40-2.27 (m, 3H), 2.26-1.84 (m, 3H). MS: 571.2 (M+1).sup.+.
##STR00273##
[0219] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.30-8.15 (m,
2H), 7.68 (s, 1H), 7.38 (m, 1H), 7.24-6.85 (m, 6H), 6.46-6.16 (m,
2H), 4.94 (d, J=6.0 Hz, 1H), 4.32 (s, 1H), 3.10-2.74 (m, 3H),
2.60-2.43 (m, 2H), 2.36 (m, 4H), 2.23-1.91 (m, 2H). MS: 571.2
(M+1).sup.+.
##STR00274##
[0220] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.17 (d, J=8.3
Hz, 1H), 7.56 (m, 2H), 7.25-6.96 (m, 5H), 6.89 (m, 2H), 6.42 (s,
1H), 6.21 (s, 1H), 5.12-4.96 (m, 1H), 4.31 (m, 1H), 3.14-2.74 (m,
3H), 2.55 (s, 3H), 2.51-2.28 (m, 3H), 2.20 (m, 1H), 2.05-1.87 (m,
1H). MS: 571.2 (M+1).sup.+.
##STR00275##
[0221] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.72 (m, 1H),
7.88 (m, 1H), 7.65 (s, 1H), 7.57-7.30 (m, 2H), 7.23-7.09 (m, 2H),
7.02 (s, 2H), 6.96-6.83 (m, 1H), 6.44 (s, 1H), 6.05 (d, J=6.5 Hz,
1H), 5.31-4.93 (m, 1H), 4.33 (s, 1H), 3.02 (m, 2H), 2.86 (m, 1H),
2.63-2.45 (m, 2H), 2.44-2.23 (m, 2H), 2.01 (m, 1H). MS: 625.1
(M+1).sup.+.
##STR00276##
[0222] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.91-8.34 (m,
2H), 8.03 (s, 1H), 7.79-7.34 (m, 3H), 7.22-6.75 (m, 5H), 6.46 (s,
1H), 6.02 (d, J=6.5 Hz, 1H), 4.95 (dd, J=9.4, 3.1 Hz, 1H), 4.35 (s,
1H), 3.13-2.76 (m, 3H), 2.68-1.83 (m, 5H). MS: 625.1
(M+1).sup.+.
##STR00277##
[0223] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.65 (d, J=23.6
Hz, 2H), 7.87 (s, 1H), 7.59-7.29 (m, 3H), 7.26-6.71 (m, 5H), 6.59
(s, 1H), 6.28 (s, 1H), 4.83 (d, J=8.2 Hz, 1H), 4.12 (s, 1H),
3.10-2.62 (m, 3H), 2.56 (m, 1H), 2.36-1.84 (m, 4H). MS: 625.1
(M+1).sup.+.
##STR00278##
[0224] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.74 (s, 1H),
8.53 (s, 1H), 7.71 (s, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.25-6.80 (m,
6H), 6.44 (s, 1H), 6.08 (s, 1H), 4.95 (m, 1H), 4.35 (s, 1H),
3.15-2.76 (m, 3H), 2.66-2.17 (m, 4H), 2.03 (s, 1H). MS: 625.1
(M+1).sup.+.
##STR00279##
[0225] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.29 (dd, J=8.1,
2.0 Hz, 1H), 7.74 (m, 2H), 7.31 (m, 2H), 7.22-7.12 (m, 2H), 7.00
(s, 2H), 6.93 (m, 1H), 6.67 (dd, J=7.9, 2.4 Hz, 1H), 6.46 (m, 1H),
6.06 (m, 1H), 4.86 (m, 1H), 4.35 (m, 1H), 2.93 (m, 3H), 2.59-2.39
(m, 2H), 2.23 (m, 1H), 2.02 (m, 1H). MS: 575.1 (M+1).sup.+.
##STR00280##
[0226] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.40 (m, 1H),
8.24 (m, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.49-7.30 (m, 2H), 7.28-7.21
(m, 1H), 7.12 (m, 2H), 7.04-6.88 (m, 3H), 6.67 (m, 1H), 6.42 (s,
2H), 4.90 (m, 1H), 4.27 (m, 1H), 3.07-2.76 (m, 3H), 2.58-2.29 (m,
3H). MS: 575.0 (M+1).sup.+.
##STR00281##
[0227] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.27 (m, 1H),
7.64-7.30 (m, 3H), 7.27-6.62 (m, 7H), 6.47-6.30 (m, 1H), 6.28-6.07
(m, 1H), 5.00-4.55 (m, 1H), 4.26 (m, 1H), 3.12-2.67 (m, 3H),
2.65-2.36 (m, 3H), 2.22 (m, 2H). MS: 575.1 (M+1).sup.+.
##STR00282##
[0228] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.37 (t, J=8.9
Hz, 1H), 7.63 (m, 2H), 7.49-6.84 (m, 8H), 6.44 (s, 1H), 5.94 (m,
1H), 5.07-4.74 (m, 1H), 4.25 (d, J=51.6 Hz, 1H), 3.10-2.67 (m, 3H),
2.63-1.85 (m, 5H), 1.25 (s, 1H). MS: 591.1 (M+1).sup.+.
##STR00283##
[0229] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.38 (d, J=8.2
Hz, 1H), 7.86-7.34 (m, 4H), 7.25-6.79 (m, 6H), 6.46 (s, 1H), 5.99
(s, 1H), 4.95 (d, J=9.2 Hz, 1H), 4.34 (s, 1H), 3.12-2.70 (m, 3H),
2.63-1.87 (m, 6H). MS: 591.1 (M+1).sup.+.
##STR00284##
[0230] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.59-8.19 (m,
2H), 7.82-7.57 (m, 2H), 7.45-7.34 (m, 2H), 7.01 (m, 4H), 6.45 (s,
1H), 5.94 (s, 1H), 4.89 (dd, J=9.3, 3.1 Hz, 1H), 4.30 (m, 1H),
3.21-2.69 (m, 3H), 2.61-1.88 (m, 5H). MS: 591.1 (M+1).sup.+.
##STR00285##
[0231] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.63-8.03 (m,
2H), 7.67 (s, 1H), 7.23-6.65 (m, 8H), 6.45-5.93 (m, 2H), 4.84 (m,
1H), 4.23 (m, 1H), 3.04-2.65 (m, 4H), 2.65-1.83 (m, 5H). MS: 591.1
(M+1).sup.+.
##STR00286##
[0232] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.79-8.51 (m,
2H), 7.88 (s, 1H), 7.51-7.29 (m, 2H), 7.22 (m, 2H), 7.08 (t, J=7.3
Hz, 1H), 6.99 (t, J=7.2 Hz, 1H), 6.78 (s, 1H), 6.51 (d, J=5.8 Hz,
1H), 6.28 (s, 1H), 4.79 (m, 1H), 4.14 (s, 1H), 3.02-2.66 (m, 3H),
2.55 (m, 1H), 2.33-1.99 (m, 4H). MS: 582.1 (M+1).sup.+.
##STR00287##
[0233] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.74 (s, 1H),
8.52 (s, 1H), 7.85-7.30 (m, 3H), 7.24-6.79 (m, 5H), 6.43 (s, 1H),
6.12 (s, 1H), 4.92 (d, J=6.8 Hz, 1H), 4.34 (s, 1H), 2.90 (m, 3H),
2.64-2.46 (m, 1H), 2.46-2.11 (m, 3H), 1.97 (m, 1H). MS: 582.1
(M+1).sup.+.
##STR00288##
[0234] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.66-8.38 (m,
2H), 7.90 (d, J=7.0 Hz, 1H), 7.68 (s, 1H), 7.37 (m, 1H), 7.25-6.80
(m, 6H), 6.44 (s, 1H), 5.97 (d, J=6.6 Hz, 1H), 4.91 (d, J=6.7 Hz,
1H), 4.32 (s, 1H), 3.30-2.78 (m, 4H), 2.41 (m, 4H), 2.02 (s, 1H).
MS: 582.1 (M+1).sup.+.
##STR00289##
[0235] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.58 (d, J=9.3
Hz, 1H), 8.11 (d, J=8.7 Hz, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.86-7.59
(m, 3H), 7.48 (m, 2H), 7.18 (m, 3H), 6.97 (m, 3H), 6.38 (s, 1H),
6.11 (s, 1H), 5.20 (s, 1H), 4.30 (s, 1H), 3.09-2.77 (m, 3H),
2.67-2.44 (m, 2H), 2.36-2.21 (m, 2H), 2.10-1.92 (m, 1H). MS: 607.2
(M+1).sup.+.
##STR00290##
[0236] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.69 (d, J=4.8
Hz, 2H), 7.71 (s, 1H), 7.31 (m, 1H), 7.18 (m, 1H), 7.13-6.77 (m,
6H), 6.46 (s, 1H), 6.22 (s, 1H), 5.00-4.62 (m, 1H), 4.35 (s, 1H),
3.19-2.71 (m, 3H), 2.69-1.83 (m, 5H). MS: 451.2 (M+1).sup.+.
##STR00291##
[0237] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.15-8.01 (m,
1H), 7.62-7.52 (m, 1H), 7.31-6.69 (m, 9H), 6.24 (s, 1H), 5.65-4.66
(m, 1H), 2.60 (m, 1H), 2.20-2.05 (m, 3H), 1.76-0.83 (m, 4H). MS:
451.2 (M+1).sup.+.
##STR00292##
[0238] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.70 (s, 1H),
8.48-8.26 (m, 2H), 7.72 (s, 1H), 7.46-7.31 (m, 1H), 7.28-7.15 (m,
2H), 7.13-6.89 (m, 3H), 6.55-6.14 (m, 2H), 4.82 (m, 1H), 4.26 (m,
1H), 2.90 (m, 3H), 2.64-2.40 (m, 2H), 2.34-1.99 (m, 3H). MS: 558.1
(M+1).sup.+.
##STR00293##
[0239] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.54 (d, J=3.5
Hz, 1H), 7.45-7.29 (m, 3H), 7.28-6.95 (m, 6H), 6.44 (d, J=6.0 Hz,
1H), 6.24 (s, 1H), 4.92 (m, 1H), 4.25 (s, 1H), 3.11-2.79 (m, 3H),
2.61 (m, 1H), 2.43 (m, 1H), 2.39-2.27 (m, 2H), 2.27-2.11 (m, 1H).
MS: 563.1 (M+1).sup.+.
##STR00294##
[0240] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.66 (s, 1H),
7.48 (s, 1H), 7.35 (s, 1H), 7.26-6.82 (m, 8H), 6.43 (s, 1H), 6.09
(d, J=6.3 Hz, 1H), 4.98 (d, J=8.7 Hz, 1H), 4.34 (s, 1H), 3.08-2.84
(m, 2H), 2.63-2.36 (m, 4H), 2.32 (m, 1H), 2.15 (m, 1H). MS: 563.1
(M+1).sup.+.
##STR00295##
[0241] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.78-7.49 (m,
2H), 7.39 (m, 4H), 7.24-6.82 (m, 4H), 6.38 (m, 3H), 5.94 (m, 1H),
4.50 (m, 1H), 4.22 (m, 1H), 3.10-2.59 (m, 3H), 2.59-1.99 (m, 6H).
MS: 556.2 (M+1).sup.+.
Example 3
Preparation of
(S)--N--((S)-1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethy-
l)-N-(3-fluorophenyl)-5-oxo-1-(thiazol-4-yl)pyrrolidine-2-carboxamide
[0242] Compounds 42 and 43 were prepared according to the following
scheme, using the following protocol.
##STR00296##
[0243] A mixture
(2S)--N-(1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-N-
-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide (200 mg, 0.417
mmol), 4-bromothiazole (0.045 mL, 0.626 mmol, 1.5 eq),
K.sub.3PO.sub.4 (124 mg, 0.585 mmol, 1.4 eq), CuI (8 mg, 0.1 eq)
and trans-1,2-diaminocyclohexane (0.24 eq) in dioxane (2 mL) was
stirred at 110.degree. C. under microwave for 30 min. The resulting
mixture was filtered through a Celite pad. The filtrate was
concentrated and the residue was purified by a standard method to
give the desired product.
(S)--N--((R)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-N-(3-fluorophenyl)-5-oxo-1-(thiazol-4-yl)pyrrolidine-2-carboxamide
(Compound 42)
##STR00297##
[0245] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.68 (d, J=2.1
Hz, 1H), 7.65 (m, 5H), 7.30-6.90 (m, 4H), 6.47 (s, 1H), 6.23 (s,
1H), 4.88 (dd, J=9.3, 3.0 Hz, 1H), 4.20 (s, 1H), 3.17-2.63 (m, 3H),
2.58-1.99 (m, 5H). MS: 563.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-N-(3-fluorophenyl)-5-oxo-1-(thiazol-4-yl)pyrrolidine-2-carboxamide
(Compound 43)
##STR00298##
[0247] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.60 (s, 1H),
8.06-7.56 (m, 2H), 7.35 (s, 1H), 7.22-6.79 (m, 5H), 6.42 (s, 1H),
6.13 (s, 1H), 4.96 (d, J=7.8 Hz, 1H), 4.25 (m, 1H), 3.14-2.70 (m,
4H), 2.63-2.21 (m, 4H). MS: 563.1 (M+1).sup.+.
Example 4
Preparation of
(S)--N--((S)-1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethy-
l)-N-(3-fluorophenyl)-5-oxo-1-(pyridin-2-ylmethyl)pyrrolidine-2-carboxamid-
e
[0248] Compound 44 was prepared according to the following scheme,
using the following protocol.
##STR00299##
Compound 44.
[0249] To a solution of
(2S)--N-(1-(2-chlorophenyl)-2-(3,3-difluorocyclobutyl-amino)-2-oxoethyl)--
N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide (200 mg, 0.42
mmol) in dry DMF (20 mL) was added NaH (20 mg, 0.84 mmol) at
0.degree. C. The mixture was stirred at this 0.degree. C. for 0.5 h
followed by addition of 2-(bromomethyl)pyridine (106 mg, 0.42
mmol). The mixture was then allowed warm to room temperature and
stirred overnight. The resulting mixture was slowly added dropwise
to 100 mL of water, and then extracted with EtOAc (3.times.20 mL).
The combined organic layers were washed with saturated aq. LiCl,
dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo.
The residue was purified by a standard method to afford the desired
product. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.51 (s, 1H),
7.88-7.37 (m, 3H), 7.19-5.95 (m, 10H), 5.14 (m, 1H), 4.34 (m, 1H),
4.10 (m, 2H), 3.00 (m, 2H), 2.81-1.57 (m, 6H). MS: 571.2
(M+1).sup.+.
Example 5
Preparation of
(S)--N--((S)-1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethy-
l)-N-(3-fluorophenyl)-3-hydroxy-2-(pyrimidin-2-ylamino)propanamide
[0250] Compound 9 was prepared according to the following scheme,
using the following protocol.
##STR00300##
Step A: (S)-2-Oxooxazolidine-4-carboxylic acid
[0251] To a solution of NaOH (0.8 g, 20 mmol) in water (4 mL) was
added (S)-2-(benzyloxycarbonylamino)-3-hydroxypropanoic acid (1 g,
4.2 mmol) portionwise at 0.degree. C. over 3 min. The resulting
solution was warmed to r.t and stirred for 2 h. After cooling to
0.degree. C., the solution was adjusted to pH=1-2 with 2 N HCl. The
mixture was extracted with EtOAc (4.times.10 mL). The combined
organic layers were dried over anhydrous Na.sub.2SO.sub.4 and
concentrated in vacuo to give the desired product as a white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 13.93-12.30 (m, 1H),
8.15 (s, 1H), 4.49 (t, J=8.6 Hz, 1H), 4.32 (m, 2H); MS: 130.0
(M-1).sup.-.
Step B:
(4S)--N-(1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoe-
thyl)-N-(3-fluoro-phenyl)-2-oxooxazolidine-4-carboxamide
[0252] 2-Chlorobenzaldehyde (160 mg, 1.14 mmol), 3-fluoroaniline
(127 mg, 1.14 mmol), (S)-2-oxooxazolidine-4-carboxylic acid (150
mg, 1.14 mmol) and 1,1-difluoro-3-isocyanocyclobutane (181 mg, 90%
of purity, 1.37 mmol) were used in the UGI reaction to give the
desired product as a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.15-8.01 (m, 1H), 7.62-7.52 (m, 1H),
7.31-6.69 (m, 9H), 6.24 (s, 1H), 5.65-4.66 (m, 4H), 2.60 (m, 1H),
2.20-2.05 (m, 3H), 1.76-1.51 (m, 5H), 1.29-0.83 (m, 5H); MS: 482.1
(M+1).sup.+.
Step C:
(S)--N-aR)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-ox-
oethyl)-N-(3-fluorophenyl)-2-oxo-3-(pyrimidin-2-yl)oxazolidine-4-carboxami-
de and
(S)--N--((S)-1-(2-chloro-phenyl)-2-(3,3-difluorocyclobutylamino)-2--
oxoethyl)-N-(3-fluorophenyl)-2-oxo-3-(pyrimidin-2-yl)oxazolidine-4-carboxa-
mide
[0253] A mixture of
(4S)--N-(1-(2-chlorophenyl)-2-(3,3-difluorocyclo-butylamino)-2-oxoethyl)--
N-(3-fluorophenyl)-2-oxooxazolidine-4-carboxamide (350 mg, 0.73
mmol), 2-bromopyrimidine (150 mg, 0.94 mmol), Cs.sub.2CO.sub.3 (500
mg, 1.52 mmol), Pd.sub.2(dba).sub.3 (66 mg, 0.07 mmol) and
Xant-Phos (42 mg, 0.07 mmol) in 1,4-dioxane (15 mL) was stirred
under N.sub.2 at 80.degree. C. for 18 h and then filtered through a
Celite pad. The filtrate was concentrated in vacuo and the residue
was purified a standard method to give
(S)--N--((R)-1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-ox-
oethyl)-N-(3-fluorophenyl)-2-oxo-3-(pyrimidin-2-yl)oxazolidine-4-carboxami-
de (8). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.73 (d, J=4.8
Hz, 2H), 7.95 (s, 0.8H), 7.74 (s, 0.2H), 7.41 (d, J=7.5 Hz, 1.6H),
7.24 (t, J=7.2 Hz, 1H), 7.17-6.94 (m, 4.3H), 6.73 (d, J=6.7 Hz,
1H), 6.48 (d, J=73.8 Hz, 2H), 4.93 (s, 1H), 4.41 (dd, J=8.6, 4.8
Hz, 1H), 4.29 (t, J=8.6 Hz, 1H), 4.14 (m, 1H), 2.80 (m, 2H), 2.21
(s, 1H), 2.18-2.07 (m, 1H); MS: 560.1 (M+1).sup.+, and
(S)--N--((S)-1-(2-chloro-phenyl)-2-(3,3-difluorocyclo-butylamino)-2-oxoet-
hyl)-N-(3-fluoro-phenyl)-2-oxo-3-(pyrimidin-2-yl)oxazolidine-4-carboxamide
(9). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.68 (d, J=4.8 Hz,
2H), 7.65 (s, 1H), 7.30 (s, 1H), 7.18 (s, 1H), 7.13-6.86 (m, 5H),
6.50 (s, 1H), 6.38 (m, 1H), 5.00 (m, 1H), 4.43 (dd, J=8.7, 4.8 Hz,
1H), 4.32 (m, 1H), 4.20 (m, 1H), 2.99 (m, 2H), 2.50 (m, 2H). MS:
560.1 (M+1).sup.+.
Example 6
Preparation of
(S)--N--((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)-amino)-2-oxoe-
thyl)-N-(3-fluorophenyl)-6-oxo-1-(pyrimidin-2-yl)piperidine-2-carboxamide
[0254] Compounds 19 and 20 were prepared according to the following
scheme, using the following protocol.
##STR00301##
Step A. (S)-6-Oxopiperidine-2-carboxylic acid
[0255] A solution of (S)-2-aminohexanedioic acid (470 mg, 2.9 mmol)
in 20% AcOH (5 mL) was stirred at 110.degree. C. overnight. The
solvent was removed in vacuo and the residue was dissolved in EtOH
(10 mL). The unreacted amino acid was precipitated and filtered
off. The filtrate was concentrated to give the crude desired
product which was used directly in the next step. MS: 142.1
(M-1).sup.-.
Step B.
(S)--N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxo-
ethyl)-N-(3-fluoro-phenyl)-6-oxopiperidine-2-carboxamide
[0256] 3-Fluoroaniline (217 mg, 1.96 mmol), 2-chlorobenzaldehyde
(274 mg, 1.96 mmol), (S)-6-oxopiperidine-2-carboxylic acid (280 mg,
1.96 mmol) and 1,1-difluoro-3-isocyanocyclobutane (280 mg, 1.96
mmol) were used in the UGI reaction to give the desired product.
MS: 494.1 (M+1).sup.+.
Step C.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)--
2-oxoethyl)-N-(3-fluorophenyl)-6-oxo-1-(pyrimidin-2-yl)piperidine-2-carbox-
amide and
(S)--N--((R)-1-(2-chloro-phenyl)-2-((3,3-difluorocyclobutyl)amin-
o)-2-oxoethyl)-N-(3-fluorophenyl)-6-oxo-1-(pyrimidin-2-yl)piperidine-2-car-
boxamide
[0257] A mixture consisting of
(1R)--N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-
-N-(3-fluorophenyl)-3-oxo-2-(pyrimidin-2-yl)cyclohexanecarboxamide
(250 mg, 0.51 mmol), 2-bromopyrimidine (121 mg, 0.76 mmol),
Cs.sub.2CO.sub.3 (331 mg, 1.01 mmol), Pd.sub.2(dba).sub.3 (46 mg,
0.05 mmol) and Xant-Phos (29 mg, 0.04 mmol) in 1,4-dioxane (15 mL)
was stirred under N.sub.2 at 80.degree. C. overnight and then
filtered. The filtrate was concentrated in vacuo and the residue
was purified by a standard method to give the desired products.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-N-(3-fluoro-phenyl)-6-oxo-1-(pyrimidin-2-yl)piperidine-2-carboxamide
(Compound 19)
[0258] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.73 (m, 2H),
7.70 (s, 1H), 7.26-6.95 (m, 6H), 6.87 (t, J=7.2 Hz, 1H), 6.53 (s,
1H), 6.33 (s, 1H), 4.77 (d, J=5.3 Hz, 1H), 4.33 (s, 1H), 3.01 (d,
J=5.5 Hz, 2H), 2.85-2.28 (m, 4H), 2.05 (m, 2H), 1.81 (s, 2H). MS:
571.1 (M+1).sup.+.
(S)--N--((R)-1-(2-Chloro-phenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoet-
hyl)-N-(3-fluoro-phenyl)-6-oxo-1-(pyrimidin-2-yl)piperidine-2-carboxamide
(Compound 20)
[0259] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.74 (d, J=4.8
Hz, 2H), 7.99 (m, 1H), 7.56-7.32 (m, 1H), 7.27-6.85 (m, 6H), 6.72
(s, 1H), 6.51 (m, 1H), 4.67-4.48 (m, 1H), 4.34-4.01 (m, 1H),
2.95-2.60 (m, 2H), 2.59-2.40 (m, 1H), 2.40-2.19 (m, 2H), 2.15-2.00
(m, 2H), 1.97-1.59 (m, 4H). MS: 571.1 (M+1).sup.+.
Example 7
Preparation of
(S)--N--((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoet-
hyl)-N-(3-fluorophenyl)-5-oxo-4-(pyrimidin-2-yl)morpholine-3-carboxamide
[0260] Compound 30 was prepared according to the following scheme,
using the following protocol.
##STR00302##
Step A: (S)-3-Hydroxy-2-(4-methoxybenzylamino)propanoic acid
[0261] (S)-2-amino-3-hydroxypropanoic acid (8.4 g, 80 mmol) was
dissolved in a solution of NaOH (3.2 g, 80 mmol) in H.sub.2O (40
mL). After cooling to 10.degree. C., 4-methoxybenzaldehyde (21.7 g,
160 mmol) was added dropwise over 10 min. The mixture was stirred
at room temperature for 30 min and then cooled to 0.degree. C.
NaBH.sub.4 (1.67 g, 44 mmol) was added portionwise and the
resulting mixture was warmed slowly to r.t and stirred for 2 h. The
mixture was washed with Et.sub.2O (2.times.50 mL). The aqueous
phase was adjusted to pH 4.5 with 2 N HCl at 0.degree. C. The
precipitate was filtered, washed with petroleum ether (20 mL) and
dried in vacuo to give the desired product as a white solid. MS:
226.1 (M+1).sup.+.
Step B:
(S)-Benzyl-4-(4-methoxybenzyl)-5-oxomorpholine-3-carboxylate
[0262] (S)-3-Hydroxy-2-((4-methoxybenzyl)amino)propanoic acid (5.0
g, 22 mmol) was dissolved in a solution of NaOH (1.15 g, 29 mmol)
in H.sub.2O (60 mL). After cooling to 0.degree. C., 2-chloroacetyl
chloride (3.6 mL, 44 mmol) was added dropwise followed by aq. NaOH
(30% wt) to keep pH=13. After stirring for another 4 h, the
reaction was cooled to 0.degree. C. and acidified with 2 N HCl to
adjust pH=2-3. The resulting mixture was extracted with EtOAc
(2.times.30 mL). The combined organic layers were dried over
anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was
dissolved in acetone (150 mL) and then treated with BnBr (9.7 g, 51
mmol) and DIPEA (19 mL, 111 mmol). The reaction mixture was stirred
for 24 h at room temperature and concentrated in vacuo. The residue
was purified by column chromatography to afford the desired product
as a white solid. MS: 356.1 (M+1).sup.+.
Step C: (S)-Benzyl 5-oxomorpholine-3-carboxylate
[0263] To a solution of (S)-benzyl
4-(4-methoxybenzyl)-5-oxomorpholine-3-carboxylate (200 mg, 0.56
mmol) in CH.sub.3CN (5 mL) and H.sub.2O (5 mL) was added CAN (ceric
ammonium nitrate) (1.5 g, 2.8 mmol) at 0.degree. C. The resulting
mixture was stirred at 0.degree. C. for 1 h. DIPEA was added at
0.degree. C. to adjust the pH to 6-7 and the mixture was
concentrated in vacuo. The residue was purified by column
chromatography to afford the desired product as a white solid. MS:
236.1 (M+1).sup.+.
Step D: (S)-5-Oxomorpholine-3-carboxylic acid
[0264] To a mixture of (S)-benzyl 5-oxomorpholine-3-carboxylate
(160 mg, 0.7 mmol) in MeOH (8 mL) was added 10% Pd/C (about 5 mg).
The reaction was stirred under an atmosphere of hydrogen for 30 min
at room temperature. The reaction mixture was filtered through a
Celite pad and concentrated in vacuo to afford the desired product
as a white solid. MS: 146.1 (M+1).sup.+.
Step E:
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)--
2-oxoethyl)-N-(3-fluorophenyl)-5-oxomorpholine-3-carboxamide
[0265] 3-Chlorobenzaldehyde (104 mg, 0.74 mmol), 3-fluoroaniline
(83 mg, 0.74 mmol), (S)-5-oxomorpholine-3-carboxylic acid (108 mg,
0.74 mmol) and 1,1-difluoro-3-isocyanocyclobutane (248 mg, 1.48
mmol) were used in the UGI reaction to afford the desired product.
MS: 496.1 (M+1).sup.+.
Step F: Compound 30
[0266] A mixture of
(S)--N--((S)-1-(2-chlorophenyl)-2-((3,3-difluoro-cyclobutyl)amino)-2-oxoe-
thyl)-N-(3-fluorophenyl)-5-oxomorpholine-3-carboxamide (100 mg, 0.2
mmol), 2-bromopyrimidine (36 mg, 0.22 mmol), Pd.sub.2(dba).sub.3
(28 mg, 0.03 mmol), XantPhos (16 mg, 0.03 mmol) and
Cs.sub.2CO.sub.3 (160 mg, 0.5 mmol) in 1,4-dioxane (4 mL) was
stirred at 100.degree. C. for 3.5 h under N.sub.2. The reaction
mixture was then cooled to room temperature and filtered. The solid
was washed with DCM (2.times.20 mL). The filtrate was evaporated
and the residue was purified by a standard method to afford the
desired product. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.77
(m, 2H), 7.85 (m, 1H), 7.41 (s, 1H), 7.28-7.21 (m, 1H), 7.21-7.10
(m, 2H), 7.09-6.90 (m, 3H), 6.87 (m, 1H), 6.68-6.33 (m, 2H), 4.80
(m, 1H), 4.43-4.22 (m, 2H), 4.13 (m, 2H), 3.94 (m, 1H), 2.99 (m,
1H), 2.86 (m, 1H), 2.63-2.26 (m, 2H). MS: 474.1 (M+1).sup.+
Example 8
[0267] The following analogs were synthesized via the procedure set
forth above, using the appropriate aldehyde, amine, carboxylic
acid, isocyanide and halo-substituted aromatic ring or heterocyclic
(heteroaromatic) ring using the reagents and solvents set forth
above, and purified via standard methods.
(2S)--N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclopentyl)amino)-2-oxoethyl)-
-N-(3-fluoro
phenyl)-5-oxo-1-(pyrimidin-2-yl)pyrrolidine-2-carboxamide
(racemic)--Compound 73
##STR00303##
[0269] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.71 (d, J=4.8
Hz, 2H), 7.72 (s, 1H), 7.37 (s, 1H), 7.18 (s, 1H), 7.11-6.85 (m,
5H), 6.47 (s, 1H), 5.70 (d, J=7.3 Hz, 1H), 4.86 (d, J=7.0 Hz, 1H),
4.53 (d, J=6.3 Hz, 1H), 3.51 (s, 1H), 2.95-2.88 (m, 1H), 2.64-2.47
(m, 2H), 2.40-1.65 (m, 8H). MS: 572.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamid-
e (single enantiomer)--Compound 64
##STR00304##
[0271] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.74 (s, 1H),
8.52 (s, 1H), 7.72 (d, J=7.1 Hz, 1H), 7.43-7.33 (m, 1H), 7.25-7.17
(m, 1H), 7.13-6.81 (m, 4H), 6.43 (s, 1H), 6.12 (s, 1H), 4.92 (d,
J=6.8 Hz, 1H), 4.37-4.28 (m, 1H), 3.10-2.82 (m, 3H), 2.59-2.49 (m,
2H), 2.42-2.36 (m, 1H), 2.31-2.22 (m, 1H), 2.06-1.88 (m, 2H). MS:
582.1 (M+1).sup.+.
(S)-1-(4-Cyanopyridin-2-yl)-N--((S)-2-((3,3-difluorocyclobutyl)amino)-2-ox-
o-1-phenylethyl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide
(single enantiomer)--Compound 138
##STR00305##
[0273] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.78 (s, 1H),
8.44 (d, J=4.9 Hz, 1H), 7.65 (s, 1H), 7.39-7.15 (m, 6H), 7.14-6.92
(m, 4H), 6.65 (m, 1H), 6.16 (s, 1H), 5.82 (s, 1H), 4.86 (d, J=6.8
Hz, 1H), 4.31 (s, 1H), 3.15-2.77 (m, 3H), 2.68-1.91 (m, 5H). MS:
548.2 (M+1).sup.+.
(S)-1-(4-Cyanopyridin-2-yl)-N--((S)-2-((3,3-difluorocyclobutyl)amino)-1-(2-
-fluorophenyl)-2-oxoethyl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxami-
de (single enantiomer)--Compound 149
##STR00306##
[0275] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.74 (m, 1H),
8.50 (d, J=4.2 Hz, 1H), 7.65 (s, 1H), 7.45-7.14 (m, 4H), 7.13-6.69
(m, 5H), 6.25 (m, 2H), 4.88 (dd, J=9.2, 3.1 Hz, 1H), 4.33 (s, 1H),
3.21-2.72 (m, 3H), 2.65-1.88 (m, 5H). MS: 566.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyrimidin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carbox-
amide (single enantiomer)--Compound 68
##STR00307##
[0277] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.95 (d, J=4.7
Hz, 1H), 7.68 (s, 1H), 7.34 (d, J=4.6 Hz, 2H), 7.16 (s, 1H), 7.04
(d, J=3.6 Hz, 3H), 6.92 (s, 2H), 6.51 (s, 1H), 5.92 (s, 1H), 4.81
(d, J=9.5 Hz, 1H), 4.33 (s, 1H), 2.91 (m, 3H), 2.64-2.26 (m, 4H),
2.01 (s, 1H). MS: 583.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyrimidin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carbox-
amide (single enantiomer)--Compound 85
##STR00308##
[0279] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.98 (d, J=4.7
Hz, 1H), 7.74 (s, 1H), 7.38 (dd, J=11.2, 5.7 Hz, 2H), 7.06 (m, 5H),
6.52 (s, 1H), 5.47 (d, J=7.7 Hz, 1H), 4.85 (d, J=9.2 Hz, 1H), 3.99
(s, 1H), 2.93 (dd, J=18.6, 8.9 Hz, 1H), 2.62 (d, J=9.5 Hz, 1H),
2.36 (s, 1H), 1.97 (m, 7H), 1.57-1.38 (m, 2H). MS: 611.2
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-N-(3,5-difluoro-phenyl)-5-oxo-1-(pyrimidin-2-yl)pyrrolidine-2-carboxam-
ide (single enantiomer)--Compound 70
##STR00309##
[0281] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.70 (d, J=4.8
Hz, 2H), 7.60 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.26-7.19 (m, 1H),
7.13-7.04 (m, 2H), 7.03-6.97 (m, 1H), 6.86 (s, 1H), 6.69 (dd,
J=9.8, 7.6 Hz, 1H), 6.46 (s, 1H), 6.07 (d, J=6.7 Hz, 1H), 4.87 (dd,
J=9.1, 3.1 Hz, 1H), 4.36 (s, 1H), 3.11-2.83 (m, 3H), 2.64-2.34 (m,
3H), 2.21 (m, 1H), 2.10-1.97 (m, 1H). MS: 576.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carb-
oxamide (single enantiomer)--Compound 71
##STR00310##
[0283] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.73 (d, J=7.1
Hz, 1H), 8.60-8.46 (m, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.38-7.32 (m,
1H), 7.31-7.27 (m, 1H), 7.26-7.18 (m, 1H), 7.14-7.00 (m, 1H), 6.96
(m, 1H), 6.85 (s, 1H), 6.69 (m, 1H), 6.40 (s, 1H), 6.02 (d, J=6.6
Hz, 1H), 4.98-4.74 (m, 1H), 4.39-4.10 (m, 1H), 3.11-2.67 (m, 3H),
2.64-1.95 (m, 5H). MS: 600.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyrimidin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-ca-
rboxamide (single enantiomer)--Compound 86
##STR00311##
[0285] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.98 (d, J=4.8
Hz, 1H), 7.56 (s, 1H), 7.40 (m, 2H), 7.23 (t, J=7.0 Hz, 1H), 7.08
(t, J=7.6 Hz, 1H), 7.01-6.84 (m, 2H), 6.71 (t, J=8.6 Hz, 1H), 6.51
(s, 1H), 6.00 (d, J=6.7 Hz, 1H), 4.85 (dd, J=9.3, 2.7 Hz, 1H), 4.36
(s, 1H), 3.15-2.80 (m, 3H), 2.67-2.26 (m, 4H), 2.08 (dt, J=9.7, 8.1
Hz, 1H). MS: 601 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-1-(4-cyanopyridin-2-yl)-5-oxo-N-(3-sulfamoylphenyl)pyrrolidine-2-carboxa-
mide (single enantiomer)--Compound 53
##STR00312##
[0287] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.74 (s, 1H),
8.50 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.33 (d, J=9.3 Hz, 1H),
7.25-6.80 (m, 6H), 6.40 (s, 1H), 5.61 (d, J=6.9 Hz, 1H), 4.91 (d,
J=8.0 Hz, 1H), 3.97 (s, 1H), 2.99-2.79 (m, 1H), 2.55 (dd, J=13.7,
9.9 Hz, 1H), 2.25 (t, J=11.3 Hz, 1H), 2.03-1.74 (m, 5H), 1.56-1.36
(m, 2H). MS: 610.2 (M+1).sup.+.
(2S)--N-(1-(2-Chlorophenyl)-2-(4,4-difluorocyclohexylamino)-2-oxoethyl)-1--
(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamid-
e (single enantiomer)--Compound 81
##STR00313##
[0289] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.75 (s, 1H),
8.51 (d, J=5.0 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 7.37 (d, J=7.9 Hz,
1H), 7.27 (d, J=5.1 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 7.06 (t, J=7.5
Hz, 1H), 6.99 (d, J=6.9 Hz, 1H), 6.88 (d, J=7.4 Hz, 1H), 6.69 (t,
J=8.6 Hz, 1H), 6.41 (s, 1H), 5.69 (d, J=7.8 Hz, 1H), 4.95 (dd,
J=9.3, 3.2 Hz, 1H), 3.98 (m, 1H), 2.95-2.84 (m, 1H), 2.65-2.55 (m,
1H), 2.30-2.20 (m, 1H), 2.05-2.12 (m, 1H), 2.03 (s, 2H), 1.94-1.78
(m, 2H), 1.68-1.35 (m, 3H), 0.85-0.95 (m, 1H). MS: 628.2
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyrimidin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-ca-
rboxamide (single enantiomer)--Compound 87
##STR00314##
[0291] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.97 (d, J=4.8
Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.46-7.34 (m, 2H), 7.22 (t, J=7.8
Hz, 1H), 7.06 (t, J=7.6 Hz, 1H), 7.00-6.87 (m, 2H), 6.70 (t, J=8.6
Hz, 1H), 6.48 (s, 1H), 5.64 (d, J=7.7 Hz, 1H), 4.86 (dd, J=9.3, 2.7
Hz, 1H), 3.98 (d, J=7.7 Hz, 1H), 2.96-2.86 (m, 1H), 2.63-2.55 (m,
1H), 2.37-2.29 (m, 1H), 2.15-1.99 (m, 5H), 1.96-1.77 (m, 2H),
1.61-1.34 (m, 2H). MS: 629.2 (M+1).sup.+.
(S)-1-(4-Cyanopyridin-2-yl)-N--((S)-1-(2,4-dichlorophenyl)-2-((3,3-difluor-
ocyclobutyl)-amino)-2-oxoethyl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2--
carboxamide (single enantiomer)--Compound 196
##STR00315##
[0293] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.77 (s, 1H),
8.49 (d, J=5.1 Hz, 1H), 7.56 (s, 1H), 7.40 (d, J=2.1 Hz, 1H), 7.30
(s, 1H), 7.08 (dd, J=8.4, 2.1 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.90
(s, 1H), 6.79-6.72 (m, 1H), 6.35 (s, 1H), 5.99 (d, J=6.6 Hz, 1H),
4.93 (dd, J=9.3, 3.1 Hz, 1H), 4.33 (s, 1H), 3.12-2.95 (m, 2H),
2.95-2.83 (m, 1H), 2.66-2.32 (m, 3H), 2.24-2.18 (m, 1H), 2.12-1.99
(m, 1H). MS: 634.1 (M+1).sup.+.
(S)-1-(4-Cyanopyridin-2-yl)-N--((S)-1-(2,5-dichlorophenyl)-2-((3,3-difluor-
ocyclobutyl)-amino)-2-oxoethyl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2--
carboxamide (single enantiomer)--Compound 201
##STR00316##
[0295] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.76 (s, 1H),
8.49 (dd, J=5.0, 0.6 Hz, 1H), 7.58 (s, 1H), 7.30 (t, J=5.2 Hz, 2H),
7.22 (dd, J=8.6, 2.5 Hz, 1H), 7.02 (d, J=2.4 Hz, 1H), 6.88 (s, 1H),
6.76 (tt, J=8.6, 2.3 Hz, 1H), 6.34 (s, 1H), 6.14 (d, J=6.8 Hz, 1H),
4.94 (dd, J=9.3, 3.2 Hz, 1H), 4.43-4.28 (m, 1H), 3.09-3.02 (m, 2H),
2.93-2.84 (m, 1H), 2.65-2.32 (m, 3H), 2.27-2.16 (m, 1H), 2.14-2.00
(m, 1H). MS: 634.1 (M+1).sup.+.
(S)-1-(4-Cyanopyridin-2-yl)-N--((S)-1-(2,6-dichlorophenyl)-2-(3,3-difluoro-
cyclobutylamino)-2-oxoethyl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxa-
mide (single enantiomer)--Compound 63
##STR00317##
[0297] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.77 (s, 1H),
8.45 (t, J=5.6 Hz, 1H), 7.88 (t, J=10.0 Hz, 1H), 7.40-7.32 (m, 1H),
7.26-7.21 (m, 2H), 7.10-7.05 (m, 2H), 6.92 (d, J=2.4 Hz, 1H), 6.62
(d, J=8.6 Hz, 1H), 5.53 (d, J=5.3 Hz, 1H), 4.84-4.75 (m, 1H), 4.40
(s, 1H), 3.06-2.92 (m, 3H), 2.65-2.42 (m, 4H), 2.18-2.02 (m, 1H).
MS: 616.1 (M+1).sup.+.
(S)-1-(4-Cyanopyridin-2-yl)-N--((S)-1-(2,6-dichlorophenyl)-2-((3,3-difluor-
ocyclobutyl)amino)-2-oxoethyl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-c-
arboxamide (single enantiomer)--Compound 199
##STR00318##
[0299] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.78 (s, 1H),
8.44 (d, J=5.0 Hz, 1H), 7.80-7.22 (m, 5H), 6.91 (s, 1H), 6.81 (tt,
J=8.7, 2.3 Hz, 1H), 6.45 (d, J=8.5 Hz, 1H), 5.56 (d, J=6.8 Hz, 1H),
4.83 (dd, J=9.4, 2.7 Hz, 1H), 4.40 (d, J=8.0 Hz, 1H), 3.23-2.92 (m,
3H), 2.69-2.39 (m, 4H), 2.23-2.02 (m, 1H). MS: 634.2
(M+1).sup.+.
(2S)-1-(4-Cyanopyridin-2-yl)-N-(1-(2,3-dichlorophenyl)-2-(3,3-difluoro-cyc-
lobutylamino)-2-oxoethyl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carbox-
amide (racemic)--Compound 195
##STR00319##
[0301] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.72 (s, 1H),
8.57 (s, 1H), 7.44 (d, J=7.9, 1H), 7.32-7.29 (m, 1H), 7.17-6.68 (m,
4H), 6.53-6.41 (m, 1H), 6.32-6.12 (m, 1H), 4.90-4.65 (m, 1H),
4.41-4.05 (m, 1H), 3.13-2.01 (m, 8H). MS: 634.1 (M+1).sup.+.
(S)-1-(4-Cyanopyridin-2-yl)-N--((S)-2-(3,3-difluorocyclobutylamino)-1-(2-f-
luorophenyl)-2-oxoethyl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxa-
mide (single enantiomer)--Compound 208
##STR00320##
[0303] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.63 (s, 1H),
8.40 (d, J=4.9 Hz, 1H), 7.43 (s, 1H), 7.20 (s, 1H), 7.16 (d, J=5.0
Hz, 1H), 6.90 (t, J=8.2 Hz, 3H), 6.62 (t, J=8.7 Hz, 2H), 6.20 (s,
1H), 6.14 (d, J=6.4 Hz, 1H), 4.81 (dd, J=9.1, 2.9 Hz, 1H), 4.25 (s,
1H), 2.92 (s, 2H), 2.85-2.70 (m, 1H), 2.56-2.22 (m, 3H), 2.15 (m,
1H), 2.04-1.90 (m, 1H). MS: 584.2 (M+1).sup.+.
(S)-1-(4-Cyanopyridin-2-yl)-N--((S)-2-(3,3-difluorocyclobutylamino)-2-oxo--
1-phenylethyl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide
(single enantiomer)--Compound 210
##STR00321##
[0305] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.77 (s, 1H),
8.41 (d, J=5.1 Hz, 1H), 7.49 (s, 1H), 7.27 (dd, J=8.2, 5.0 Hz, 2H),
7.24 (d, J=5.4 Hz, 2H), 7.04 (d, J=6.7 Hz, 2H), 6.71 (t, J=8.8 Hz,
1H), 6.44 (s, 1H), 6.15 (s, 1H), 5.70 (d, J=6.3 Hz, 1H), 4.86 (dd,
J=9.3, 2.8 Hz, 1H), 4.29 (s, 1H), 2.99 (m, 2H), 2.90 (m, 1H),
2.62-2.52 (m, 1H), 2.45 (m, 1H), 2.38-2.25 (m, 2H), 2.07 (m, 1H).
MS: 566.2 (M+1).sup.+.
(S)--N--((S)-1-(3-Chloropyridin-2-yl)-2-(3,3-difluorocyclobutylamino)-2-ox-
oethyl)-1-(4-cyano
pyridin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide
(single enantiomer)--Compound 198
##STR00322##
[0307] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.75 (s, 1H),
8.49 (d, J=5.0 Hz, 1H), 8.31 (d, J=3.4 Hz, 1H), 7.65-7.56 (m, 2H),
7.27 (m, 1H), 7.19-7.15 (m, 1H), 6.98 (m, 1H), 6.76-6.56 (m, 2H),
6.11 (d, J=6.8 Hz, 1H), 5.04-5.01 (m, 1H), 4.38 (m, 1H), 3.05-2.98
(m, 2H), 2.92-2.83 (m, 1H), 2.60-2.52 (m, 1H), 2.51-2.37 (m, 2H),
2.37-2.27 (m, 1H), 2.07-2.02 (m, 1H). MS: 601.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-1-(4-cyanopyridin-2-yl)-5-oxo-N-(3-sulfamoylphenyl)pyrrolidine-2-carboxa-
mide (single enantiomer)--Compound 84
##STR00323##
[0309] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.73 (d, J=10.0
Hz, 1H), 8.57-8.45 (d, J=8.0 Hz, 1H), 8.12 (d, J=7.7 Hz, 1H),
7.83-7.76 (m, 2H), 7.61-7.56 (m, 1H), 7.48-7.32 (m, 1H), 7.19 (t,
J=7.1 Hz, 1H), 7.05-6.87 (m, 2H), 6.82-6.81 (m, 1H), 6.55-6.43 (m,
1H), 6.27 (d, J=6.7 Hz, 1H), 5.24 (s, 1H), 4.84 (d, J=7.2 Hz, 1H),
4.69 (s, 1H), 4.33 (s, 1H), 2.98-2.87 (m, 3H), 2.63-2.24 (m, 4H),
2.09-2.00 (m, 1H). MS: 643.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-N-(3-cyano-phenyl)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2-carboxam-
ide (single enantiomer)--Compound 128
##STR00324##
[0311] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.76 (s, 1H),
8.51 (s, 1H), 8.23 (m, 1H), 7.58-7.27 (m, 4H), 6.93 (m, 3H), 6.43
(s, 1H), 5.85 (s, 1H), 4.78 (s, 1H), 4.34 (s, 1H), 3.10-2.82 (m,
3H), 2.37-2.52 (m, 3H), 2.21-2.23 (m, 1H), 1.89-1.99 (m, 1H). MS:
589.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-N-(3-cyano
phenyl)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2-carboxamide
(single enantiomer)--Compound 166
##STR00325##
[0313] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.77 (s, 1H),
8.49 (d, J=13.9 Hz, 1H), 8.22-8.32 (m, 1H), 7.61-7.27 (m, 4H),
7.17-7.19 (m, 2H), 6.90-7.00 (m, 2H), 6.42 (s, 1H), 5.50 (s, 1H),
4.80 (d, J=9.5 Hz, 1H), 3.97 (s, 1H), 2.99-2.80 (m, 1H), 2.56-2.58
(m, 1H), 2.21-2.24 (m, 1H), 1.70-2.10 (m, 6H), 1.41-1.44 (m, 2H).
MS: 617.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-N-(3-cyano
phenyl)-1-(4-cyanopyrimidin-2-yl)-5-oxopyrrolidine-2-carboxamide
(single enantiomer)--Compound 167
##STR00326##
[0315] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.91-9.00 (m,
1H), 8.33-8.17 (m, 1H), 7.62-7.32 (m, 5H), 7.20 (t, J=7.0 Hz, 1H),
7.02-7.06 (m, 1H), 6.95-6.83 (m, 1H), 6.55 (s, 1H), 6.05-5.88 (m,
1H), 4.72 (d, J=9.3 Hz, 1H), 4.37 (s, 1H), 2.91-3.05 (m, 3H),
2.70-2.25 (m, 4H), 2.13-1.92 (m, 1H). MS: 590.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-N-(3-cyanophenyl)-1-(4-cyanopyrimidin-2-yl)-5-oxopyrrolidine-2-carboxa-
mide (single enantiomer)--Compound 178
##STR00327##
[0317] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.99 (s, 1H),
8.32 (s, 1H), 7.57 (m, 1H), 7.54-7.28 (m, 2H), 7.19 (t, J=7.2 Hz,
3H), 7.04 (t, J=6.8 Hz, 1H), 6.93 (d, J=7.7 Hz, 1H), 6.53 (s, 1H),
5.64-5.44 (m, 1H), 4.74 (d, J=9.3 Hz, 1H), 3.99 (s, 1H), 2.94 (dd,
J=17.8, 9.4 Hz, 1H), 2.62 (m, 1H), 2.41-2.24 (m, 1H), 2.10-1.82 (m,
7H). MS: 618.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-N-(3-cyano-5-fluorophenyl)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2-ca-
rboxamide (single enantiomer)--Compound 177
##STR00328##
[0319] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.74 (s, 1H),
8.50 (s, 1H), 8.13-8.08 (m, 1H), 7.44-7.27 (m, 2H), 7.23 (dd,
J=12.6, 6.3 Hz, 2H), 7.07 (t, J=7.3 Hz, 1H), 6.93 (t, J=6.4 Hz,
1H), 6.43 (d, J=6.1 Hz, 1H), 6.14 (dd, J=13.9, 6.7 Hz, 1H), 4.81
(dd, J=9.0, 2.3 Hz, 1H), 4.42-4.28 (m, 1H), 3.12-2.94 (m, 2H),
2.94-2.80 (m, 1H), 2.67-2.29 (m, 3H), 2.23-1.92 (m, 2H). MS: 607.1
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(4,4-difluorocyclohexylamino)-2-oxoethyl-
)-N-(3-cyano-5-fluorophenyl)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2-ca-
rboxamide (single enantiomer)--Compound 184
##STR00329##
[0321] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.77 (s, 1H),
8.50 (s, 1H), 8.25-8.03 (m, 1H), 7.52-7.28 (m, 2H), 7.22 (t, J=7.7
Hz, 2H), 7.01 (dt, J=14.1, 10.1 Hz, 2H), 6.42 (d, J=6.9 Hz, 1H),
5.58 (t, J=9.9 Hz, 1H), 4.83 (dd, J=9.1, 2.3 Hz, 1H), 4.05-3.86 (m,
1H), 3.04-2.81 (m, 1H), 2.59 (m, 1H), 2.36-1.70 (m, 7H), 1.58-1.31
(m, 3H). MS: 636.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-N-(3-cyano-5-fluorophenyl)-1-(4-cyanopyrimidin-2-yl)-5-oxopyrrolidine--
2-carboxamide (single enantiomer)--Compound 185
##STR00330##
[0323] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.97 (d, J=4.4
Hz, 1H), 8.12 (m, 1H), 7.50-7.32 (m, 3H), 7.23 (d, J=6.7 Hz, 2H),
7.06 (m, 1H), 6.95 (s, 1H), 6.50 (d, J=8.6 Hz, 1H), 5.60 (d, J=7.5
Hz, 1H), 4.74 (d, J=8.8 Hz, 1H), 3.98 (s, 1H), 2.90 (m, 1H),
2.72-2.49 (m, 1H), 2.28 (s, 1H), 2.17-1.67 (m, 7H), 1.43 (m, 2H).
MS: 637.2 (M+1).sup.+.
(S)--N-(3-Cyano-5-fluorophenyl)-1-(4-cyanopyridin-2-yl)-N--((S)-2-(3,3-dif-
luorocyclobutyl-amino)-2-oxo-1-phenylethyl)-5-oxopyrrolidine-2-carboxamide
(single enantiomer)--Compound 211
##STR00331##
[0325] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.71 (d, J=10.1
Hz, 1H), 8.38 (s, 1H), 8.02 (m, 1H), 7.23 (m, 5H), 6.97 (d, J=7.3
Hz, 3H), 6.20 (s, 1H), 5.97 (s, 1H), 4.70 (dd, J=9.2, 2.4 Hz, 1H),
4.27 (s, 1H), 2.93 (m, 2H), 2.85 (t, J=8.9 Hz, 1H), 2.59-2.48 (m,
1H), 2.49-2.29 (m, 2H), 2.29-2.20 (m, 1H), 2.08-1.99 (m, 1H). MS:
573.2 (M+1).sup.+.
(S)--N-(3-Cyano-5-fluorophenyl)-1-(4-cyanopyridin-2-yl)-N--((S)-2-((3,3-di-
fluorocyclobutyl)amino)-1-(2-fluorophenyl)-2-oxoethyl)-5-oxopyrrolidine-2--
carboxamide (single enantiomer)--Compound 207
##STR00332##
[0327] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.78 (s, 1H),
8.62 (d, J=5.1 Hz, 1H), 8.48 (s, 1H), 8.04-7.83 (m, 1H), 7.78 (s,
1H), 7.57 (s, 1H), 7.23 (m, 2H), 7.14 (d, J=9.9 Hz, 1H), 6.95 (t,
J=7.5 Hz, 1H), 6.84 (s, 1H), 6.20 (s, 1H), 4.72 (s, 1H), 4.04 (s,
1H), 4.00-3.82 (m, 1H), 3.09-2.67 (m, 2H), 2.33 (m, 1H), 1.91 (s,
2H), 1.83 (s, 1H), 1.27-1.05 (m, 1H). MS: 591.2 (M+1).sup.+.
(2S)--N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)--
1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carbox-
amide (racemic)--Compound 91
##STR00333##
[0329] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.10-8.03 (m,
4H), 7.47-7.39 (m, 2H), 7.27-6.84 (m, 3H), 6.51-6.01 (m, 2H),
4.84-4.70 (m, 1H), 4.36-4.20 (m, 1H), 3.25-1.86 (m, 8H). MS: 583.1
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carb-
oxamide (single enantiomer)--Compound 176
##STR00334##
[0331] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.95-8.70 (m,
1H), 8.49 (d, J=4.7 Hz, 1H), 8.36-8.11 (m, 1H), 8.12 (d, J=8.6 Hz,
1H), 7.33 (d, J=8.0 Hz, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.04 (t, J=7.6
Hz, 1H), 6.48-6.41 (m, 1H), 6.30-6.21 (m, 1H), 4.84-6.79 (m, 1H),
4.38-4.30 (m, 1H), 3.11-2.74 (m, 3H), 2.65-1.91 (m, 5H). MS: 583.1
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(4,4-difluorocyclohexylamino)-2-oxoethyl-
)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carb-
oxamide (single enantiomer)-Compound 193
##STR00335##
[0333] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.77 (s, 1H),
8.49 (d, J=5.2 Hz, 1H), 8.40-8.27 (m, 1H), 8.21-8.04 (m, 1H),
7.41-7.36 (m, 1H), 7.26-7.23 (m, 1H), 7.20 (t, J=6.9 Hz, 1H), 7.04
(t, J=7.2 Hz, 1H), 6.93 (m, 1H), 6.52-6.34 (m, 1H), 5.49 (s, 1H),
4.84 (d, J=7.4 Hz, 1H), 4.01-3.94 (m, 1H), 2.99-2.91 (m, 1H),
2.62-2.54 (m, 1H), 2.22-1.71 (m, 7H), 1.31 (s, 3H). MS: 611.2
(M+1).sup.+.
(S)-1-(4-Cyanopyridin-2-yl)-N--((S)-2-((3,3-difluorocyclobutyl)amino)-2-ox-
o-1-phenylethyl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide
(single enantiomer)--Compound 147
##STR00336##
[0335] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.86 (m, 1H),
8.39 (m, 2H), 8.03 (m, 1H), 7.28 (d, J=5.9 Hz, 4H), 6.98 (m, 2H),
6.29 (s, 1H), 5.85 (s, 1H), 4.85 (m, 1H), 4.33 (s, 1H), 3.26-2.82
(m, 3H), 2.69-1.88 (m, 5H). MS: 549.2 (M+1).sup.+.
(S)-1-(4-Cyanopyridin-2-yl)-N--((S)-2-((3,3-difluorocyclobutyl)amino)-1-(2-
-fluorophenyl)-2-oxoethyl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-car-
boxamide (single enantiomer)--Compound 148
##STR00337##
[0337] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.99-8.60 (m,
1H), 8.55-7.97 (m, 3H), 7.35-7.19 (m, 3H), 7.07-6.89 (m, 3H), 6.36
(m, 1H), 6.12 (s, 1H), 4.80 (s, 1H), 4.35 (s, 1H), 3.22-2.79 (m,
3H), 2.64-1.85 (m, 5H). MS: 567.2 (M+1).sup.+.
(S)-1-(4-Cyanopyridin-2-yl)-N--((S)-2-((3,3-difluorocyclobutyl)amino)-2-ox-
o-1-phenylethyl)-N-(5-isocyanopyridin-3-yl)-5-oxopyrrolidine-2-carboxamide
(single enantiomer)--Compound 212
##STR00338##
[0339] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.34 (s, 1H),
8.87-8.56 (m, 4H), 8.41 (s, 2H), 8.27 (s, 1H), 7.54 (s, 7H), 7.01
(d, J=6.9 Hz, 3H), 6.35 (s, 2H), 5.73 (s, 2H), 4.66 (s, 2H), 4.35
(s, 2H), 2.99 (m, 5H), 2.73-2.20 (m, 7H), 2.07 (s, 2H). MS: 556.2
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-1-(3-cyano-phenyl)-N-(1H-indazol-7-yl)-5-oxopyrrolidine-2-carboxamide
(single enantiomer)--Compound 186
##STR00339##
[0341] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.72-8.71 (m,
1H), 8.66 (s, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.67 (s, 1H),
7.50-7.49 (m, 1H), 7.36-7.34 (m, 1H), 7.11-7.07 (m, 1H), 7.00-6.96
(m, 1H), 6.83-6.76 (m, 2H), 6.48 (s, 1H), 5.07-5.07 (m, 1H),
4.38-4.33 (m, 1H), 3.05-2.91 (m, 2H), 2.80-2.71 (m, 1H), 2.65-2.60
(m, 1H), 2.53-2.46 (m, 2H), 2.03-1.99 (m, 1H), 1.75-1.67 (m, 1H).
MS: 603.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(4,4-difluorocyclohexylamino)-2-oxoethyl-
)-3-(3-cyano
phenyl)-N-(1H-indazol-7-yl)-2-oxooxazolidine-4-carboxamide (single
enantiomer)--Compound 142
##STR00340##
[0343] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 13.03 (s, 1H),
8.73 (s, 1H), 8.55-8.54 (m, 1H), 8.02 (s, 1H), 8.58-8.56 (m, 1H),
8.50-8.48 (m, 1H), 7.27-7.24 (m, 2H), 7.03-6.99 (m, 1H), 6.91-6.87
(m, 1H), 6.80-6.78 (m, 1H), 6.72-6.68 (m, 1H), 6.33 (s, 2H),
5.70-5.69 (m, 1H), 4.99-4.97 (m, 1H), 4.05-4.03 (m, 1H), 2.78-2.95
(m, 1H), 2.47-2.40 (m, 1H), 2.08-4.99 (m, 6H), 1.90-1.82 (m, 2H),
1.67-1.63 (m, 1H), 1.58-1.62 (m, 1H). MS: 633.2 (M+1).sup.+.
(2S)--N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)--
1-(4-cyanopyridin-2-yl)-N-(1H-indazol-4-yl)-5-oxopyrrolidine-2-carboxamide
(racemic)--Compound 152
##STR00341##
[0345] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 13.05 (m, 1H),
8.70 (m, 2H), 8.54 (d, J=6.7 Hz, 1H), 8.21 (s, 1H), 7.80 (d, J=6.9
Hz, 1H), 7.63 (d, J=5.0 Hz, 1H), 7.36 (m, 2H), 7.24 (d, J=8.0 Hz,
1H), 7.18-6.97 (m, 1H), 6.92-6.79 (m, 1H), 6.77-6.70 (m, 1H), 6.35
(d, 1H), 4.66 (m, 1H), 4.20-4.01 (m, 1H), 3.05-2.78 (m, 2H),
2.68-2.52 (m, 2H), 2.49-2.26 (m, 2H), 2.22-1.53 (m, 2H). MS: 604.2
(M+1).sup.+.
(S)--N-(3-(1H-Pyrazol-4-yl)phenyl)-N--((S)-1-(2-chlorophenyl)-2-(3,3-diflu-
orocyclobutylamino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2-
-carboxamide (single enantiomer)--Compound 200
##STR00342##
[0347] .sup.1H NMR (400 MHz, MeOD): .delta. 8.73-8.54 (m, 2H),
8.14-7.91 (m, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.56-7.28 (m, 4H),
7.25-6.92 (m, 4H), 6.70 (d, J=7.6 Hz, 1H), 6.54-6.39 (m, 1H), 5.03
(dd, J=9.4, 2.9 Hz, 1H), 4.31-4.05 (m, 1H), 3.00-2.73 (m, 3H),
2.64-2.00 (m, 5H). MS: 630.2 (M+1).sup.+.
(2S)--N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)--
1-(4-cyanopyrimidin-2-yl)-5-oxo-N-(3-(trifluoromethoxy)phenyl)pyrrolidine--
2-carboxamide (racemic)--Compound 180
##STR00343##
[0349] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.96 (t, J=5.5
Hz, 1H), 7.88 (s, 1H), 7.44-7.32 (m, 2H), 7.21 (m, 2H), 7.10 (t,
J=7.3 Hz, 1H), 7.04-6.95 (m, 1H), 6.91 (m, 1H), 6.52 (m, 1H), 6.18
(m, 1H), 4.89-4.67 (m, 1H), 4.31 (m, 1H), 3.22-2.75 (m, 3H),
2.70-1.92 (m, 5H). MS: 649.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyano
pyridin-2-yl)-N-(3-(difluoromethoxy)phenyl)-5-oxopyrrolidine-2-carboxamid-
e (single enantiomer)--Compound 181
##STR00344##
[0351] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.74 (s, 1H),
8.44 (m, 1H), 7.76 (d, J=9.0 Hz, 1H), 7.33 (m, 2H), 7.21-6.83 (m,
6H), 6.44 (t, J=8.8 Hz, 1H), 6.28-6.13 (m, 1H), 4.91 (m, 1H), 4.34
(s, 1H), 3.10-2.66 (m, 3H), 2.65-1.84 (m, 5H). MS: 630.1
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyano
pyrimidin-2-yl)-N-(3-(difluoromethoxy)phenyl)-5-oxopyrrolidine-2-carboxam-
ide (single enantiomer)--Compound 194
##STR00345##
[0353] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.04-8.59 (m,
1H), 7.74 (s, 1H), 7.43-7.26 (m, 4H), 6.96 (m, 3H), 6.36 (m, 2H),
4.81 (t, J=9.3 Hz, 1H), 4.55 (m, 1H), 4.33 (s, 1H), 4.06-3.89 (m,
1H), 3.15-2.69 (m, 2H), 2.69-1.86 (m, 5H). MS: 631.1
(M+1).sup.+.
(S)--N--((S)-1-(2C)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cya-
no pyridin-2-yl)-N-(3-methoxyphenyl)-5-oxopyrrolidine-2-carboxamide
(single enantiomer)--Compound 129
##STR00346##
[0355] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.75 (s, 1H),
8.51 (d, J=5.0 Hz, 1H), 7.47 (m, 1H), 7.38-7.08 (m, 3H), 6.99 (d,
J=6.7 Hz, 3H), 6.89-6.66 (m, 2H), 6.41 (s, 1H), 6.09 (d, J=6.6 Hz,
1H), 4.97 (dd, J=9.3, 3.2 Hz, 1H), 4.34 (s, 1H), 3.72 (m, 3H), 3.01
(dd, J=7.5, 4.0 Hz, 3H), 2.65-2.23 (m, 4H), 2.04 (d, J=9.0 Hz, 1H).
MS: 594.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutyl-amino)-2-oxoethy-
l)-1-(4-cyanopyrimidin-2-yl)-N-(3-methoxyphenyl)-5-oxopyrrolidine-2-carbox-
amid (single enantiomer)--Compound 164
##STR00347##
[0357] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.92 (s, 1H),
7.48-7.39 (m, 1H), 7.33-7.26 (m, 2H), 7.22-7.08 (m, 2H), 7.04-6.82
(m, 3H), 6.73 (s, 2H), 6.48 (d, J=9.5 Hz, 1H), 6.18 (m, 1H),
4.88-4.85 (m, 1H), 4.32 (s, 1H), 3.78 (s, 1H), 3.62 (s, 2H),
3.01-2.81 (m, 3H), 2.58-2.49 (m, 2H), 2.42-2.30 (m, 2H), 2.09-1.98
(m, 1H). MS: 595 (M+1).sup.+.
(2S)--N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)--
1-(4-cyanopyrimi-din-2-yl)-N-(3-cyclopropoxyphenyl)-5-oxopyrrolidine-2-car-
boxamide (racemic)--Compound 192
##STR00348##
[0359] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.06-8.88 (m,
1H), 7.61-7.30 (m, 4H), 7.27-7.22 (m, 1H), 7.18 (t, J=7.4 Hz, 2H),
7.08-6.92 (m, 1H), 6.87 (dd, J=8.7, 2.1 Hz, 1H), 6.78 (t, J=9.5 Hz,
1H), 6.50 (s, 1H), 6.04 (m, 3H), 5.57-5.14 (m, 2H), 4.88 (m, 1H),
4.77-4.10 (m, 3H), 3.15-2.75 (m, 3H), 2.68-2.47 (m, 2H), 2.45-2.21
(m, 3H), 2.20-1.90 (m, 1H). MS: 621.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-1-(4-cyanopyridin-2-yl)-N-(3-(hydroxymethyl)phenyl)-5-oxopyrrolidine-2-c-
arboxamide (single enantiomer)--Compound 131
##STR00349##
[0361] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.73 (s, 1H),
8.53 (s, 1H), 7.94-7.70 (m, 1H), 7.31 (s, 1H), 7.26 (dd, J=5.1, 1.3
Hz, 1H), 7.22-7.10 (m, 4H), 7.02-6.87 (m, 2H), 6.44 (d, J=10.5 Hz,
1H), 6.12 (d, J=6.4 Hz, 1H), 4.91 (dd, J=9.3, 3.2 Hz, 1H), 4.69 (s,
1H), 4.48 (s, 1H), 4.42-4.26 (m, 1H), 3.07-2.85 (m, 3H), 2.65-2.17
(m, 4H), 2.01 (s, 2H). MS: 594.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Xhlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-1-(4-cyanopyridin-2-yl)-N-(3-(1-hydroxycyclopropyl)phenyl)-5-oxopyrrolid-
ine-2-carboxamide (single enantiomer)--Compound 140
##STR00350##
[0363] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 8.73 (s, 1H), 8.52-8.44 (m, 1H),
7.64-7.30 (m, 3H), 7.22-6.90 (m, 5H), 6.42-6.38 (m, 1H), 6.03 (m,
1H), 4.87 (m, 1H), 4.30 (m, 1H), 3.05-2.82 (m, 3H), 2.60-1.88 (m,
5H), 1.21 (d, J=3.2 Hz, 4H). MS: 620.2 (M+1).sup.+.
(S)--N--((S)-1-(2C)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cya-
no
pyridin-2-yl)-N-(3-(2-hydroxypropan-2-yl)phenyl)-5-oxopyrrolidine-2-car-
boxamide (single enantiomer)--Compound 179
##STR00351##
[0365] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.69 (s, 1H),
8.54 (d, J=5.0 Hz, 1H), 7.93-7.70 (m, 1H), 7.40-7.19 (m, 4H), 7.11
(m, 2H), 7.01-6.72 (m, 2H), 6.45 (m, 2H), 5.05-4.76 (m, 1H), 4.33
(s, 1H), 3.13-2.58 (m, 3H), 2.42 (m, 4H), 2.09-1.83 (m, 1H), 1.33
(s, 6H). MS: 622.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoeth-y-
l)-1-(4-cyanopyri-din-2-yl)-N-(3-fluoro-5-(2-hydroxypropan-2-yl)phenyl)-5--
oxopyrrolidine-2-carboxamide (single enantiomer)--Compound 150
##STR00352##
[0367] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.66 (s, 1H),
8.49 (d, J=4.8 Hz, 1H), 7.73-7.48 (m, 1H), 7.26-6.83 (m, 7H),
6.53-6.42 (m, 2H), 4.91 (d, J=6.4 Hz, 1H), 4.32 (s, 1H), 3.02-2.72
(m, 3H), 2.58-1.85 (m, 6H), 1.63 (s, 2H), 1.51 (d, J=7.0 Hz, 2H),
1.29 (d, J=8.6 Hz, 4H). MS: 640.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(3-fluoro-5-(2-hydroxypropan-2-yl)phenyl)-5--
oxopyrrolidine-2-carboxamide (single enantiomer)--Compound 155
##STR00353##
[0369] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.80 (s, 1H),
8.43 (s, 1H), 7.51 (d, 1H), 7.24 (m, 4H), 7.06 (s, 3H), 6.64 (m,
1H), 6.15 (m, 1H), 5.73 (s, 1H), 4.86 (s, 1H), 4.32 (s, 1H), 3.01
(m, 3H), 2.68-2.27 (m, 4H), 2.12 (s, 1H), 1.44 (s, 1H), 1.29 (d,
J=9.0 Hz, 6H). MS: 639.2 (M+1).sup.+
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(3-(2-hydroxyethyl)phenyl)-5-oxopyrrolidine--
2-carboxamide (single enantiomer)--Compound 160
##STR00354##
[0371] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.76 (s, 1H),
8.52 (d, J=5.0 Hz, 1H), 7.74 (s, 1H), 7.32-7.36 (m, 1H), 7.27-7.11
(m, 2H), 7.09-6.87 (m, 4H), 6.39-6.45 (m, 1H), 6.05 (d, J=6.9 Hz,
1H), 4.33 (s, 1H), 3.82 (s, 1H), 3.59 (s, 1H), 3.12-2.79 (m, 4H),
2.74-2.16 (m, 5H), 1.99-2.07 (m, 1H). MS: 608.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyano
pyridin-2-yl)-N-(3-(2-hydroxyethoxy)phenyl)-5-oxopyrrolidine-2-carboxamid-
e (single enantiomer)--Compound 130
##STR00355##
[0373] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.72 (s, 1H),
8.48 (d, J=5.0 Hz, 1H), 7.54-7.28 (m, 2H), 7.18-7.21 (m, 2H),
7.01-6.94 (m, 2H), 6.75-6.77 (m, 2H), 6.39 (s, 1H), 5.99 (s, 1H),
4.94 (dd, J=9.3, 3.4 Hz, 1H), 4.31 (s, 1H), 3.79-4.06 (m, 4H),
3.07-2.80 (m, 3H), 2.58-2.21 (m, 4H), 1.87-2.00 (m, 2H). MS: 624.2
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-1-(4-cyanopyridin-2-yl)-N-(3-fluoro-5-((S)-methylsulfinyl)phenyl)-5-oxop-
yrrolidine-2-carboxamide (single enantiomer)--Compound 190
##STR00356##
[0375] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.75 (s, 1H),
8.54 (m, 1H), 8.02-7.78 (m, 1H), 7.33 (s, 3H), 7.21 (m 1H), 7.06
(t, J=7.4 Hz, 1H), 6.96 (m, 1H), 6.45 (m, 1H), 6.27 (m, 1H), 4.86
(m, 1H), 4.35 (m, 1H), 3.16-2.82 (m, 3H), 2.71 (s, 1H), 2.65-2.47
(m, 2H), 2.41 (m, 3H), 2.22 (m, 1H), 2.09 (m, 1H). MS: 644.1
(M+1).sup.+.
(2S)--N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)--
1-(4-cyanopyridin-2-yl)-N-(3-(methylsulfonyl)phenyl)-5-oxopyrrolidine-2-ca-
rboxamide (single enantiomer)--Compound 96
##STR00357##
[0377] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.84-8.11 (m,
3H), 7.93-7.35 (m, 4H), 7.25-6.75 (m, 2H), 6.64-5.94 (m, 2H),
4.89-4.69 (m, 1H), 4.28 (d, J=5.7 Hz, 1H), 3.13-2.74 (m, 6H),
2.68-2.48 (m, 2H), 2.46-2.15 (m, 3H), 2.04 (s, 1H). MS: 642.1
(M+1).sup.+.
(2S)--N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)--
1-(4-cyanopyrimidin-2-yl)-N-(3-(methylsulfonyl)phenyl)-5-oxopyrrolidine-2--
carboxamide (racemic)--Compound 102
##STR00358##
[0379] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.93 (t, J=5.3
Hz, 1H), 8.50-8.15 (m, 1H), 7.94-7.71 (m, 2H), 7.66-7.46 (m, 1H),
7.38 (t, J=6.4 Hz, 1H), 7.28 (t, J=3.6 Hz, 1H), 7.20-7.07 (m, 1H),
7.05-6.87 (m, 2H), 6.74 (m, 1H), 6.52 (m, 1H), 4.72 (dd, J=9.2, 2.5
Hz, 1H), 4.34 (d, J=6.4 Hz, 1H), 3.00 (s, 3H), 2.90-2.75 (m, 3H),
2.56-2.19 (m, 5H), 1.98 (m, 1H). MS: 643.1 (M+1).sup.+.
(2S)--N-(1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoethyl)--
1-(4-cyanopyridin-2-yl)-N-(3-(methylsulfonyl)phenyl)-5-oxopyrrolidine-2-ca-
rboxamide (racemic)--Compound 95
##STR00359##
[0381] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.87-8.13 (m,
3H), 8.02-7.37 (m, 4H), 7.24-6.87 (m, 2H), 6.51-6.39 (m, 1H),
5.77-5.28 (m, 1H), 4.89-4.65 (m, 1H), 3.94 (d, J=5.2 Hz, 1H),
3.16-2.73 (m, 4H), 2.68-2.53 (m, 1H), 2.44-2.20 (m, 1H), 2.03 (m,
8H), 1.44 (m, 2H). MS: 670.2 (M+1).sup.+.
(S)--N--((S)-1-(2C)-2-((4,4-difluorocyclohexyl)amino)-2-oxoethyl)-1-(4-cya-
nopyrimidin-2-yl)-N-(3-(methylsulfonyl)phenyl)-5-oxopyrrolidine-2-carboxam-
ide (single enantiomer)--Compound 103
##STR00360##
[0383] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.94 (dd, J=7.9,
4.8 Hz, 1H), 8.56-8.15 (m, 1H), 7.97-7.62 (m, 2H), 7.56-7.29 (m,
3H), 7.13 (t, J=7.6 Hz, 1H), 7.06-6.84 (m, 2H), 6.51 (d, J=4.2 Hz,
1H), 6.10 (dd, J=3.2, 7.4 Hz, 1H), 4.74 (d, J=6.6 Hz, 1H), 3.98 (s,
1H), 3.01 (s, 1H), 2.93-2.72 (m, 3H), 2.52 (d, J=9.6 Hz, 1H),
2.37-2.20 (m, 1H), 2.13-1.78 (m, 7H), 1.63-1.40 (m, 2H). MS: 671
(M+1).sup.+.
(2S)--N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)--
1-(4-cyanopyridin-2-yl)-N-(3-fluoro-5-(methylsulfonyl)phenyl)-5-oxopyrroli-
dine-2-carboxamide (racemic)--Compound 110
##STR00361##
[0385] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.45-8.79 (m,
2H), 8.40-8.13 (s, 1H), 8.09-7.67 (m, 1H), 7.63-7.30 (m, 2H),
7.23-6.87 (m, 3H), 6.55-6.30 (m, 1H), 6.22-5.94 (m, 1H), 4.96-4.61
(m, 1H), 4.26 (m, 4H), 3.16-1.87 (m, 7H), 1.27 (d, 1H). MS: 660.1
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyrimidin-2-yl)-N-(3-fluoro-5-(methylsulfonyl)phenyl)-5-oxop-
yrrolidine-2-carboxamide (single enantiomer)--Compound 109
##STR00362##
[0387] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.96 (d, J=4.6
Hz, 3H), 7.99 (d, J=8.5 Hz, 2H), 7.75 (s, 2H), 7.52 (d, J=7.0 Hz,
3H), 7.37 (d, J=4.9 Hz, 5H), 7.19 (t, J=7.7 Hz, 3H), 7.01 (dt,
J=7.1 Hz, 6H), 6.40-6.60 (m, 3H), 6.06 (d, J=6.5 Hz, 3H), 4.76 (d,
J=9.2 Hz, 1H), 4.35 (m, 4H), 3.14-1.87 (m, 8H). MS: 661.1
(M+1).sup.+.
(2S)--N-(1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoethyl)--
1-(4-cyanopyridin-2-yl)-N-(3-fluoro-5-(methylsulfonyl)phenyl)-5-oxopyrroli-
dine-2-carboxamide (racemic)--Compound 105
##STR00363##
[0389] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.96 (t, J=4.6
Hz, 1H), 7.53-7.36 (m, 3H), 7.23 (m, J=7.8, 1.5 Hz, 1H), 7.14-6.94
(m, 3H), 6.68 (m, J=8.6, 2.3 Hz, 1H), 6.60 (d, J=3.1 Hz, 1H), 6.07
(d, J=6.7 Hz, 1H), 4.75 (q, J=4.0, 2.1 Hz, 1H), 4.38 (d, J=6.7 Hz,
1H), 3.78-3.67 (m, 2H), 3.39 (m, 1H), 3.26-2.92 (m, 3H), 2.67-2.36
(m, 2H). MS: 688.1 (M+1).sup.+.
(2S)--N-(1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoethyl)--
1-(4-cyanopyrimidin-2-yl)-N-(3-fluoro-5-(methylsulfonyl)phenyl)-5-oxopyrro-
lidine-2-carboxamide (single enantiomer)--Compound 108
##STR00364##
[0391] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.97 (s, 1H),
8.20-8.60 (m, 1H), 8.09-7.68 (m, 1H), 7.63-7.32 (m, 5H), 7.22-6.93
(m, 3H), 6.64-6.03 (m, 2H), 5.62 (s, 1H), 4.60-4.85 (m, 1H),
3.21-1.70 (m, 12H), 1.50-1.14 (m, 2H). MS: 689.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-1-(4-cyano
pyrimidin-2-yl)-N-(3-fluoro-5-(methylsulfonyl)phenyl)-5-oxopyrrolidine-2--
carboxamide (single enantiomer)--Compound 168
##STR00365##
[0393] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.0 (s, 1H),
8.05-8.02 (m, 1H), 7.80 (m, 1H), 7.56-7.00 (m, 7H), 6.58 (m, 1H),
5.65 (m, 1H), 4.80 (m, 1H), 4.14 (m, 1H), 3.00-0.88 (m, 15H). MS:
689.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-1-(4-cyanopyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)-5-oxopyrrolidine-
-2-carboxamide (single enantiomer)--Compound 159
##STR00366##
[0395] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.78 (s, 1H),
8.84-8.61 (m, 2H), 8.56 (s, 1H), 7.66 (m, 2H), 7.49-7.15 (m, 3H),
7.15-6.79 (m, 4H), 6.25 (m, 1H), 4.89-4.74 (m, 1H), 4.19-4.04 (m,
1H), 3.03-2.83 (m, 3H), 2.72-2.59 (m, 3H), 2.54 (m, 2H), 2.44-2.28
(m, 1H), 1.99 (m, 2H). MS: 657.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-1-(4-cyanopyri-din-2-yl)-N-(3-(dimethylamino)phenyl)-5-oxopyrrolidine-2--
carboxamide (single enantiomer)--Compound 161
##STR00367##
[0397] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.71 (d, J=9.9
Hz, 1H), 8.50-8.41 (m, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.22 (dd,
J=5.0, 1.3 Hz, 1H), 7.18-7.05 (m, 2H), 6.99-6.86 (m, 3H), 6.56-6.47
(m, 2H), 6.37 (d, J=6.6 Hz, 1H), 6.11 (s, 1H), 5.01 (d, J=9.2 Hz,
1H), 4.34-4.28 (m, 1H), 3.07-2.70 (m, 8H), 2.61-2.42 (m, 2H),
2.35-2.25 (m, 2H), 2.01-1.97 (m, 1H). MS: 607.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(2-fluorophenyl)-5-oxopyrrolidine-2-carboxam-
ide (single enantiomer)--Compound 187
##STR00368##
[0399] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.74 (m, 1H),
8.48 (m, 1H), 7.96-7.92 (m, 1H), 7.40 (m, 1H), 7.28-6.72 (m, 7H),
6.59-5.79 (m, 2H), 4.86-4.78 (m, 1H), 4.28 (s, 1H), 3.04-2.90 (m,
3H), 2.66-2.01 (m, 5H). MS: 582.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(2,3-difluorophenyl)-5-oxopyrrolidine-2-carb-
oxamide (single enantiomer)--Compound 188
##STR00369##
[0401] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.73 (m, 1H),
8.47 (d, J=5.0 Hz, 1H), 7.84-7.73 (m, 1H), 7.43 (d, J=8.1 Hz, 1H),
7.28-7.20 (m, 2H), 7.13 (dd, J=8.2, 4.4 Hz, 2H), 7.01-6.83 (m, 2H),
6.62 (s, 1H), 6.42-5.85 (m, 1H), 4.85-4.77 (m, 1H), 4.20 (m, 1H),
3.13-2.78 (m, 3H), 2.68-2.28 (m, 4H), 2.25-2.04 (m, 1H). MS: 600.1
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(2,5-difluorophenyl)-5-oxopyrrolidine-2-carb-
oxamide (single enantiomer)--Compound 197
##STR00370##
[0403] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.73 (m, 1H),
8.54-8.41 (m, 1H), 7.83-7.78 (m, 1H), 7.44-7.39 (m, 1H), 7.28-7.21
(m, 2H), 7.13-6.88 (m, 3H), 6.81-6.80 (m, 1H), 6.61-6.31 (m, 1H),
5.91 (d, J=6.5 Hz, 1H), 4.86-4.79 (m, 1H), 4.29 (dd, J=8.2, 6.7 Hz,
1H), 3.51 (s, 1H), 3.12-2.85 (m, 3H), 2.68-2.56 (m, 1H), 2.54-2.45
(m, 1H), 2.43-2.24 (m, 2H), 2.23-2.06 (m, 1H). MS: 600.1
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-1-(4-cyano
pyridin-2-yl)-N-(1H-indazol-5-yl)-5-oxopyrrolidine-2-carboxamide
(single enantiomer)--Compound 203
##STR00371##
[0405] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.78 (s, 1H),
8.56 (m, 1H), 8.39 (s, 1H), 8.13-7.88 (m, 1H), 7.44-7.32 (m, 2H),
7.28-7.00 (m, 4H), 6.99-6.79 (m, 2H), 6.48 (m, 1H), 5.75-5.48 (m,
1H), 5.06-4.75 (m, 1H), 4.00 (s, 1H), 3.10-2.77 (m, 1H), 2.63-2.44
(m, 1H), 2.37-2.20 (m, 1H), 2.15-1.77 (m, 7H), 1.42 (m, 2H). MS:
632.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(1H-indazol-6-yl)-5-oxopyrrolidine-2-carboxa-
mide (single enantiomer)--Compound 205
##STR00372##
[0407] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.78 (s, 1H),
8.57 (t, J=5.0 Hz, 1H), 8.23-7.76 (m, 2H), 7.54-7.30 (m, 2H), 7.16
(s, 1H), 7.04-6.86 (m, 3H), 6.47 (d, J=11.7 Hz, 1H), 6.02 (d, J=6.1
Hz, 1H), 4.92 (m, 1H), 4.36 (s, 1H), 2.97 (m, 3H), 2.65-2.20 (m,
4H), 1.99 (m, 1H). MS: 604.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(1H-indazol-6-yl)-5-oxopyrrolidine-2-carboxa-
mide (single enantiomer)--Compound 136
##STR00373##
[0409] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 10.41-9.94 (m,
1H), 8.79 (s, 1H), 8.57 (t, J=5.1 Hz, 1H), 8.28-8.09 (m, 1H), 7.93
(m, 1H), 7.52 (s, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.33 (d, J=7.5 Hz,
1H), 7.15-6.98 (m, 1H), 6.46 (d, J=12.7 Hz, 1H), 5.50 (d, J=7.9 Hz,
1H), 5.06-4.76 (m, 1H), 4.02 (s, 1H), 2.92 (dd, 1H), 2.63-2.49 (m,
1H), 2.31 (s, 1H), 2.03 (m, 6H), 1.45 (s, 2H). MS: 632.2
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(1H-indazol-5-yl)-5-oxopyrrolidine-2-carboxa-
mide (single enantiomer)--Compound 175
##STR00374##
[0411] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.75 (s, 1H),
8.64-8.46 (m, 1H), 8.34 (s, 1H), 8.09 (s, 1H), 7.94-7.92 (m, 1H),
7.42-7.32 (m, 2H), 7.24-7.02 (m, 2H), 6.94-6.85 (m, 2H), 6.49-6.45
(m, 1H), 6.08-6.06 (m, 1H), 5.00-4.76 (m, 1H), 4.35-4.31 (s, 1H),
3.00-2.85 (m, 3H), 2.64-2.11 (m, 4H), 2.01-1.93 (m, 1H). MS: 604.2
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyano
pyridin-2-yl)-N-(1H-indol-5-yl)-5-oxopyrrolidine-2-carboxamide
(single enantiomer)--Compound 206
##STR00375##
[0413] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.74 (s, 1H),
8.55 (m, 1H), 8.12 (d, J=13.8 Hz, 2H), 7.52-7.29 (m, 2H), 7.18-6.80
(m, 5H), 6.46 (m, 2H), 5.83 (s, 1H), 5.83 (s, 1H), 5.08-4.81 (m,
1H), 4.33 (s, 1H), 2.92 (m, 3H), 2.64-2.16 (m, 4H), 2.01 (m, 1H).
MS: 603.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyano
pyridin-2-yl)-N-(1-methyl-1H-indol-5-yl)-5-oxopyrrolidine-2-carboxamide
(single enantiomer)--Compound 209
##STR00376##
[0415] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.83-8.39 (m,
1H), 8.01 (m, 1H), 7.68-7.32 (m, 1H), 7.28-6.72 (m, 8H), 6.55-6.38
(m, 1H), 5.90 (m, 1H), 5.00-4.73 (m, 1H), 4.33 (s, 1H), 3.80-3.62
(m, 3H), 2.91 (m, 3H), 2.62-1.78 (m, 5H). MS: 617.2
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(3-cyclopropylphenyl)-5-oxopyrrolidine-2-car-
boxamide (single enantiomer)--Compound 173
##STR00377##
[0417] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.76 (s, 1H),
8.59 (d, J=4.8 Hz, 1H), 7.50-7.60 (m, 1H), 7.41 (d, J=7.8 Hz, 1H),
7.28-7.19 (m, 2H), 7.14-6.94 (m, 2H), 6.62-6.79 (m, 1H), 6.26-6.07
(m, 2H), 4.86 (dd, J=9.3, 2.9 Hz, 1H), 4.16-4.19 (m, 1H), 3.02-2.76
(m, 3H), 2.57-2.59 (m, 1H), 2.40-2.16 (m, 3H), 2.02-2.12 (m, 1H),
1.28-1.29 (m, 2H), 0.90 (t, J=6.9 Hz, 2H). MS: 604.2
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyri-midin-2-yl)-N-(3-cyclopropylphenyl)-5-oxopyrrolidine-2--
carboxamide (single enantiomer)--Compound 182
##STR00378##
[0419] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.94 (d, J=4.5
Hz, 1H), 7.57-7.49 (m, 1H), 7.43-7.28 (m, 2H), 7.19-7.14 (m, 2H),
7.05-6.79 (m, 4H), 6.51-6.46 (m, 1H), 6.00-5.97 (m, 1H), 4.82-4.80
(m, 1H), 4.32-4.33 (m, 1H), 3.09-2.81 (m, 3H), 2.64-2.24 (m, 4H),
2.05-1.72 (m, 2H), 0.99-0.76 (m, 4H). MS: 605.2 (M+1).sup.+.
(S)--N-(3-(tert-Butyl)phenyl)-N--((S)-1-(2-chlorophenyl)-2-((3,3-difluoroc-
yclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyrimidin-2-yl)-5-oxopyrrolidine-2--
carboxamide (single enantiomer)--Compound 165
##STR00379##
[0421] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.94 (d, J=4.8
Hz, 1H), 8.00-7.54 (m, 1H), 7.41-7.32 (m, 2H), 7.24-7.15 (m, 2H),
7.14-7.02 (m, 2H), 6.97-6.81 (m, 2H), 6.53 (s, 1H), 6.20 (dd,
J=12.7, 6.8 Hz, 1H), 4.86 (m, 1H), 4.34 (s, 1H), 3.15-2.80 (m, 3H),
2.63-2.27 (m, 4H), 2.13-1.92 (m, 1H), 1.29 (s, 9H). MS: 621.2
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(3-cyclopropyl-5-fluorophenyl)-5-oxopyrrolid-
ine-2-carboxamide (single enantiomer)--Compound 204
##STR00380##
[0423] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.77 (s, 1H),
8.50 (s, 1H), 7.50-7.33 (m, 2H), 7.24-7.17 (m, 1H), 7.01 (m, 2H),
6.68 (m, 2H), 6.39 (m, 1H), 6.00 (s, 1H), 4.93 (s, 1H), 4.34 (s,
1H), 3.15-2.83 (m, 3H), 2.59-2.53 (m, 2H), 2.40-2.37 (m, 2H), 2.07
(s, 1H), 1.27 (s, 1H), 1.05 (s, 1H), 0.91 (d, J=6.7 Hz, 1H), 0.67
(s, 1H), 0.43 (m, 1H). MS: 622.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-1-(4-cyano
pyridin-2-yl)-N-(3-cyclopropyl-5-fluorophenyl)-5-oxopyrrolidine-2-carboxa-
mide (single enantiomer)--Compound 202
##STR00381##
[0425] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.79 (s, 1H),
8.50 (s, 1H), 7.40 (m, 2H), 7.15 (m, 1H), 7.01 (m, 3H), 6.84-6.56
(m, 2H), 6.38 (m, 1H), 5.50 (s, 1H), 4.94 (s, 1H), 3.99 (s, 1H),
2.90 (m, 1H), 2.57 (m, 1H), 2.28 (s, 1H), 2.05 (m, 5H), 1.92-1.77
(m, 2H), 1.30 (m, 2H), 0.91 (t, J=6.7 Hz, 2H), 0.67 (s, 2H). MS:
650.2 (M+1).sup.+.
((S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethy-
l)-1-(4-cyanopyri-din-2-yl)-N-(3-(N-methylsulfamoyl)phenyl)-5-oxopyrrolidi-
ne-2-carboxamide (single enantiomer)--Compound 157
##STR00382##
[0427] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.89-8.59 (m,
3H), 8.50-8.01 (m, 2H), 7.69-7.31 (m, 5H), 7.17 (t, J=7.6 Hz, 2H),
7.03 (t, J=7.6 Hz, 2H), 6.95 (t, J=7.9 Hz, 2H), 6.51 (s, 1H), 4.98
(s, 1H), 4.24 (s, 2H), 3.01-2.45 (m, 7H), 2.35 (s, 3H), 2.10-2.05
(m, 1H). MS: 657.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-1-(4-cyanopyri-din-2-yl)-N-(3-(N,N-dimethylsulfamoyl)phenyl)-5-oxopyrrol-
idine-2-carboxamide (single enantiomer)--Compound 156
##STR00383##
[0429] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.70 (s, 1H),
8.60 (d, J=4.9 Hz, 1H), 8.17 (d, J=7.7 Hz, 1H), 7.86 (s, 1H),
7.63-7.55 (m, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.27 (s, 1H), 7.20-6.92
(m, 4H), 6.50 (d, J=6.9 Hz, 2H), 4.79 (d, J=7.0 Hz, 1H), 4.32 (s,
1H), 3.05-2.75 (m, 4H), 2.60-1.90 (m, 10H). MS: 671.2
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(3-cyanopyridin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxam-
ide (single enantiomer)--Compound 69
##STR00384##
[0431] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.14 (d, J=8.0
Hz, 1H), 7.93 (d, J=4.0 Hz, 1H), 7.92 (m, 1H), 7.17-7.28 (m, 4H),
6.91-7.04 (m, 4H), 6.42 (s, 1H), 6.31 (s, 1H), 4.87-4.91 (m, 1H),
4.35 (m, 1H), 2.97-3.02 (m, 2H), 2.79-2.86 (m, 1H), 2.45-2.57 (m,
3H), 2.23-2.26 (m, 1H), 2.09-2.11 (m, 1H). MS: 582.1
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyano-3-fluoropyridin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-
-carboxamide (single enantiomer)--Compound 82
##STR00385##
[0433] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.36 (d, J=4.7
Hz, 1H), 7.70 (s, 1H), 7.39 (m, 2H), 7.25-6.63 (m, 5H), 6.39 (s,
1H), 5.96 (s, 1H), 4.85 (s, 1H), 4.34 (s, 1H), 3.12-2.69 (m, 3H),
2.64-2.01 (m, 5H). MS: 600.0 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-1-(4-cyano-3-fluoropyridin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-
-carboxamide (single enantiomer)--Compound 83
##STR00386##
[0435] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.37 (d, J=4.6
Hz, 1H), 7.75 (s, 1H), 7.39 (m, 2H), 7.24-6.89 (m, 4H), 6.87-6.65
(d, 1H), 6.50-6.27 (m, 1H), 5.59-5.40 (m, 1H), 4.92-4.75 (m, 1H),
4.05-3.87 (m, 1H), 2.95-2.68 (m, 1H), 2.62-2.43 (m, 1H), 2.41-2.25
(m, 1H), 2.25-2.09 (m, 2H), 2.05-1.74 (m, 4H), 1.59-1.24 (m, 3H).
MS: 628.0 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyano-3-fluoropyridin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidi-
ne-2-carboxamide (single enantiomer)--Compound 88
##STR00387##
[0437] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.73 (s, 1H),
8.49 (m, 1H), 7.96 (s, 1H), 7.59-7.30 (m, 3H), 7.26-6.68 (m, 6H),
6.52-6.12 (m, 1H), 5.96 (d, J=10.5 Hz, 1H), 4.95 (s, 1H), 4.63 (m,
1H), 4.49 (m, 1H), 4.22 (s, 1H), 4.14-4.02 (m, 1H), 3.46-2.65 (m,
4H), 2.55-2.00 (m, 2H), 1.69-1.49 (m, 2H). MS: 618.1
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(4,4-difluorocyclohexylamino)-2-oxoethyl-
)-N-(3-fluorophenyl)-5-oxo-1-(pyrazin-2-yl)pyrrolidine-2-carboxamide
(single enantiomer)--Compound 58
##STR00388##
[0439] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.74 (d, J=1.5
Hz, 1H), 8.32 (m, 2H), 7.71 (s, 1H), 7.36 (m, 1H), 7.16 (m, 1H),
6.97 (m, 4H), 6.41 (s, 1H), 5.44 (d, J=7.0 Hz, 1H), 4.85 (d, J=6.0
Hz, 1H), 3.96 (m, 1H), 2.98-2.82 (m, 1H), 2.61-2.48 (m, 1H),
2.35-2.21 (m, 1H), 2.02 (m, 5H), 1.88 (m, 2H), 1.47-1.19 (m, 2H).
MS: 586.2 (M+1).sup.+.
2-(((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(3-
-fluorophenyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate (single
enantiomer)--Compound 74
##STR00389##
[0441] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.60 (s, 1H),
7.89 (s, 1H), 7.71 (s, 1H), 7.45-7.29 (m, 2H), 7.25-6.86 (m, 5H),
6.41 (s, 1H), 5.54 (s, 1H), 4.98 (s, 1H), 3.98 (s, 1H), 3.16-2.66
(m, 2H), 2.51 (s, 1H), 2.26 (s, 1H), 1.98 (m, 7H), 1.55 (m, 3H).
MS: 591.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-N-(3-fluoro-phenyl)-2-oxo-3-(pyrimidin-2-yl)oxazolidine-4-carboxamide
(single enantiomer)--Compound 76
##STR00390##
[0443] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.70 (d, J=4.7
Hz, 2H), 7.67 (d, J=8.0 Hz, 1H), 7.43-7.31 (m, 1H), 7.19 (d, J=7.3
Hz, 1H), 7.13-6.86 (m, 5H), 6.46 (s, 1H), 5.58 (d, J=6.8 Hz, 1H),
5.02 (d, J=4.4 Hz, 1H), 4.47 (dd, J=8.7, 5.0 Hz, 1H), 4.24-4.13 (m,
1H), 3.98 (s, 1H), 2.14-1.79 (m, 6H), 1.57-1.41 (m, 2H). MS: 588.2
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-3-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-2-oxooxazolidine-4-carboxamid-
e (single enantiomer)--Compound 77
##STR00391##
[0445] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.48 (s, 1H),
7.62 (d, J=7.9 Hz, 1H), 7.33 (d, J=8.9 Hz, 1H), 7.19 (d, J=7.2 Hz,
2H), 7.10-6.85 (m, 5H), 6.44 (d, J=5.1 Hz, 1H), 6.20-6.08 (m, 1H),
5.01 (m, 1H), 4.46 (dd, J=8.7, 4.7 Hz, 1H), 4.31-4.20 (m, 2H),
3.09-2.91 (m, 2H), 2.58-2.30 (m, 2H). MS: 584.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-3-(4-cyano-pyridin-2-yl)-N-(3-fluorophenyl)-2-oxooxazolidine-4-carboxa-
mide (single enantiomer)--Compound 78
##STR00392##
[0447] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.55 (s, 1H),
8.50 (t, J=5.8 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.43-7.29 (m, 2H),
7.20 (d, J=7.6 Hz, 1H), 7.15-6.89 (m, 4H), 6.43 (d, J=4.4 Hz, 1H),
5.54 (d, J=7.9 Hz, 1H), 5.06 (d, J=4.7 Hz, 1H), 4.51 (dd, J=8.8,
5.0 Hz, 1H), 4.25 (m, 1H), 3.98 (s, 1H), 2.19-1.74 (m, 6H), 1.49
(m, 2H). MS: 612.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-N-(3-cyano-5-fluorophenyl)-3-(3-cyanophenyl)-2-oxooxazolidine-4-carboxam-
ide (single enantiomer)--Compound 134
##STR00393##
[0449] .sup.1HNMR (400 MHz, CDCl.sub.3): .delta. 8.51-8.47 (m, 1H),
8.39-8.37 (d, 0.5H), 8.07-7.99 (m, 1H), 7.38 (s, 0.5H), 7.33-7.31
(m, 1H), 7.26-7.22 (m, 1H), 7.08-7.07 (m, 1H), 6.90-6.87 (m, 1H),
6.53-6.46 (m, 2H), 4.94-4.91 (m, 1H), 4.44-4.40 (m, 1H). 4.34-4.32
(m, 1H), 4.28-4.23 (m, 1H), 3.00-2.99 (m, 2H), 2.50-2.43 (m, 2H).
MS: 608.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-3-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-2-oxooxazolidine-4-ca-
rboxamide (single enantiomer)--Compound 135
##STR00394##
[0451] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.58-8.28 (m,
3H), 8.08 (d, J=8.5 Hz, 1H), 7.32 (dd, J=5.1, 1.0 Hz, 2H),
7.28-7.20 (m, 1H), 7.07 (m, 1H), 6.91 (m, 1H), 6.66-6.22 (m, 2H),
5.05-4.85 (m, 1H), 4.57-4.09 (m, 3H), 3.02 (m, 2H), 2.69-2.30 (m,
2H). MS: 585.1 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-3-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-2-oxooxazolidine-4-ca-
rboxamide (single enantiomer)--Compound 132
##STR00395##
[0453] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.91 (s, 1H),
8.41 (m, 4H), 8.11 (s, 1H), 7.23 (s, 1H), 7.05 (s, 1H), 6.91 (s,
1H), 6.52 (m, 1H), 6.05 (m, 1H), 4.95 (m, 1H), 4.37 (m, 2H), 3.95
(s, 1H), 1.71 (m, 10H). MS: 613.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-N-(3-fluoro
phenyl)-2-oxo-3-(thiazol-4-yl)oxazolidine-4-carboxamide (single
enantiomer)--Compound 72
##STR00396##
[0455] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.70-8.47 (m,
1H), 7.69-7.52 (m, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.42-7.26 (m, 1H),
7.25-6.84 (m, 5H), 6.42 (s, 1H), 6.21-6.02 (m, 1H), 5.03 (d, J=4.6
Hz, 1H), 4.42 (m, 1H), 4.38-4.05 (m, 2H), 2.98 (m, 2H), 2.64-2.29
(m, 2H). MS: 565.1 (M+1).sup.+.
(4S)--N-(1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-3--
(4-cyanopyridin-2-yl)-N-(3-fluoro-5-(2-hydroxypropan-2-yl)phenyl)-2-oxooxa-
zolidine-4-carboxamide (racemic)--Compound 145
##STR00397##
[0457] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.63-8.50 (m,
1H), 8.42 (m, 1H), 7.48-7.40 (m, 1H), 7.29 (d, J=7.0 Hz, 2H),
7.25-7.19 (m, 2H), 7.14-6.95 (m, 3H), 6.89 (m, 1H), 6.67 (d, J=6.9
Hz, 1H), 6.54-6.42 (m, 1H), 5.11-4.96 (m, 1H), 4.51-4.40 (m, 1H),
4.32 (d, J=9.1 Hz, 1H), 4.24-4.09 (m, 1H), 3.12-2.73 (m, 2H), 1.52
(m, 2H), 1.32 (d, J=9.0 Hz, 4H). MS: 642.2 (M+1).sup.+.
(4S)--N-(1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-3--
(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-2-oxo-1,3-oxazinane-4-carboxamide
(racemic)--Compound 90
##STR00398##
[0459] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.57 (s, 1H),
8.40 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.25-6.91 (m, 8H), 6.48 (s,
1H), 6.25 (s, 1H), 5.08 (s, 1H), 4.51-4.46 (m, 1H), 4.31 (m, 2H),
3.01 (m, 2H), 2.53-2.50 (m, 2H), 2.29-2.13 (m, 2H). MS: 598.1
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-3-(4-cyanopy-ridin-2-yl)-N-(3,5-difluorophenyl)-2-oxo-1,3-oxazinane-4--
carboxamide (single enantiomer)--Compound 133
##STR00399##
[0461] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.55 (d, J=5.0
Hz, 1H), 8.34 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.31 (dd, J=5.0, 1.1
Hz, 1H), 7.26-7.16 (m, 2H), 7.13-7.04 (m, 1H), 6.98 (t, J=6.6 Hz,
2H), 6.72-6.63 (m, 1H), 6.49 (s, 1H), 6.44 (d, J=6.9 Hz, 1H), 5.11
(dd, J=6.4, 3.5 Hz, 1H), 4.51-4.22 (m, 3H), 2.98-3.04 (m, 2H),
2.67-2.41 (m, 2H), 2.33-2.09 (m, 2H). MS: 627.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-3-(4-cyano
pyridin-2-yl)-N-(3,5-difluorophenyl)-2-oxo-1,3-oxazinane-4-carboxamide
(single enantiomer)--Compound 139
##STR00400##
[0463] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.64 (d, J=5.0
Hz, 1H), 8.47 (s, 1H), 7.45 (d, J=7.4 Hz, 1H), 7.38-7.30 (m, 2H),
7.24 (d, J=7.1 Hz, 1H), 7.15-7.12 (m, 1H), 6.81-6.77 (m, 1H), 6.06
(s, 1H), 5.51 (d, J=7.5 Hz, 1H), 5.05-4.88 (m, 1H), 4.62-4.56 (m,
1H), 4.42-4.30 (m, 1H), 3.87 (s, 1H), 2.35-2.15 (m, 2H), 1.97-1.79
(m, 5H), 1.40 (m, 2H). MS: 643.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-3-(4-cyano
pyrimidin-2-yl)-N-(3,5-difluorophenyl)-2-oxo-1,3-oxazinane-4-carboxamide
(single enantiomer)--Compound 144
##STR00401##
[0465] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.96 (d, J=4.7
Hz, 1H), 7.56 (d, J=10.0 Hz, 1H), 7.41 (dd, J=9.7, 6.4 Hz, 2H),
7.24-7.22 (m, 1H), 7.14-6.95 (m, 3H), 6.70 (t, J=8.6 Hz, 1H), 6.52
(s, 1H), 5.53 (d, J=7.6 Hz, 1H), 4.96 (dd, J=7.8, 4.0 Hz, 1H), 4.46
(d, J=8.8 Hz, 1H), 4.31 (dd, J=10.7, 5.1 Hz, 1H), 3.99 (s, 1H),
2.49-2.31 (m, 1H), 2.29-2.01 (m, 5H), 1.98-1.78 (m, 2H), 1.49 (dd,
J=17.9, 8.5 Hz, 1H). MS: 645.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-3-(4-cyanopy-rimidin-2-yl)-N-(3,5-difluorophenyl)-2-oxo-1,3-oxazinane--
4-carboxamide (single enantiomer)--Compound 154
##STR00402##
[0467] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.89 (d, J=4.8
Hz, 1H), 7.52 (d, J=8.9 Hz, 1H), 7.40 (d, J=4.8 Hz, 1H), 7.22 (dd,
J=8.0, 1.2 Hz, 1H), 7.16-7.15 (m, 1H), 7.08-6.97 (m, 2H), 6.94 (dd,
J=7.7, 1.5 Hz, 1H), 6.66 (dd, J=9.7, 7.4 Hz, 1H), 6.56 (s, 1H),
6.43 (d, J=6.8 Hz, 1H), 4.91 (dd, J=8.3, 4.5 Hz, 1H), 4.41-4.33 (m,
2H), 4.24-4.20 (m, 1H), 3.06-2.86 (m, 2H), 2.66-2.42 (m, 2H),
2.39-2.25 (m, 1H), 2.24-2.12 (m, 1H). MS: 617.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-3-(4-cyano
pyridin-2-yl)-N-(5-fluoropyridin-3-yl)-2-oxo-1,3-oxazinane-4-carboxamide
(single enantiomer)--Compound 143
##STR00403##
[0469] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.08-7.79 (m,
3H), 7.62-6.70 (m, 5H), 6.50 (m, 2H), 4.95 (m, 1H), 4.62-4.03 (m,
3H), 2.99 (s, 2H), 2.51 (s, 2H), 2.18 (m, 2H). MS: 599.1
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-3-(4-cyano-pyridin-2-yl)-N-(5-fluoropyridin-3-yl)-2-oxo-1,3-oxazinane--
4-carboxamide (single enantiomer)--Compound 137
##STR00404##
[0471] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.43-8.90 (m,
3H), 8.30 (s, 1H), 7.49-8.13 (m, 1H), 7.29-7.31 (m, 2H), 7.17-7.21
(m, 1H), 6.94-7.08 (m, 2H), 6.45-6.53 (m, 1H), 5.80-593 (m, 1H),
4.96-5.00 (m, 1H), 4.47-4.51 (m, 1H), 4.30-4.33 (m, 1H), 3.96-3.98
(m, 1H), 2.09-2.28 (m, 6H), 1.83-1.95 (m, 2H), 1.49-1.63 (m, 2H).
MS: 627.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-3-(4-cyanopyridin-2-yl)-N-(3-fluoro-5-(2-hydroxypropan-2-yl)phenyl)-2-ox-
o-1,3-oxazinane-4-carboxamide (single enantiomer)--Compound 146
##STR00405##
[0473] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.56 (t, J=6.0
Hz, 1H), 8.36 (s, 1H), 7.72-7.45 (m, 1H), 7.23-7.16 (m, 1H), 7.12
(t, J=7.1 Hz, 1H), 7.06-6.86 (m, 3H), 6.38 (s, 1H), 6.28 (d, J=6.9
Hz, 1H), 5.17-5.01 (m, 1H), 4.50-4.44 (m, 1H), 4.30 (m, 2H), 2.99
(d, J=7.8 Hz, 2H), 2.62-2.37 (m, 2H), 2.36-2.06 (m, 2H), 1.49 (d,
J=6.2 Hz, 2H), 1.32 (m, 4H). MS: 656.2 (M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-6-oxopiperidine-2-carboxamide
(single enantiomer)--Compound 55
##STR00406##
[0475] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.59 (s, 1H),
8.28 (s, 1H), 7.72 (d, J=7.2 Hz, 1H), 7.43-7.33 (m, 1H) 7.26-7.12
(m, 2H), 7.11-6.96 (m, 2H), 6.89 (dd, J=8.3, 2.2 Hz, 1H), 6.46 (s,
1H), 6.27 (s, 1H), 5.00 (t, J=4.6 Hz, 1H), 4.37-4.28 (m, 1H),
3.13-2.95 (m, 2H), 2.78-2.69 (m, 1H), 2.62-2.35 (m, 3H), 2.15-2.09
(m, 1H), 2.05-1.92 (m, 1H), 1.89-1.70 (m, 3H). MS: 596.2
(M+1).sup.+.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoeth-
yl)-1-(4-cyano-pyridin-2-yl)-N-(3-fluorophenyl)-6-oxopiperidine-2-carboxam-
ide (single enantiomer)--Compound 75
##STR00407##
[0477] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.60 (s, 1H),
8.31 (s, 1H), 7.73-7.75 (m, 1H), 7.30 (m, 1H), 7.00-7.17 (m, 5H),
6.87-6.91 (m, 1H), 6.45 (s, 1H), 5.50 (d, J=7.0 Hz, 1H), 5.00-5.02
(m, 1H), 3.99 (m, 1H), 2.60-2.74 (m, 1H), 2.58-2.60 (m, 1H),
2.01-2.14 (m, 6H), 1.83-1.92 (m, 4H), 1.42-1.46 (m, 3H). MS: 624.2
(M+1).sup.+.
(2S,4R)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-ox-
oethyl)-1-(4-cyanopyridin-2-yl)-4-fluoro-N-(3-fluorophenyl)-5-oxopyrrolidi-
ne-2-carboxamide (single enantiomer)--Compound 151
##STR00408##
[0479] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.75 (s, 1H),
8.57 (s, 1H), 7.76 (s, 1H), 7.36 (m, 2H), 7.06 (m, 6H), 6.39 (s,
1H), 5.51 (d, J=6.6 Hz, 1H), 5.12 (m, 1H), 4.82 (s, 1H), 3.91 (m,
1H), 2.69-2.26 (m, 2H), 2.05 (m, 6H), 1.53-1.38 (m, 2H). MS: 628.2
(M+1).sup.+.
Example 9
Preparation of
(2S)--N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-
-1-(4-cyanopyridin-2-yl)-N-(3,5-dicyanophenyl)-5-oxopyrrolidine-2-carboxam-
ide (racemic)--Compound 191
##STR00409##
[0480] Step A: 5-Nitroisophthaloyl dichloride
[0481] To a solution of 5-nitroisophthalic acid (2.3 g, 11 mmol) in
SOCl.sub.2 (6 mL) was added a drop of DMF and the mixture was
stirred at reflux for 3 hr. The resulting reaction mixture was
concentrated to give the crude product which was used directly in
the next step.
Step B: 5-Nitroisophthalamide
[0482] 5-Nitroisophthaloyl dichloride (2.7 g, 9.7 mmol) was added
portionwise to a cold solution of NH.sub.3.H.sub.2O (40 mL) at
0.degree. C. The reaction mixture was stirred overnight and a white
precipitate formed. The mixture was then filtered, washed with
excess of water, and dried at 110.degree. C. to give the crude
product which was used directly in the next step.
Step C: 5-Aminoisophthalamide
[0483] To a solution of 5-nitroisophthalamide (2 g, 9.6 mmol) in
MeOH (200 mL) was added Pd/C (200 mg). The reaction was stirred
overnight under a hydrogen atmosphere. The suspension was filtered
and the filtrate was concentrated to afford the desired product
which was used directly in the next step.
Step D:
5-((2S)--N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-
-oxoethyl)1-(4-cyano
pyridin-2-yl)-5-oxopyrrolidine-2-carboxamido)isophthalamide
[0484] A mixture of 2-chlorobenzaldehyde (1.0 mL, 7.3 mmol) and
5-aminoisophthalamide (1.3 g, 7.3 mmol) was stirred at room
temperature for 30 min under N.sub.2, followed by addition of
(S)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2-carboxylic acid (1.7
g, 7.3 mmol). After stirring for 10 min,
1,1-difluoro-3-isocyanocyclobutane (854 mg, 7.3 mmol) was added.
The mixture was then stirred overnight and filtered and purified by
a standard method to give the title product.
Step E:
(2S)--N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-ox-
oethyl)1-(4-cyano
pyridin-2-yl)-N-(3,5-dicyanophenyl)-5-oxopyrrolidine-2-carboxamide
[0485] To a mixture of
5-((2S)--N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)1-(4-cyano
pyridin-2-yl)-5-oxopyrrolidine-2-carboxamido)isophthalamide (850
mg, 1.3 mmol) in pyridine (0.62 mL, 7.8 mmol) and DCM (10 mL) was
added TFAA (0.9 mL, 6.5 mmol). The reaction solution was stirred at
room temperature overnight. The resulting mixture was concentrated
and the residue was purified by a standard method to afford the
title product. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.77 (s,
1H), 8.62-8.42 (m, 2H), 7.87 (s, 1H), 7.75 (s, 1H), 7.40 (d, J=7.8
Hz, 1H), 7.31 (d, J=4.2 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.10 (t,
J=7.3 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H), 6.47 (s, 1H), 6.11 (d, J=6.6
Hz, 1H), 4.73 (dd, J=9.4, 2.7 Hz, 1H), 4.35 (s, 1H), 3.14-2.82 (m,
3H), 2.68-2.31 (m, 3H), 2.19 (m, 1H), 2.09-1.91 (m, 1H). MS: 614.1
(M+1).sup.+.
[0486] The following analogs were synthesized via the procedure set
forth above, using the appropriate aldehyde, amine, carboxylic
acid, isocyanide and halo-substituted aromatic ring or heterocyclic
(heteroaromatic) ring using the reagents and solvents set forth
above, and purified via standard methods.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyano
pyridin-2-yl)-N-(3,5-dicyanophenyl)-5-oxopyrrolidine-2-carboxamide
(single enantiomer)--Compound 153
##STR00410##
[0488] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.74 (s, 1H),
8.53 (m, 2H), 7.81 (m, 2H), 7.48-7.16 (m, 4H), 7.09 (t, J=7.5 Hz,
1H), 6.90 (d, J=7.6 Hz, 1H), 6.46 (s, 1H), 6.17 (d, J=6.7 Hz, 1H),
4.72 (dd, J=9.1, 2.3 Hz, 1H), 4.35 (s, 1H), 3.18-2.71 (m, 3H),
2.68-1.83 (m, 5H). MS: 614.1 (M+1).sup.+.
Example 10
Preparation of (S)-tert-butyl
3-(((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(-
3,5-difluorophenyl)carbamoyl)-5-oxopiperazine-1-carboxylate (single
enantiomer)--Compound 97
[0489] Compound 97 was synthesized via the UGI reaction procedure
set forth herein, using the appropriate aldehyde, amine, carboxylic
acid, isocyanide and halo-substituted aromatic ring or heterocyclic
(heteroaromatic) ring and purified via standard methods.
##STR00411##
[0490] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.75-8.44 (m,
2H), 7.81-7.41 (m, 1H), 7.46-7.35 (m, 2H), 7.24 (t, J=7.2 Hz, 1H),
7.16-6.97 (m, 2H), 6.84-6.75 (m, 2H), 6.43-5.82 (m, 1H), 5.09-4.98
(m, 1H), 4.77-4.73 (m, 1H), 4.48 (d, J=13.5 Hz, 1H), 4.27-4.07 (m,
2H), 3.45-2.76 (m, 4H), 1.54 (s, 9H). MS: 613.2 (M+1).sup.+.
Example 11
Preparation of (3S)-tert-butyl
3-((1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(3,5--
difluorophenyl)carbamoyl)-4-(4-cyanopyrimidin-2-yl)-5-oxopiperazine-1-carb-
oxylate (racemic)--Compound 98
##STR00412##
[0492] A mixture of
(3S)-tert-butyl3-((1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-
-oxoethyl)(3,5-difluorophenyl)carbamoyl)-5-oxopiperazine-1-carboxylate
(200 mg, 0.326 mmol), 2-bromopyrimidine-4-carbonitrile (0.489
mmol), Pd.sub.2(dba).sub.3 (30.2 mg, 0.0323 mmol), XantPhos (19.1
mg, 0.03 mmol) and Cs.sub.2CO.sub.3 (148.7 mg, 0.46 mmol) in
1,4-dioxane (10 mL) was stirred at 80.degree. C. for 3 hr under
N.sub.2. The reaction mixture was cooled to room temperature and
filtered. The filtrate was concentrated and the residue was
purified by a standard method to afford the desired product.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.97 (d, J=4.3 Hz, 1H),
7.85-7.55 (d, 1H), 7.51-7.39 (m, 2H), 7.25 (t, J=7.6 Hz, 1H),
7.13-6.26 (m, 6H), 5.91 (d, J=7.6 Hz, 1H), 4.92-4.08 (m, 5H), 3.38
(t, J=14.9 Hz, 1H), 3.02 (s, 2H), 2.83-2.22 (d, 2H), 1.61 (s, 9H).
MS: 716.1 (M+1).sup.+.
[0493] The following analogs were synthesized via the procedure set
forth above, using the appropriate aldehyde, amine, carboxylic
acid, isocyanide and halo-substituted aromatic ring or heterocyclic
(heteroaromatic) ring using the reagents and solvents set forth
above, and purified via standard methods.
(S)-tert-Butyl
3-(((S)-1-(2-chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoethyl)(-
3,5-difluorophenyl)carbamoyl)-4-(4-cyanopyrimidin-2-yl)-5-oxopiperazine-1--
carboxylate (chiral)--Compound 93
##STR00413##
[0495] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.96 (d, J=4.3
Hz, 1H), 7.83 (s, 1H), 7.43 (m, 2H), 7.21 (t, J=7.4 Hz, 1H),
7.08-6.62 (m, 4H), 6.63-6.37 (m, 1H), 5.93 (m, 1H), 4.85 (t, J=3.6
Hz, 1H), 4.63-4.23 (m, 2H), 4.16 (m, 1H), 3.93 (s, 1H), 3.43 (m,
1H), 2.24-1.91 (m, 5H), 1.79 (m, 3H), 1.60 (m, 1H). MS: 744.2
(M+1).sup.+.
(3S)-tert-Butyl
3-((1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(3-fl-
uorophenyl)carbamoyl)-4-(4-cyanopyridin-2-yl)-5-oxopiperazine-1-carboxylat-
e (single enantiomer)--Compound 89
##STR00414##
[0497] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.80-8.37 (m,
1H), 8.05-7.57 (m, 1H), 7.58-7.31 (m, 3H), 7.21 (s, 1H), 7.16-6.89
(m, 3H), 6.90-6.68 (m, 1H), 6.67-6.30 (m, 1H), 6.22-5.84 (m, 1H),
5.09-4.87 (m, 1H), 5.83-4.57 (m, 1H), 4.50 (m, 1H), 4.25 (s, 1H),
4.08 (m, 1H), 3.50-2.70 (m, 4H), 2.60-2.10 (m, 1H), 1.70 (s, 2H),
1.54 (m, 1H). MS: 697.2 (M+1).sup.+.
Example 12
Preparation of
(S)--N--((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoet-
hyl)-1-(4-cyanopyrimidin-2-yl)-N-(3,5-difluorophenyl)-6-oxopiperazine-2-ca-
rboxamide (single enantiomer)--Compound 99
##STR00415##
[0499] TFA (0.3 mL) was added to a solution of (5)-tert-butyl
3-(((R)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(-
3,5-difluorophenyl)carbamoyl)-4-(4-cyanopyridin-2-yl)-5-oxopiperazine-1-ca-
rboxylate (60 mg, 0.08 mmol) in DCM (1.0 mL) at 0.degree. C. The
mixture was warmed to room temperature and stirred for 1 hr, and
then concentrated. The residue was purified by a standard method to
give the desired product. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.94 (t, J=4.6 Hz, 1H), 7.48-7.36 (m, 3H), 7.21 (m, J=7.8,
1.5 Hz, 1H), 7.12-6.94 (m, 3H), 6.71-6.55 (m, 2H), 6.05 (d, J=6.7
Hz, 1H), 4.73 (q, J=4.0, 2.1 Hz, 1H), 4.36 (d, J=6.7 Hz, 1H),
3.77-3.65 (m, 2H), 3.50-3.35 (m, 1H), 3.18 (m, 1H), 3.12-2.96 (m,
2H), 2.64-2.35 (m, 2H). MS: 616.1 (M+1).sup.+.
[0500] The following compound was synthesized via the procedure set
forth above, using the appropriate aldehyde, amine, carboxylic
acid, isocyanide and halo-substituted aromatic ring or heterocyclic
(heteroaromatic) ring using the reagents and solvents set forth
above, and purified via standard methods.
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyano
pyridin-2-yl)-N-(3,5-difluorophenyl)-6-oxopiperazine-2-carboxamide
(single enantiomer)--Compound 100
##STR00416##
[0502] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.68-8.28 (m,
1H), 7.61-7.28 (m, 2H), 7.20 (dd, J=7.9, 1.3 Hz, 0H), 7.02-6.90 (m,
1H), 6.66 (tt, J=8.6, 2.3 Hz, 1H), 6.49 (d, J=2.7 Hz, 0H), 6.09 (m,
1H), 4.90 (dd, J=3.8, 2.0 Hz, 1H), 4.42-4.16 (m, 1H), 3.71 (m, 1H),
3.50-3.23 (m, 1H), 3.18-2.78 (m, 2H), 2.63-2.13 (m, 2H). MS: 615.2
(M+1).sup.+.
Example 13
(S)-4-Acetyl-N--((S)-1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2--
oxo
ethyl)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-6-oxopiperazine-2-ca-
rboxamide (single enantiomer)--Compound 92
##STR00417##
[0504] To a solution of (3S)-tert-butyl
3-((1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)(3-fluo-
rophenyl)carbamoyl)-4-(4-cyanopyridin-2-yl)-5-oxopiperazine-1-carboxylate
(100 mg, 0.14 mmol) in DCM (3 mL) was added TFA dropwise (1 mL) at
0.degree. C. The mixture was stirred at room temperature for 2 hr
and then concentrated. The residue was dissolved in DCM and cooled
to 0.degree. C. DIPEA (0.055 mL, 0.34 mmol) was added to the
mixture followed by Ac.sub.2O (0.031 mL, 0.34 mmol) at 0.degree. C.
Then the mixture was stirred at room temperature for 2 hr. The
solution was concentrated and the residue was purified by a
standard method to afford the desired product. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 8.54 (s, 2H), 7.70-744 (m, 2H), 7.36 (m,
2H), 7.20 (t, J=7.2 Hz, 1H), 7.14-6.99 (m, 2H), 6.94 (t, J=7.4 Hz,
1H), 6.80 (s, 1H), 6.66 (d, J=7.8 Hz, 1H), 6.58-6.42 (m, 1H), 5.09
(dt, J=5.2, 3.1 Hz, 1H), 4.93 (m, 1H), 4.63 (m, 1H), 4.54-4.41 (m,
1H), 4.35-4.31 (m, 1H), 3.16 (s, 1H), 3.12-2.96 (m, 3H), 2.86 (s,
1H), 2.25 (s, 3H). MS: 639.2 (M+1).sup.+.
Example 14
Preparation of
(S)--N--((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoet-
hyl)-1-(4-cyanopyridin-2-yl)-4-cyclopropyl-N-(3,5-difluorophenyl)-6-oxopip-
erazine-2-carboxamide (single enantiomer)--Compound 106
##STR00418##
[0506] TFA (0.3 mL) was added to a solution of (S)-tert-butyl
3-(((R)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(-
3,5-difluorophenyl)carbamoyl)-4-(4-cyanopyridin-2-yl)-5-oxopiperazine-1-ca-
rboxylate (60 mg, 0.084 mmol) in DCM (1.0 mL) at 0.degree. C. The
mixture was stirred at room temperature for 1 hr then concentrated.
The residue was dissolved in MeOH (2 mL) followed by addition of
(1-ethoxycyclopropoxy)trimethylsilane (88 mg, 0.50 mmol), AcOH (50
mg, 0.84 mmol) and NaBH.sub.3(CN) (27 mg, 0.42 mmol). The resulting
suspension was stirred at 80.degree. C. under N.sub.2 for 1.5 hr.
The reaction mixture was partitioned between EtOAc and H.sub.2O.
The organic layer was separated, washed with brine, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was
purified by a standard method to afford the desired product.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.64 (d, J=7.8 Hz, 1H),
7.30 (d, J=5.3 Hz, 2H), 7.19 (s, 1H), 7.07 (s, 3H), 6.66 (s, 1H),
6.32 (s, 1H), 6.09 (m, 1H), 5.09 (s, 1H), 4.28 (s, 1H), 3.76-3.59
(m, 1H), 3.46-3.33 (m, 1H), 3.08-2.89 (m, 4H), 2.59-2.31 (m, 2H),
0.94 (s, 1H), 0.61-0.37 (m, 4H). MS: 655.2 (M+1).sup.+.
Example 15
Preparation of
(S)--N--((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoet-
hyl)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-4-methyl-6-oxopiperazi-
ne-2-carboxamide (single enantiomer)--Compound 101
##STR00419##
[0508] TFA (0.6 mL) was added to a solution of (3S)-tert-butyl
3-((1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(3,5--
difluorophenyl)carbamoyl)-4-(4-cyanopyridin-2-yl)-5-oxopiperazine-1-carbox-
ylate (30 mg, 0.042 mmol) in DCM (2 mL) at 0.degree. C. The mixture
was stirred at room temperature for 1 hr and then concentrated. The
residue was dissolved in MeCN (4 mL) followed by addition of
K.sub.2CO.sub.3 (10 mg, 0.072 mmol) and iodomethane (2 mL). The
resulting mixture was stirred at room temperature for 2 hr and then
concentrated. The residue was purified by a standard method to
afford the desired product. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.60 (m, 2H), 7.80 (s, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.33
(m, 1H), 7.07 (d, J=4.3 Hz, 2H), 6.74 (t, J=8.6 Hz, 1H), 6.48-5.91
(m, 3H), 4.92 (t, J=4.7 Hz, 1H), 4.20 (m, 1H), 3.61-3.40 (m, 1H),
3.14 (m, 1H), 3.02-2.77 (m, 3H), 2.71 (m, 1H), 2.42-2.26 (m, 5H),
2.04 (d, J=9.0 Hz, 1H). MS: 629 (M+1).sup.+.
Example 16
Preparation of
(S)--N--((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoet-
hyl)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-4-(2-hydroxyethyl)-6-o-
xopiperazine-2-carboxamide (single enantiomer)--Compound 107
##STR00420##
[0510] To a solution of (S)-tert-butyl
3-(4S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(3-
,5-difluorophenyl)carbamoyl)-4-(4-cyanopyridin-2-yl)-5-oxopiperazine-1-car-
boxylate (30 mg, 0.04 mmol) in DCM (3 mL) was added TFA (1 mL) at
0.degree. C. The mixture was stirred at room temperature for 1 hr
and concentrated in vacuo. The residue was dissolved in EtOH (3 mL)
followed by addition of TBAI (16 mg, 0.04 mmol), Et.sub.3N (10 mg,
0.1 mol) and 2-bromoethanol (7 mg, 0.056 mmol). The resulting
mixture was stirred at 85.degree. C. for 3 hr and then filtered.
The filtrate was concentrated and the residue was purified by a
standard method to afford the desired product. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 8.96 (t, J=4.6 Hz, 1H), 7.53-7.36 (m,
3H), 7.23 (m, J=7.8, 1.5 Hz, 1H), 7.14-6.94 (m, 3H), 6.68 (m,
J=8.6, 2.3 Hz, 1H), 6.60 (d, J=3.1 Hz, 1H), 6.07 (d, J=6.7 Hz, 1H),
4.75 (q, J=4.0, 2.1 Hz, 1H), 4.38 (d, J=6.7 Hz, 1H), 3.78-3.67 (m,
2H), 3.39 (m, 1H), 3.26-2.92 (m, 3H), 2.67-2.36 (m, 2H). MS: 659.2
(M+1).sup.+.
[0511] The following compound was synthesized via the procedure set
forth above, using the appropriate aldehyde, amine, carboxylic
acid, isocyanide and halo-substituted aromatic ring or heterocyclic
(heteroaromatic) ring using the reagents and solvents set forth
above, and purified via standard methods.
##STR00421##
[0512] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.60-8.56 (m,
2H), 7.47-7.28 (m, 3H), 7.22-7.01 (m, 4H), 6.72-6.67 (m, 1H),
6.54-6.44 (m, 2H), 5.24 (m, 1H), 4.37-4.13 (m, 3H), 3.63-2.97 (m,
8H), 2.44-2.06 (m, 2H), 1.34-1.28 (m, 3H). MS: 701.2
(M+1).sup.+.
Example 17
Preparation of
(S)--N--((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoet-
hyl)-1-(5-cyanooxa-zol-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-car-
boxamide (single enantiomer)--Compound 162
##STR00422##
[0513] Step A: Oxazole-5-carboxamide
[0514] Ethyl oxazole-5-carboxylate (2 g, 14.2 mmol) was dissolved
in NH.sub.3 solution (7 M in MeOH, 25 mL). The solution was stirred
at room temperature for 2 hr and filtered. The solid was dried to
give the desired product (1.5 g, 92% yield) as a white powder which
was used directly in the next step.
Step B: 2-Iodooxazole-5-carboxamide
[0515] Oxazole-5-carboxamide (560 mg, 5.0 mmol) was dissolved in
anhydrous THF (7.5 mL) and flushed with N.sub.2. The solution was
cooled to -42.degree. C. and treated with fresh LiHMDS (15 mL, 1 M
in THF). The solution became dark yellow was stirred for 20 min and
followed by the addition of a solution of ZnCl.sub.2 (30 mL, 0.5 M
in THF). The reaction was warmed to 0.degree. C. for 1 hr. After
solid iodine (1.65 g, 6.5 mmol) was added, the reaction mixture was
stirred at room temperature for another 1 hr and then poured into
saturated Na.sub.2S.sub.2O.sub.3 solution containing 25% aq.
NH.sub.3 solution. The resulting mixture was extracted with EtOAc
(3.times.30 mL). The combined organic layers were washed with
brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The
resulting residue was purified by a standard method to give the
desired product. MS: 239.0 (M+1).sup.+.
Step C:
2-((S)-2-(((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino-
)-2-oxoethyl)(3,5-difluorophenyl)carbamoyl)-5-oxopyrrolidin-1-yl)oxazole-5-
-carboxamide
[0516] The product was prepared by the general procedure for the
Buchwald reaction. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.59
(s, 1H), 7.53 (s, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.20 (t, J=7.0 Hz,
1H), 7.04 (t, J=7.6 Hz, 1H), 6.96 (d, J=7.9 Hz, 2H), 6.68 (t, J=8.7
Hz, 1H), 6.46 (s, 1H), 6.36 (d, J=6.4 Hz, 1H), 5.68 (s, 1H), 4.82
(dd, J=9.3, 2.6 Hz, 1H), 4.33 (s, 1H), 4.16-4.09 (m, 1H), 3.03-3.00
(m, 2H), 2.90-2.77 (m, 1H), 2.62-2.35 (m, 3H), 2.29-2.28 (m, 1H),
2.19-2.08 (m, 1H). MS: 608.1 (M+1).sup.+.
Step D:
(S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)--
2-oxoethyl)-1-(5-cyanooxazol-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-
-2-carboxamide
[0517]
2-((S)-2-(((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-
-2-oxoethyl)(3,5-difluoro-phenyl)carbamoyl)-5-oxopyrrolidin-1-yl)oxazole-5-
-carboxamide (100 mg, 0.16 mmol) was dissolved in DCM (3 mL) and
dry pyridine (0.8 mL). TFAA (0.1 mL) was added and the reaction
solution was stirred for 25 min at room temperature and then
concentrated in vacuo. The residue was dissolved in EtOAc and
washed with H.sub.2O, saturated aq. NaHCO.sub.3 and brine. The
organic phase was separated, dried over anhydrous Na.sub.2SO.sub.4,
and concentrated. The residue was purified by a standard method to
give the desired product. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 7.63 (s, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.41 (d, J=7.1 Hz,
1H), 7.25 (td, J=7.8, 1.5 Hz, 1H), 7.08 (t, J=7.6 Hz, 1H),
6.98-6.91 (m, 1H), 6.80 (d, J=6.7 Hz, 1H), 6.71 (dd, J=9.7, 7.4 Hz,
1H), 6.49 (s, 1H), 5.97 (d, J=6.8 Hz, 1H), 4.80 (dd, J=9.3, 2.8 Hz,
1H), 4.36 (s, 1H), 3.06-3.03 (m, 2H), 2.92-2.79 (m, 1H), 2.62-2.29
(m, 4H), 2.18-2.12 (m, 1H). MS: 590.1 (M+1).sup.+.
Example 18
Preparation of
(2S,4R)--N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-N-(3-cyano-phenyl)-1-(4-cyanopyridin-2-yl)-4-hydroxy-5-oxopyrrolidine--
2-carboxamide (racemic)--Compound 170
##STR00423##
[0518] Step A: (2S,4R)-1-tert-Butyl 2-methyl
4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate
[0519] Imidazole (2.8 g, 40.8 mmol) was added to a solution of
(2S,4R)-1-tert-butyl 2-methyl
4-hydroxypyrrolidine-1,2-dicarboxylate (5.0 g, 20.4 mmol) and TBSCl
(4.6 g, 30.6 mmol) in anhydrous DMF (100 mL). The mixture was
stirred at room temperature overnight and then partitioned between
EtOAc and H.sub.2O. The organic layer was separated, washed with
aq. LiCl (10%) and brine, dried over anhydrous Na.sub.2SO.sub.4,
and then concentrated. The residue was purified by column
chromatography to afford the desired product as a colorless oil.
MS: 360.2 (M+1).sup.+.
Step B: (2S,4R)-1-tert-Butyl 2-methyl
4-((tert-butyldimethylsilyl)oxy)-5-oxopyrrolidine-1,2-dicarboxylate
[0520] To a solution of NaIO.sub.4 (7.5 g, 35.0 mmol) in water (80
mL) was added RuO.sub.2 (370 mg, 2.8 mmol) under the atmosphere of
nitrogen. The resulting green-yellow solution was stirred for 5 min
followed by addition of
(2S,4R)-1-tert-butyl-2-methyl-4-((tert-butyldimethyl
silyl)oxy)pyrrolidine-1,2-dicarboxylate (5.0 g, 14.0 mmol) in EtOAc
(44 mL) in one portion. The mixture was stirred at room temperature
overnight. The resulting mixture was then diluted with EtOAc and
filtered through a pad of Celite. The organic layer was separated
and washed with saturated aq. NaHSO.sub.3, which resulted in
precipitation of Ru black. The organic layer was then washed with
brine and dried over anhydrous Na.sub.2SO.sub.4. Evaporation of the
solvent gave the desired product as a colorless oil. MS: 374.2
(M+1).sup.+.
Step C:
(2S,4R)-4-((tert-Butyldimethylsilyl)oxy)-5-oxopyrrolidine-2-carbox-
ylic acid
[0521] TFA (6 mL) was added to a solution of (2S,4R)-1-tert-butyl
2-methyl
4-((tert-butyldimethylsilyl)oxy)-5-oxopyrrolidine-1,2-dicarboxylate
(2.5 g, 6.68 mmol) in DCM (18 mL) at 0.degree. C. The mixture was
stirred at room temperature for 1 h then concentrated. The residue
was dissolved in MeOH/THF (10 mL/10 mL) followed by addition of a
solution of LiOH (842 mg, 20.1 mmol) in water (5 mL). The resulting
mixture was stirred at room temperature for 1 h and then
partitioned between EtOAc and H.sub.2O. The aqueous layer was
separated and then adjusted to pH=6 with 1 N HCl aq. and extracted
with EtOAc (3.times.20 mL). Combined organic layers were washed
with brine, dried over anhydrous Na.sub.2SO.sub.4, and then
concentrated to afford the desired product. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 12.87 (s, 1H), 8.17 (s, 1H), 4.21 (t, J=8.0
Hz, 1H), 4.02 (d, J=8.4 Hz, 1H), 2.39-2.23 (m, 1H), 2.09 (m, 1H),
0.84 (s, 9H), 0.07 (s, 6H). MS: 260.1 (M+1).sup.+.
Step D
[0522] The same as general procedure for UGI reaction set forth
herein.
Step E
[0523] The same as general procedure for Buchwald reaction set
forth herein.
Step F:
(2S,4R)--N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-
-oxoethyl)-N-(3-cyano-phenyl)-1-(4-cyanopyridin-2-yl)-4-hydroxy-5-oxopyrro-
lidine-2-carboxamide
[0524] TBAF in THF (1N, 0.3 mL) was added to a solution of
(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-N-(1-(2-chlorophenyl)-2-((3,3-di-
fluorocyclobutyl)amino)-2-oxoethyl)-N-(3-cyanophenyl)-1-(4-cyano
pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide (0.15 mmol) in THF at
0.degree. C. and the reaction solution was stirred at this
temperature for 20 min. The resulting mixture was concentrated and
the residue was purified by a standard method to afford the desired
product. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.82-8.43 (m,
2H), 8.40-8.17 (m, 1H), 7.63-7.30 (m, 3H), 7.26-6.66 (m, 4H),
6.68-6.34 (m, 2H), 6.65-6.31 (m, 2H), 4.87-4.56 (m, 2H), 4.23 (m,
1H), 4.01-3.76 (m, 1H), 3.15-1.96 (m, 6H). MS: 605.1
(M+1).sup.+.
[0525] The following analogs were synthesized via the procedure set
forth herein, using the appropriate aldehyde, amine, carboxylic
acid, isocyanide and halo-substituted aromatic ring or heterocyclic
(heteroaromatic) ring using the reagents and solvents set forth
herein, and purified via various standard methods.
(2S,4R)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoe-
thyl)-1-(4-cyano-pyridin-2-yl)-N-(3-fluorophenyl)-4-hydroxy-5-oxopyrrolidi-
ne-2-carboxamide (single enantiomer)--Compound 113
##STR00424##
[0527] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.70 (m, 1H),
8.53 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.32 (d, J=4.9 Hz, 2H), 7.18
(d, J=6.0 Hz, 1H), 7.09-6.85 (m, 4H), 6.43 (s, 1H), 6.20 (d, J=5.3
Hz, 1H), 4.89 (s, 1H), 4.74 (t, J=9.2 Hz, 1H), 4.37-4.32 (m, 1H),
3.40 (s, 1H), 3.11-2.87 (m, 2H), 2.77-2.14 (m, 3H), 2.03-1.91 (m,
1H). MS: 598.1 (M+1).sup.+.
(2S,4R)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-ox-
oethyl)-1-(4-cyanopyrimidin-2-yl)-N-(3-fluorophenyl)-4-hydroxy-5-oxopyrrol-
idine-2-carboxamide--Compound 120
##STR00425##
[0529] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.98 (d, J=4.4
Hz, 1H), 7.70 (s, 1H), 7.39 (d, J=4.9 Hz, 2H), 7.20-6.86 (m, 4H),
6.50 (s, 1H), 5.75 (s, 1H), 5.35 (s, 1H), 4.92-4.63 (m, 2H), 4.34
(s, 1H), 2.91 (m, 3H), 2.21 (m, 4H). MS: 599.1 (M+1).sup.+.
(2S,4R)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-ox-
oethyl)-1-(4-cyano
pyridin-2-yl)-N-(3-fluorophenyl)-4-hydroxy-5-oxopyrrolidine-2-carboxamide
(single enantiomer)--Compound 121
##STR00426##
[0531] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.78 (s, 1H),
8.54 (s, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.45-7.30 (m, 2H), 7.25-6.83
(m, 5H), 6.42 (s, 1H), 5.49 (d, J=7.4 Hz, 1H), 4.83 (m 2H), 4.00
(s, 1H), 3.02 (s, 1H), 2.74 (m, 1H), 2.25-1.74 (m, 7H), 1.56-1.33
(m, 2H). MS: 626.2 (M+1).sup.+.
(2S,4R)--N--OR)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxo-
ethyl)-1-(4-cyanopyrimidin-2-yl)-N-(3-fluorophenyl)-4-hydroxy-5-oxopyrroli-
dine-2-carboxamide (single enantiomer)--Compound 122
##STR00427##
[0533] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.00 (d, J=4.8
Hz, 1H), 7.83 (m, 1H), 7.42 (t, J=6.6 Hz, 2H), 7.22 (m, 2H),
7.18-7.08 (m, 1H), 7.08-6.67 (m, 2H), 6.17 (m, 1H), 5.70 (d, J=7.6
Hz, 1H), 4.93-4.66 (m, 2H), 3.88 (d, J=7.7 Hz, 1H), 3.37 (s, 1H),
2.71 (m, 1H), 2.03 (m, 5H), 1.88-1.64 (m, 4H). MS: 627.2
(M+1).sup.+.
(2S,4R)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-ox-
oethyl)-1-(4-cyano
pyrimidin-2-yl)-N-(3-fluorophenyl)-4-hydroxy-5-oxopyrrolidine-2-carboxami-
de--Compound 123
##STR00428##
[0535] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.99 (d, J=4.4
Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.47-7.29 (m, 3H), 7.08 (m, 6H),
6.51 (s, 1H), 5.61 (s, 1H), 4.81 (m, 2H), 4.02 (d, J=7.2 Hz, 1H),
3.38 (s, 1H), 2.89-2.65 (m, 1H), 2.23-1.81 (m, 8H), 1.58-1.48 (m,
1H). MS: 627.2 (M+1).sup.+.
(2S,4R)--N--OR)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxo-
ethyl)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-4-hydroxy-5-oxopyrro-
lidine-2-carboxamide (single enantiomer)--Compound 114
##STR00429##
[0537] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.71 (d, J=5.8
Hz, 1H), 8.64-8.50 (m, 1H), 7.94-7.56 (m, 1H), 7.47-7.31 (m, 2H),
7.29 (d, J=2.2 Hz, 1H), 7.26-7.18 (m, 1H), 7.16-6.95 (m, 2H),
6.88-6.65 (m, 1H), 6.44-6.35 (m, 1H), 6.29 (s, 1H), 6.11 (d, J=6.7
Hz, 1H), 4.77 (m, 2H), 4.40-4.08 (m, 1H), 3.27 (s, 1H), 3.09-2.58
(m, 3H), 2.54-2.12 (m, 2H), 2.10-1.95 (m, 1H). MS: 616
(M+1).sup.+.
(2S,4R)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-ox-
oethyl)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-4-hydroxy-5-oxopyrr-
olidine-2-carboxamide (single enantiomer)--Compound 115
##STR00430##
[0539] .sup.1H NMR (400 MHz, MeOD): .delta. 8.65-8.50 (m, 2H), 7.54
(d, J=9.5 Hz, 1H), 7.43-7.32 (m, 1H), 7.22-7.12 (m, 2H), 7.03 (m,
1H), 6.97-6.87 (m, 1H), 6.84-6.75 (m, 2H), 6.36 (d, J=8.5 Hz, 1H),
4.89 (d, J=8.6 Hz, 1H), 4.65-4.49 (m, 2H), 4.13 (m, 1H), 2.93-2.72
(m, 2H), 2.57-2.26 (m, 3H), 1.85 (m, 1H). MS: 616.1
(M+1).sup.+.
(2S,4R)--N--OR)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxo-
ethyl)-1-(4-cyanopyrimidin-2-yl)-N-(3,5-difluorophenyl)-4-hydroxy-5-oxopyr-
rolidine-2-carboxamide (single enantiomer)--Compound 116
##STR00431##
[0541] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.98 (t, J=5.0
Hz, 1H), 7.88 (s, 1H), 7.88 (s, 1H), 7.50-7.37 (m, 2H), 7.33-7.20
(m, 2H), 7.19-7.06 (m, 2H), 6.83-6.66 (m, 1H), 6.48 (m, 2H), 6.27
(s, 1H), 4.23 (s, 1H), 3.32 (s, 1H), 2.87 (m, 2H), 2.66 (m, 1H),
2.35-2.02 (m, 3H). MS: 617.1 (M+1).sup.+.
(2S,4R)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-ox-
oethyl)-1-(4-cyanopyrimidin-2-yl)-N-(3,5-difluorophenyl)-4-hydroxy-5-oxopy-
rrolidine-2-carboxamide--Compound 117
##STR00432##
[0543] .sup.1H NMR (400 MHz, MeOD): .delta. 8.88 (d, J=4.9 Hz, 1H),
7.56 (m, 2H), 7.34 (dd, J=8.0, 1.1 Hz, 1H), 7.16 (td, J=7.8, 1.6
Hz, 1H), 7.09-7.00 (m, 1H), 6.98-6.85 (m, 2H), 6.81 (m, 1H), 6.42
(s, 1H), 4.87 (d, J=8.8 Hz, 1H), 4.59-4.42 (m, 2H), 4.27-4.09 (m,
1H), 2.98-2.74 (m, 2H), 2.46 (m, 3H), 2.02-1.76 (m, 1H). MS: 617.1
(M+1).sup.+.
(2S,4R)--N--OR)-1-(2-Chlorophenyl)-2-(4,4-difluorocyclohexylamino)-2-oxoet-
hyl)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-4-hydroxy-5-oxopyrroli-
dine-2-carboxamide (single enantiomer)--Compound 124
##STR00433##
[0545] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.71 (s, 1H),
8.64 (d, J=5.0 Hz, 1H), 7.79 (s, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.35
(dd, J=5.0, 1.0 Hz, 1H), 7.30-7.24 (m, 1H), 7.16 (d, J=6.3 Hz, 1H),
7.14-7.05 (m, 1H), 6.79-6.68 (m, 2H), 6.27 (s, 1H), 5.87 (d, J=7.5
Hz, 1H), 4.82 (t, J=6.9 Hz, 1H), 4.74 (t, J=9.2 Hz, 1H), 3.90-3.71
(m, 1H), 3.27 (s, 1H), 2.65 (m, 1H), 2.15-1.72 (m, 8H), 1.57-1.43
(m, 1H). MS: 644.2 (M+1).sup.+.
(2S,4R)--N--((S)-1-(2-Chlorophenyl)-2-(4,4-difluorocyclohexylamino)-2-oxoe-
thyl)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-4-hydroxy-5-oxopyrrol-
idine-2-carboxamide (single enantiomer)--Compound 125
##STR00434##
[0547] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.83-8.47 (m,
2H), 7.62 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.32 (d, J=5.0
Hz, 1H), 7.21 (t, J=7.1 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 6.98 (d,
J=7.7 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H), 6.68 (t, J=8.6 Hz, 1H), 6.40
(s, 1H), 5.62 (d, J=7.7 Hz, 1H), 4.96-4.70 (m, 2H), 4.01 (d, J=7.6
Hz, 1H), 3.37 (s, 1H), 2.70 (m, 1H), 2.14-1.74 (m, 8H), 155-1.41
(m, 1H). MS: 644.2 (M+1).sup.+.
(2S,4R)--N--OR)-1-(2-Chlorophenyl)-2-(4,4-difluorocyclohexylamino)-2-oxoet-
hyl)-1-(4-cyanopyrimidin-2-yl)-N-(3,5-difluorophenyl)-4-hydroxy-5-oxopyrro-
lidine-2-carboxamide (single enantiomer)--Compound 126
##STR00435##
[0549] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.98 (dd, J=4.7,
2.1 Hz, 1H), 7.63 (d, J=7.3 Hz, 1H), 7.50-7.33 (m, 2H), 7.28-6.87
(m, 3H), 6.84-6.38 (m, 2H), 6.19 (s, 1H), 5.82 (d, J=7.6 Hz, 1H),
4.94-4.65 (m, 2H), 3.86 (d, J=7.5 Hz, 1H), 3.57-3.49 (m, 1H), 2.68
(m, 1H), 2.16-1.86 (m, 6H), 1.81-1.77 (m, 2H). MS: 645.2
(M+1).sup.+.
(2S,4R)--N--((S)-1-(2-Chlorophenyl)-2-(4,4-difluorocyclohexylamino)-2-oxoe-
thyl)-1-(4-cyanopyrimidin-2-yl)-N-(3,5-difluorophenyl)-4-hydroxy-5-oxopyrr-
olidine-2-carboxamide (single enantiomer)--Compound 127
##STR00436##
[0551] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.99 (d, J=4.8
Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.49-7.35 (m, 2H), 7.22 (td,
J=7.8, 1.5 Hz, 1H), 7.07 (t, J=7.1 Hz, 1H), 6.98 (dd, J=7.8, 1.3
Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.72 (tt, J=8.6, 2.2 Hz, 1H), 6.48
(s, 1H), 5.64 (d, J=7.7 Hz, 1H), 4.94-4.69 (m, 2H), 4.11-3.91 (m,
1H), 3.46 (s, 1H), 2.79 (m, 1H), 2.19-1.85 (m, 7H), 1.61-1.40 (m,
2H). MS: 645.2 (M+1).sup.+.
(2S,4R)--N-(1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-
-N-(3-cyano-5-fluorophenyl)-1-(4-cyanopyridin-2-yl)-4-hydroxy-5-oxopyrroli-
dine-2-carboxamide (racemic)--Compound 169
##STR00437##
[0553] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.87-8.72 (m,
1H), 8.67-8.48 (m, 1H), 8.26-8.01 (m, 1H), 7.56-7.30 (m, 4H),
7.27-7.17 (m, 1H), 7.10 (m, 1H), 6.95 (t, J=7.3 Hz, 1H), 6.52-6.28
(m, 1H), 6.21-5.95 (m, 1H), 4.88-4.64 (m, 2H), 4.30 (m, 1H),
3.21-2.81 (m, 3H), 2.74-2.19 (m, 3H), 2.13-1.91 (m, 1H). MS: 623.1
(M+1).sup.+.
(2S,4S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoe-
thyl)-1-(4-cyano-pyri-din-2-yl)-N-(3-fluorophenyl)-4-hydroxy-5-oxopyrrolid-
ine-2-carboxamide (single enantiomer)--Compound 118
##STR00438##
[0555] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.97 (d, J=4.7
Hz, 1H), 7.81-7.62 (m, 2H), 7.41-7.35 (m, 2H), 7.26-6.96 (m, 5H),
6.46 (d, J=12.0 Hz, 1H), 4.81-4.75 (m, 1H), 4.37-4.28 (m, 1H),
4.25-4.15 (m, 1H), 2.91 (s, 2H), 2.60-2.37 (m, 3H), 2.00-1.87 (m,
1H). MS: 598.1 (M+1).sup.+.
(2S,4S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoe-
thyl)-1-(4-cyano-pyrimidin-2-yl)-N-(3-fluorophenyl)-4-hydroxy-5-oxopyrroli-
dine-2-carboxamide (single enantiomer)--Compound 119
##STR00439##
[0557] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.97 (d, J=4.7
Hz, 1H), 7.81-7.62 (m, 2H), 7.41-7.35 (m, 2H), 7.26-6.96 (m, 5H),
6.46 (d, J=12.0 Hz, 1H), 4.81-4.75 (m, 1H), 4.37-4.28 (m, 1H),
4.25-4.15 (m, 1H), 2.91 (s, 2H), 2.60-2.37 (m, 3H), 2.00-1.87 (m,
1H). MS: 599.1 (M+1).sup.+.
(2S,4S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-ox-
oethyl)-1-(4-cyano-pyridin-2-yl)-N-(3-fluorophenyl)-4-hydroxy-5-oxopyrroli-
dine-2-carboxamide (single enantiomer)--Compound 172
##STR00440##
[0559] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.87-8.57 (m,
2H), 7.96 (s, 1H), 7.50-7.30 (m, 3H), 7.26-7.12 (m, 2H), 7.09-6.96
(m, 2H), 6.28 (s, 1H), 5.67 (d, J=7.6 Hz, 1H), 4.74 (dd, J=8.1, 4.6
Hz, 1H), 4.42-4.36 (m, 1H), 4.04 (s, 1H), 3.87 (d, J=7.8 Hz, 1H),
2.54-2.41 (m, 1H), 2.22-1.76 (m, 8H), 1.50-1.32 (m, 2H). MS: 626.2
(M+1).sup.+.
(2S,4S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-ox-
oethyl)-1-(4-cyanopyrimidin-2-yl)-N-(3-fluorophenyl)-4-hydroxy-5-oxopyrrol-
idine-2-carboxamide (single enantiomer)--Compound 189
##STR00441##
[0561] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.00 (d, J=4.7
Hz, 1H), 7.76 (s, 1H), 7.47-7.30 (m, 2H), 7.24-6.88 (m, 6H), 6.47
(d, J=6.7 Hz, 1H), 5.54 (s, 1H), 4.74 (s, 1H), 4.35 (s, 1H), 3.99
(s, 1H), 3.72 (d, J=34.8 Hz, 1H), 2.58-2.18 (m, 2H), 1.88 (m, 4H),
1.56-1.42 (m, 2H). MS: 627.2 (M+1).sup.+.
(2S,4S)--N--((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-ox-
oethyl)-1-(4-cyano-pyridin-2-yl)-N-(3,5-difluorophenyl)-4-hydroxy-5-oxopyr-
rolidine-2-carboxamide (single enantiomer)--Compound 171
##STR00442##
[0563] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.68 (s, 1H),
8.52 (d, J=5.0 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.45-7.17 (m, 4H),
7.15-6.91 (m, 2H), 6.84 (d, J=8.7 Hz, 1H), 6.69 (t, J=8.7 Hz, 1H),
6.54-6.36 (m, 2H), 4.87-4.60 (m, 1H), 4.31 (m, 2H), 3.99-3.77 (m,
1H), 3.15-2.78 (m, 2H), 2.62-2.26 (m, 3H), 2.26-2.08 (m, 1H). MS:
616.1 (M+1).sup.+.
(2S,4S)--N--((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-ox-
oethyl)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-4-hydroxy-5-oxopyrr-
olidine-2-carboxamide (single enantiomer)--Compound 174
##STR00443##
[0565] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.75 (s, 1H),
8.53 (d, J=4.5 Hz, 1H), 7.62 (s, 1H), 7.44-7.18 (m, 3H), 7.09-6.96
(m, 2H), 6.86 (s, 1H), 6.71 (t, J=8.7 Hz, 1H), 6.38 (s, 1H), 5.58
(d, J=7.6 Hz, 1H), 4.80 (dd, J=8.0, 5.2 Hz, 1H), 4.37 (d, J=5.6 Hz,
1H), 3.96 (s, 1H), 3.61 (d, J=7.7 Hz, 1H), 2.62-2.29 (m, 1H), 2.13
(m, 6H), 1.48 (m, 2H). MS: 644.2 (M+1).sup.+.
Example 19
Preparation of
(2S)--N--OR)-1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethy-
l)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-4-hydroxy-4-methyl-5-oxopyrr-
olidine-2-carboxamide (single enantiomer)--Compound 183
##STR00444##
[0566] Step A. (2S)-1-tert-Butyl 2-methyl
4-(tert-butyldimethylsilyloxy)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylat-
e
[0567] LiHMDS (1 M in THF, 22.6 mL, 22.6 mmol) was added into a
mixture of (2S,4R)-1-tert-butyl 2-methyl
4-(tert-butyldimethylsilyloxy)-5-oxopyrrolidine-1,2-dicar-boxylate
(6.5 g, 17.4 mmol) in THF (60 mL) at -78.degree. C. under N.sub.2.
The mixture was stirred at -78.degree. C. for 1 hr. A solution of
iodomethane (2.7 g, 19.1 mmol) in THF (10 mL) was added dropwise to
the above mixture over 30 min. Then the solution was stirred at
-78.degree. C. for another 25 min. The resulting mixture was
allowed to warm to room temperature and stirred overnight. The
mixture was quenched with NH.sub.4Cl and extracted by ethyl acetate
(60 mL.times.3). The combined organic layers were dried and
concentrated. The residue was purified by column chromatography to
give the desired product. MS: 388 (M+1).sup.+.
Step B. (2S,4S)-Methyl
4-((tert-butyldimethylsilyl)oxy)-5-oxopyrrolidine-2-carboxylate
[0568] A solution of (2S)-1-tert-butyl 2-methyl
4-(tert-butyldimethylsilyloxy)-4-methyl-5-oxopyrroli-dine-1,2-dicarboxyla-
te (960 mg, 25 mmol) in TFA/DCM (V:V=1:3) was stirred at room
temperature for 1 h. The mixture was then concentrated to give the
desired product which was used directly in the next step. MS: 288
(M+1).sup.+.
Step C.
(2S)-4-(tert-Butyldimethylsilyloxy)-4-methyl-5-oxopyrrolidine-2-ca-
rboxylic acid
[0569] To a solution of (2S)-methyl
4-(tert-butyldimethylsilyloxy)-4-methyl-5-oxopyrrolidine-2-carbo-xylate
(400 mg, 1.4 mmol) in MeOH/THF/H.sub.2O (V:V:V=2:2:1) was added
LiOH (50 mg, 2.1 mmol). The mixture was stirred at room temperature
for 1 hr and then concentrated. The residue was partitioned between
ethyl acetate and water. The aqueous phase was separated and
adjusted to pH=3-4 with 1N HCl solution. The aqueous layer was then
extracted with ethyl acetate (2.times.20 mL). The combined organic
layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated
to give the desired product. MS: 274 (M+1).sup.+.
Step D.
(2S)-4-(tert-Butyldimethylsilyloxy)-N-(1-(2-chlorophenyl)-2-(3,3-d-
ifluorocyclobut-ylamino)-2-oxoethyl)-N-(3-fluorophenyl)-4-methyl-5-oxopyrr-
olidine-2-carboxamide
[0570] A solution of 3-fluoroaniline (83 mg, 0.75 mmol) and
2-chlorobenzaldehyde (105 mg, 0.75 mmol) in MeOH (5 mL) was stirred
for 30 min at room temperature, followed by addition of
(2S)-4-(tert-butyldimethylsilyloxy)-4-methyl-5-oxopyrrolidine-2-carboxyli-
c acid (205 mg, 0.75 mmol). The resulting mixture was stirred for
10 min and followed by the addition of
1,1-difluoro-3-isocyanocyclobutane (105 mg, 0.9 mmol). The mixture
was stirred at room temperature overnight and concentrated, and
then the residue was purified by a standard method to give the
desired product. MS: 624 (M+1).sup.+.
Step E.
(2S)-4-(tert-Butyldimethylsilyloxy)-N-(1-(2-chlorophenyl)-2-(3,3-d-
ifluorocyclobutyl-amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(3-fluoroph-
enyl)-4-methyl-5-oxopyrrolidine-2-carboxamide
[0571] A mixture consisting of
(2S)-4-(tert-butyldimethylsilyloxy)-N-(1-(2-chlorophenyl)-2-(3,3-difluoro-
cyclobutylamino)-2-oxoethyl)-N-(3-fluorophenyl)-4-methyl-5-oxopyrrolidine--
2-carboxamide (200 mg, 0.32 mmol), 2-bromoisonicotinonitrile (88
mg, 0.48 mmol), Cs.sub.2CO.sub.3 (146 mg, 0.45 mmol),
Pd.sub.2(dba).sub.3 (29 mg, 0.032 mmol), Xant-Phos (19 mg, 0.032
mmol) and 1,4-dioxane (5 mL) was stirred under N.sub.2 at
80.degree. C. overnight. After filtration, the filtrate was
concentrated in vacuo and the residue was purified by a standard
method to give desired product. MS: 726 (M+1).sup.+.
Step F.
(2S)--N--((R)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-
-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-4-hydroxy-4-methyl-5-
-oxopyrrolidine-2-carboxamide
[0572] To a solution of
(2S)-4-(tert-butyldimethylsilyloxy)-N-(1-(2-chlorophenyl)-2-(3,3-difluoro-
cyclobutylamino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-4--
methyl-5-oxopyrrolidine-2-carboxamide (50 mg, 0.07 mmol) in THF (2
mL) was added TBAF (36 mg, 0.14 mmol) at 0.degree. C. The solution
was stirred at 0.degree. C. for 30 min and then partitioned between
water and EtOAc. Combined organic layers were separated, dried, and
concentrated in vacuo. The resulting residue was purified by a
standard method to give the desired product. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.57 (d, J=5.0 Hz, 1H), 8.48 (d, J=3.8 Hz,
1H), 7.54-7.17 (m, 5H), 6.98-6.84 (m, 3H), 6.67 (dd, J=8.6 Hz, 1H),
6.33 (d, J=5.2 Hz, 1H), 6.08-6.01 (m, 1H), 4.55-4.48 (m, 1H), 4.29
(s, 1H), 3.22-2.35 (m, 6H), 1.93-1.80 (m, 1H), 1.27 (s, 3H). MS:
612.2 (M+1).sup.+.
Example 20
Preparation of
(2S)--N-(1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxo-ethyl)--
1-(4-cyanopyridin-2-yl)-N-(3-fluoro-5-sulfamoylphenyl)-5-oxopyrrolidine-2--
carboxamide (racemic)--Compound 158
##STR00445## ##STR00446##
[0573] Step A. Benzyl(3-fluoro-5-nitrophenyl)sulfane
[0574] To a solution of 1,3-difluoro-5-nitrobenzene (15.9 g, 100
mmol) in DMF (160 mL) was added K.sub.2CO.sub.3 (15.8 g, 110 mmol)
and phenylmethanethiol (12.4 g, 100 mmol) at 0.degree. C. The
reaction was stirred at room temperature for 2 hr and then quenched
with H.sub.2O. The resulting mixture extracted with EtOAc
(3.times.100 mL). The combined organic layers were dried over
anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to afford the
crude product as a yellow oil which was used in the next step
without further purification.
Step B. 3-Fluoro-5-nitrobenzene-1-sulfonyl chloride
[0575] To a solution of benzyl(3-fluoro-5-nitrophenyl)sulfane (3.0
g) in DCM (30 mL) was added deionized water (30 mL). Then chlorine
was bubbled slowly into the mixture until the complete consumption
of the starting material was observed (monitored by TLC). The
organic layer was separated, washed with sat. aq.
Na.sub.2S.sub.2O.sub.3 solution, dried and concentrated to afford
the crude product which was used in the next step without further
purification.
Step C. N-tert-butyl-3-fluoro-5-nitrobenzenesulfonamide
[0576] To a solution of 3-fluoro-5-nitrobenzene-1-sulfonyl chloride
in dry dioxane (30 mL) was slowly added tert-butylamine (10 mL) at
0.degree. C. The reaction was allowed to warm to room temperature
and stirred for 2 hr. The mixture was then concentrated and the
residue was purified by column chromatography to afford the desired
product. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.43 (s, 1H),
8.40-8.32 (m, 1H), 8.10-8.05 (m, 1H), 7.99 (s, 1H), 1.12 (s,
9H).
Step D. 3-Amino-N-tert-butyl-5-fluorobenzenesulfonamide
[0577] N-tert-butyl-3-fluoro-5-nitro-benzenesulfonamide (1.0 g, 3.6
mmol), iron powder (1.0 g, 18 mmol) and NH.sub.4Cl (1.0 g, 18 mmol)
were mixed in EtOH (95%, 10 mL). The mixture was refluxed for 16 hr
then filtered. The filtrate was concentrated and the residue was
purified by a standard method to afford the desired product.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.45 (s, 1H),
6.88-6.85 (m, 1H), 6.66-6.62 (m, 1H), 6.48-6.42 (m, 1H), 5.89 (s,
2H), 1.11 (s, 9H).
Step E
[0578] The same as general procedures for UGI reaction set forth
herein.
Step F.
[0579] The same as general procedures for Buchwald reaction set
forth herein.
Step G.
(S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2--
oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(3-fluoro-5-sulfamoylphenyl)-5-oxopyrr-
olidine-2-carboxamide
[0580] To a solution of
(2S)--N-(3-(N-tert-butylsulfamoyl)-5-fluorophenyl)-N-(1-(2-chlorophenyl)--
2-(3,3-difluorocyclo-butylamino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-5-oxo-
pyrrolidine-2-carboxamide (80 mg, 0.11 mmol) in DCM (1 mL) was
added TFA (1 mL). The reaction was stirred at room temperature for
16 hr and neutralized with saturated aq. NaHCO.sub.3. The mixture
was then extracted with EtOAc (3.times.10 mL). The combined organic
layers were dried and concentrated. The residue was purified by a
standard method to afford the target compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 8.90-8.84 (m, 1H), 8.67-8.62 (m, 1H),
8.55 (s, 1H), 8.19 (s, 1H), 7.87-7.76 (m, 1H), 7.65-7.60 (m, 2H),
7.45-7.40 (m, 3H), 7.21 (d, J=7.0 Hz, 2H), 7.11-7.04 (m, 1H),
6.93-6.86 (m, 1H), 6.33-6.26 (m, 1H), 4.83 (m, 1H), 4.13 (s, 1H),
2.94 (m, 2H), 2.63-2.53 (m, 3H), 2.42-2.32 (m, 1H), 1.97 (s, 2H).
MS: 661 (M+1).sup.+.
Example 21
Preparation of
(2S)--N-(1H-benzo[d]imidazol-7-yl)-N-(1-(2-chlorophenyl)-2-((4,4-difluoro-
cyclohexyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2-c-
arboxamide (racemic)--Compound 141
##STR00447##
[0581] Step A: 7-Nitro-1H-benzo[d]imidazole
[0582] A solution of 3-nitrobenzene-1,2-diamine (900 mg, 5.88 mmol)
in AcOH (12 mL) was stirred at 100.degree. C. overnight. The
mixture was neutralized with aq. NaHCO.sub.3 to pH=8 at 0.degree.
C. and the precipitate was collected by filtration. The precipitate
was dried in vacuo to afford the desired product.
Step B:
7-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole
[0583] NaH (331 mg, 8.28 mmol) was added to a solution of
7-nitro-1H-benzo[d]imidazole (900 mg, 5.52 mmol) in DMF (7 mL) at
0.degree. C. under N.sub.2. After stirring at 0.degree. C. for 1
hr, SEMCl (1.38 g, 8.28 mmol) was added and the resulting mixture
was stirred at room temperature for 2 hr. The reaction mixture was
quenched with H.sub.2O and extracted with EtOAc (3.times.30 mL).
The combined organic layers were washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, and concentrated. The residue was
purified by column chromatography to afford the desired product as
a yellow oil.
Step C:
1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-7-amine
[0584] To a solution of
7-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole
(600 mg, 2.05 mmol) in EtOH/EtOAc (10 mL/2 mL) was added Pd/C (60
mg). After stirring under a hydrogen atmosphere at room temperature
overnight, the reaction mixture was filtered and the filtrate was
concentrated. The residue was purified by a standard method to
afford the desired product.
Step D
[0585] The same as general procedure for UGI reaction set forth
herein.
Step E:
(2S)--N-(1H-Benzo[d]imidazol-7-yl)-N-(1-(2-chlorophenyl)-2-((4,4-d-
ifluorocyclohexyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolid-
ine-2-carboxamide
[0586] TBAF (1 M in THF, 3 mL) was added to a solution of
(2S)--N-(1-(2-chlorophenyl)-2-((4,4-difluoro-cyclohexyl)amino)-2-oxoethyl-
)-1-(4-cyanopyridin-2-yl)-5-oxo-N-(1-((2-(trimethylsilyl)ethoxy)-methyl)-1-
H-benzo[d]imidazol-7-yl)pyrrolidine-2-carboxamide in THF (0.5 mL)
at 0.degree. C. under N.sub.2. After stirring at room temperature
for 7 hr, the reaction was quenched with water at 0.degree. C. The
resulting mixture was extracted with EtOAc (3.times.10 mL). The
combined organic layers were washed with brine, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting residue
was purified by a standard method to afford the desired product.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 13.08 (s, 1H), 8.92-8.39
(m, 2H), 8.19 (m, 1H), 7.82 (m, 1H), 7.51-7.31 (m, 2H), 7.25 (d,
J=5.2 Hz, 1H), 7.13-6.70 (m, 3H), 6.41 (m, 1H), 6.20-5.29 (m, 1H),
4.85 (m, 1H), 3.86 (s, 1H), 2.97-2.39 (m, 2H), 2.36-1.70 (m, 9H),
1.40 (m, 2H). MS: 632.2 (M+1).sup.+.
Example 22
Preparation of
(4S)--N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-
-3-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-1-methyl-2-oxoimidazolidine-4--
carboxamide (racemic)--Compound 79
##STR00448##
[0587] Step A:
(S)-3-(Benzyloxycarbonyl)-2-oxoimidazolidine-4-carbo-xylic acid
[0588] To a solution of 6.6 g of sodium hydroxide in 140 mL of
water at 0.degree. C., 8.8 g of bromine was added dropwise,
followed by addition of
(S)-4-amino-2-(benzyloxycarbonylamino)-4-oxobutanoic acid (13.4 g,
50 mmol) portionwise over 3 min. The resulting yellow solution was
heated to 50.degree. C. for 1 hr and then cooled to room
temperature. After addition of sodium thiosulfate (2.0 g), the
reaction mixture was washed with ether (2.times.30 mL). The aqueous
layer was acidified to pH 1-2 with 6 N HCl. After the precipitate
was formed, the suspension was filtered. The sticky material was
collected and re-crystallized in MeOH to afford the desired product
as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
13.29 (s, 1H), 7.57 (s, 1H), 7.40-7.27 (m, 4H), 5.27-5.04 (m, 2H),
4.66 (dd, J=10.2, 3.2 Hz, 1H), 3.63 (t, J=10.0 Hz, 1H), 3.20 (dd,
J=9.7, 3.2 Hz, 1H).
Step B: (S)-Dibenzyl 2-oxoimidazolidine-1,5-dicarboxylate
[0589] To a 500 mL-flask were added
(S)-3-(benzyloxycarbonyl)-2-oxoimidazolidine-4-carboxylic acid (5.3
g, 20 mmol), BnBr (2.8 mL, 23 mmol), K.sub.2CO.sub.3 (8.28 g, 60
mmol), and acetonitrile (250 mL). The reaction solution was heated
to reflux for 6 hr, cooled and then filtered. The filtrate was
concentrated in vacuo and the residue was purified by column
chromatography to afford the desired product as white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.41-7.25 (m, 10H), 6.36
(s, 1H), 5.30-5.05 (m, 4H), 4.80 (dd, J=10.2, 3.6 Hz, 1H), 3.74 (t,
J=10.0 Hz, 1H), 3.41 (dd, J=9.7, 3.7 Hz, 1H).
Step C: (S)-Dibenzyl
3-methyl-2-oxoimidazolidine-1,5-dicarboxylate
[0590] To a dry 100 mL-flask were added (S)-dibenzyl
2-oxoimidazolidine-1,5-dicarboxylate (1.5 g, 4.24 mmol),
K.sub.2CO.sub.3 (1.17 g, 8.47 mmol), MeI (5.2 mL, 84.7 mmol), and
acetone (50 mL). The reaction solution was heated to reflux and
stirred overnight. The resulting reaction mixture was cooled and
filtered. The filtrate was concentrated in vacuo and the residue
was purified by column chromatography to afford the desired product
as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.40-7.26 (m, 10H), 5.27-5.07 (m, 4H), 4.70 (dd, J=10.2, 3.8 Hz,
1H), 3.63 (dd, J=10.1, 9.7 Hz, 1H), 3.31 (dd, J=9.6, 3.8 Hz, 1H),
2.84 (s, 3H). MS: 369 (M+1).sup.+.
Step D: (S)-1-Methyl-2-oxoimidazolidine-4-carboxylic acid
[0591] To a dry 50 mL-flask were added (S)-dibenzyl
2-oxoimidazolidine-1,5-dicarboxylate (0.5 g, 1.36 mmol), Pd/C (10%,
100 mg) and MeOH (15 mL). The suspension was stirred overnight at
room temperature under a hydrogen atmosphere. The resulting
reaction mixture was filtered. The filtrate was concentrated in
vacuo to afford the desired product as an off-white solid. .sup.1H
NMR (400 MHz, CD.sub.3OD): .delta. 4.21 (dd, J=9.9, 4.8 Hz, 1H),
3.70 (t, J=9.6 Hz, 1H), 3.55 (dd, J=9.3, 4.8 Hz, 1H), 2.74 (s, 3H).
MS: 145 (M+1).sup.+.
Step E:
(4S)--N-(1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoe-
thyl)-N-(3-fluoro-phenyl)-1-methyl-2-oxoimidazolidine-4-carboxamide
[0592] A mixture of 2-chlorobenzaldehyde (165 mg, 1.18 mmol) and
3-fluorobenzenamine (131 mg, 1.18 mmol) in MeOH (3 mL) was stirred
at room temperature for 30 min. Then
(S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid (170 mg, 1.18
mmol) was added and the reaction mixture was stirred for another 15
min, followed by addition of 1,1-difluoro-3-isocyanocyclobutane
(138 mg, 1.18 mmol). The reaction mixture was stirred overnight and
concentrated in vacuo. The residue was purified by a standard
method to give the desired product. MS: 495 (M+1).sup.+.
Step F
[0593] The same as the Buchwald reaction procedure set forth
herein. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.64-8.34 (m,
2H), 7.94-7.59 (m, 1H), 7.50-6.61 (m, 8H), 6.34-6.07 (m, 1H),
4.94-4.67 (m, 1H), 4.3-4.2 (m, 1H), 3.49 (m, 1H), 3.46-3.22 (m,
1H), 3.02-2.83 (m, 2H), 2.87 (s, 3H), 2.5-2.2 (m, 2H). MS: 597
(M+1).sup.+.
Example 23
Preparation of
(S)--N--((S)-1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethy-
l)-3-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-2-oxoimidazolidine-4-carboxa-
mide (single enantiomer)--Compound 80
##STR00449##
[0594] Step A: (S)-3,4-Dibenzyl 1-tert-butyl
2-oxoimidazolidine-1,3,4-tricarboxylate
[0595] To a 25 mL-flask were added (S)-dibenzyl
2-oxoimidazolidine-1,5-dicarboxylate (40 mg, 0.11 mmol),
(BOC).sub.2O (26 mg, 0.12 mmol), TEtOAc (0.06 mL, 0.3 mmol), DMAP
(cat.) and CH.sub.2Cl.sub.2 (2 mL). The mixture was stirred
overnight. The solvent was then removed in vacuo and the residue
was purified by column chromatography to give the desired product.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.39-7.27 (m, 10H), 5.24
(s, 2H), 5.16 (s, 2H), 4.67 (dd, J=10.2, 3.5 Hz, 1H), 3.94 (dd,
J=11.1, 10.3 Hz, 1H), 3.74 (dd, J=11.2, 3.5 Hz, 1H), 1.51 (s,
9H).
Step B: (S)-1-(tent-Butoxycarbonyl)-2-oxoimidazolidine-4-carboxylic
acid
[0596] To a dry 50 mL-flask were added (S)-3,4-dibenzyl
1-tert-butyl 2-oxoimidazolidine-1,3,4-tricarboxylate (1.24 g, 2.73
mmol), Pd/C (10%, 200 mg) and MeOH (30 mL). The suspension was
stirred overnight at room temperature under a hydrogen atmosphere.
The reaction mixture was filtered, and the filtrate was
concentrated in vacuo to afford the desired product. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 6.06 (s, 2H), 4.31 (s, 1H),
4.25-3.94 (m, 2H), 1.52 (s, 9H).
Step C: (4S)-tert-Butyl
4-((1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)(3-fluo-
rophenyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate
[0597] A mixture of 2-chlorobenzaldehyde (122 mg, 0.87 mmol) and
3-fluorobenzenamine (97 mg, 0.87 mmol) in MeOH (2 mL) was stirred
at room temperature for 30 min. Then
(S)-1-(tert-butoxycarbonyl)-2-oxoimidazolidine-4-carboxylic acid
(200 mg, 0.87 mmol) was added and the reaction mixture was stirred
for another 15 min followed by addition of
1,1-difluoro-3-isocyanocyclobutane (102 mg, 0.87 mmol). The
reaction mixture was further stirred at room temperature overnight
and then concentrated in vacuo. The residue was purified by a
standard method to give the desired product. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.46-6.59 (m, 8H), 6.45 (s, 1H), 4.41-4.04 (m,
2H), 4.01-3.78 (m, 1H), 3.64-3.30 (m, 1H), 2.92 (m, 2H), 2.71-2.27
(m, 2H), 1.46 (s, 9H). MS: 581 (M+1).sup.+.
Step D: (4S)-tert-Butyl
4-((1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)(3-fluo-
rophenyl)carbamoyl)-3-(4-cyanopyridin-2-yl)-2-oxoimidazolidine-1-carboxyla-
te
[0598] To a 25 mL flask charged with 1,4-dioxane (4.5 mL) were
added (4S)-tert-butyl 4-((1-(2-chlorophenyl)-2-(3,3-difluoro cyclo
butylamino)-2-oxoethyl)(3-fluoro-phenyl)carbamoyl)-2-oxoimidazolidine-1-c-
arboxylate (250 mg, 0.43 mmol), 2-bromoisonicotinonitrile (122 mg,
0.65 mmol), Cs.sub.2CO.sub.3 (281 mg, 0.862 mmol), Xant-Phos (25
mg, 0.043 mmol) and Pd.sub.2(dba).sub.3 (40 mg, 0.043 mmol). The
mixture was degassed and refilled with nitrogen, and then heated to
100.degree. C. for 3 hr. The resulting mixture was cooled and
filtered. The filtrate was concentrated in vacuo and the residue
was purified by a standard method to give both epimers. The epimers
were further separated by a standard method to give the desired
product. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.58 (s, 1H),
8.48 (t, J=5.9 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.37-7.16 (m, 4H),
7.15-6.76 (m, 4H), 6.56-6.31 (m, 2H), 4.95-4.75 (m, 1H), 4.31 (s,
1H), 3.86 (dd, J=10.8, 5.1 Hz, 1H), 3.66 (m, 1H), 2.99 (m, 2H),
2.61-2.27 (m, 2H), 1.56 (s, 9H). MS: 683 (M+1).sup.+.
Step E: (S)--N--((S)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclo
butylamino)-2-oxoethyl)-3-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-2-oxoi-
midazolidine-4-carboxamide
[0599] To a solution of 2N HCl/MeOH (2 mL) at 0.degree. C. was
added 50 mg of
(S)-tert-butyl-4-(((S)-1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylami-
no)-2-oxoethyl)(3-fluorophenyl)carbamoyl)-3-(4-cyanopyridin-2-yl)-2-oxoimi-
dazolidine-1-carboxylate. The reaction mixture was warmed to room
temperature and stirred for 5 hr. The solvent was removed in vacuo
and the residue was purified by a standard method to give the
desired product. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.50
(d, J=4.5 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.50-6.81 (m, 8H), 6.47
(d, J=11.6 Hz, 1H), 5.04-4.92 (m, 1H), 4.22 (m, 1H), 3.59-3.46 (m,
1H), 3.39 (dd, J=9.9, 4.5 Hz, 1H), 2.91 (m, 2H), 2.63-2.36 (m, 2H).
MS: 583 (M+1).sup.+.
Example 24
Preparation of
(4S)--N-(1-(2-chlorophenyl)-2-(3,3-difluorocyclobutyl-amino)-2-oxoethyl)--
3-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-1-(2-hydroxyeth-yl)-2-oxoimidaz-
oli-dine-4-carboxamide (racemic)
##STR00450##
[0600] Step A: (S)-Dibenzyl
3-(2-ethoxy-2-oxoethyl)-2-oxoimidazolidine-1,5-dicarboxylate
[0601] To a dry 50 mL-flask charged with DME (5 mL) were added
(S)-dibenzyl 2-oxoimidazolidine-1,5-dicarboxylate (200 mg, 0.56
mmol), K.sub.2CO.sub.3 (156 mg, 1.13 mmol), and ethyl
2-bromoacetate (0.13 mL, 1.13 mmol). The mixture was heated to
reflux for 3 hr. The reaction mixture was cooled and filtered. The
filtrate was concentrated in vacuo and the residue was purified by
column chromatography to afford the desired product as a colorless
oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.45-7.25 (m, 10H),
5.41-5.05 (m, 4H), 4.80 (dd, J=10.2, 3.5 Hz, 2H), 4.29-4.08 (m,
3H), 3.90 (dd, J=12.2, 7.2 Hz, 2H), 3.45 (dd, J=9.2, 3.5 Hz, 1H),
1.28 (td, J=7.1, 2.1 Hz, 3H).
Step B: (S)-1-(2-Ethoxy-2-oxoethyl)-2-oxoimidazolidine-4-carboxylic
acid
[0602] To a dry 50 mL-flask were added (S)-dibenzyl
3-(2-ethoxy-2-oxoethyl)-2-oxoimidazolidine-1,5-dicarboxylate (170
mg, 0.386 mmol), Pd/C (10%, 35 mg) and MeOH (4 mL). The suspension
was stirred at room temperature overnight under a hydrogen
atmosphere. The reaction mixture was filtered, and the filtrate was
concentrated in vacuo to afford the desired product as an off-white
solid. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 4.30 (dd, J=10.0,
4.8 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 4.05-3.91 (m, 2H), 3.91-3.85
(m, 1H), 3.69 (dd, J=9.0, 4.8 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H).
Step C: Ethyl
2-((4S)-4-((1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)(3-fluorophenyl)carbamoyl)-2-oxoimidazolidin-1-yl)acetate
[0603] A mixture of 2-chlorobenzaldehyde (518 mg, 3.70 mmol) and
3-fluorobenzenamine (411 mg, 3.7 mmol) in MeOH (12 mL) was stirred
at room temperature for 30 min. Then
(S)-1-(2-ethoxy-2-oxoethyl)-2-oxoimidazolidine-4-carboxylic acid
(800 mg, 3.7 mmol) was added and the reaction mixture was stirred
for another 30 min, followed by addition of
1,1-difluoro-3-isocyanocyclobutane (600 mg, 3.7 mmol). The reaction
mixture was stirred overnight and concentrated in vacuo. The
residue was purified by a standard method to give the desired
product. MS: 567: (M+1).sup.+.
Step D: Ethyl
2-((4S)-4-((1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)(3-fluorophenyl)carbamoyl)-3-(4-cyanopyridin-2-yl)-2-oxoimidazolidin-1--
yl)acetate--Compound 94
[0604] To a 25 mL-flask were added ethyl
2-((4S)-4-((1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)(3-fluoro-phenyl)carbamoyl)-2-oxoimidazolidin-1-yl)acetate (50 mg,
0.0882 mmol), 2-bromoisonicotinonitrile (21 mg, 0.115 mmol),
Cs.sub.2CO.sub.3 (58 mg, 0.176 mmol), Xant-Phos (5.2 mg, 0.009
mmol), Pd.sub.2(dba).sub.3 (8.2 mg, 0.009 mmol) and 1,4-dioxane (1
mL). The mixture was degassed and refilled with nitrogen, and then
heated to 100.degree. C. for 3 hr. The resulting mixture was cooled
and filtered and then the filtrate was concentrated in vacuo. The
residue was purified by a standard method to give both epimers.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.63-8.57 (S, 1H),
8.55-8.38 (m, 1H), 7.63 (s, 1H), 7.46-6.84 (m, 8H), 6.45-6.37 (m,
1H), 6.22-5.94 (m, 1H), 5.06-4.77 (m, 1H), 4.43-4.37 (m, 1H),
4.32-4.20 (m, 1H), 4.21 (q, J=7.1 Hz, 2H), 3.82-3.46 (m, 3H),
3.12-2.82 (m, 2H), 2.66-2.25 (m, 2H), 1.29 (t, J=7.1 Hz, 3H). MS:
669 (M+1).sup.+.
Step E:
(4S)--N-(1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutyl-amino)-2-oxo-
ethyl)-3-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-1-(2-hydroxyeth-yl)-2-ox-
oimidazolidine-4-carboxamide--Compound 112
[0605] To a solution of ethyl
2-((4S)-4-((1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl-
)(3-fluorophenyl)carbamoyl)-2-oxo-3-(pyrimidin-2-yl)imidazolidin-1-yl)acet-
ate (100 mg, 0.155 mmol) in DME (2 mL) at 0.degree. C. was added
LiBH.sub.4 (22 mg) in two portions. The mixture was stirred for 0.5
hr, then warmed to room temperature. The resulting mixture was
stirred for another 2 hr and quenched with H.sub.2O (2 mL) at
0.degree. C. The resulting mixture was extracted with EtOAc
(2.times.10 mL). The combined organic layers were combined, washed
with brine, dried over anhydrous Na.sub.2SO.sub.4, and concentrated
in vacuo. The residue was purified by a standard method to give the
desired product. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
8.62-8.55 (m, 2H), 7.63 (d, J=8.1 Hz, 1H), 7.40-6.85 (m, 8H),
6.47-6.2 (m, 2H), 4.90-4.69 (m, 1H), 4.30-4.15 (m, 1H), 3.87-3.72
(m, 2H), 3.71-3.19 (m, 5H), 3.08-2.85 (m, 2H), 2.63-2.35 (m, 2H).
MS: 603 (M+1).sup.+.
[0606] The following compound was synthesized via the procedure set
forth above, using the appropriate aldehyde, amine, carboxylic
acid, isocyanide and halo-substituted aromatic ring or heterocyclic
(heteroaromatic) ring using the reagents and solvents set forth
above, and purified via standard methods.
Ethyl
2-((4S)-4-((1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-o-
xoethyl)(3-fluoro
phenyl)carbamoyl)-3-(4-cyanopyrimidin-2-yl)-2-oxoimidazolidin-1-yl)acetat-
e (racemic)--Compound 111
##STR00451##
[0608] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.90-8.82 (m,
1H), 7.62-7.57 (m, 1H), 7.46-6.82 (m, 8H), 6.52-6.48 (m, 1H),
6.15-5.85 (m, 2H), 4.88-4.82 (m, 1H), 4.45-4.35 (m, 1H), 4.32-4.13
(m, 2H), 3.86-3.46 (m, 3H), 3.05-2.85 (m, 2H), 2.56-2.32 (m, 2H),
1.29 (t, J=7.1 Hz, 3H). MS: 670 (M+1).sup.+.
Example 25
Preparation of Additional Compounds of Formula I
General Procedures for the UGI Reaction:
[0609] A mixture of aldehyde (3.5 mmol) and aniline (3.5 mmol) in
MeOH (8 mL) was stirred at room temperature for 30 min. Then the
acid (3.5 mmol) was added and the reaction mixture was stirred for
another 30 min, followed by addition of the isocyanide (3.5 mmol).
The resulting mixture was then stirred at room temperature
overnight and quenched with H.sub.2O. The resulting mixture was
partitioned between EtOAc and H.sub.2O. The organic layer was
washed with brine, dried over anhydrous Na.sub.2SO.sub.4, and then
concentrated. The resulting residue was purified by a standard
method to afford the desired product.
General Procedures for the Buchwald Reaction:
[0610] A mixture of amine (0.30 mmol), aryl halide (0.30 mmol),
Cs.sub.2CO.sub.3 (129 mg, 0.39 mmol), Pd.sub.2(dba).sub.3 (18 mg,
0.02 mmol) and Xant-Phos (9.4 mg, 0.02 mmol) in 1,4-dioxane (10 mL)
was stirred under N.sub.2 at 80.degree. C. overnight. After
filtration, the filtrate was concentrated under reduced pressure
and the residue was purified by a standard method to give the
desired products.
[0611] The following analogs were synthesized via the procedures
set forth above, using the appropriate aldehyde, amine, carboxylic
acid, isocyanide and halo-substituted-aromatic ring or
heteroaromatic ring using the reagents and solvents set forth above
or similar reagents and solvents thereof, and purified via standard
methods.
2-(2-Chlorophenyl)-4-((S)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidin-2-yl)-N--
(3,3-difluorocyclobutyl)-3-(1H-indazol-7-yl)-4-oxobutanamide--Compound
300
##STR00452##
[0613] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 13.18 (s, 1H),
8.79 (s, 0.5H), 8.70-8.63 (m, 1H), 8.53 (d, J=5.0 Hz, 0.5H), 8.22
(s, 0.5H), 8.06 (s, 0.5H), 7.83 (d, J=8.0 Hz, 0.5H), 7.61 (d, J=8.0
Hz, 0.5H), 7.50 (d, J=7.3 Hz, 0.5H), 7.38 (m, 3H), 7.13 (t, J=7.7
Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 6.98 (d, J=7.3 Hz, 1H), 6.83 (t,
J=7.7 Hz, 0.5H), 6.67 (d, J=7.2 Hz, 0.5H), 6.24 (d, J=6.5 Hz,
0.5H), 6.02 (s, 0.5H), 5.79 (d, J=6.3 Hz, 0.5H), 5.12 (dd, J=9.3,
3.4 Hz, 0.5H), 4.95 (s, 0.5H), 4.61 (dd, J=9.2, 3.0 Hz, 0.5H), 4.22
(d, J=7.4 Hz, 1H), 3.00-2.71 (m, 3H), 2.59-2.05 (m, 4H), 2.04-1.95
(m, 1H). MS: 603.2 (M+1).sup.+.
(S)-3-(4-cyanopyridin-2-yl)-N--((R)-2-((3,3-difluorocyclobutyl)amino)-2-ox-
o-1-phenylethyl)-N-(5-fluoropyridin-3-yl)-2-oxo-1,3-oxazinane-4-carboxamid-
e--Compound 301
##STR00453##
[0615] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.54-8.21 (m,
3H), 8.08-7.99 (m, 1H), 7.31-7.27 (m, 2H), 7.26-7.20 (m, 2H),
7.09-6.87 (m, 2H), 6.38-6.17 (m, 1H), 5.89-5.60 (m, 1H), 4.93-4.70
(m, 1H), 4.62-4.46 (m, 1H), 4.42-4.21 (m, 2H), 3.12-2.91 (m, 2H),
2.60-2.10 (m, 4H). MS: 565.2 (M+1).sup.+.
(S)-3-(4-cyanopyridin-2-yl)-N--((R)-2-(3,3-difluorocyclobutylamino)-1-(2-f-
luorophenyl)-2-oxoethyl)-N-(5-fluoropyridin-3-yl)-2-oxo-1,3-oxazinane-4-ca-
rboxamide--Compound 302
##STR00454##
[0617] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.95-7.77 (m,
5H), 7.21 (s, 1H), 7.15 (s, 1H), 7.00-6.71 (m, 3H), 6.45 (m, 2H),
4.81 (m, 1H), 4.38 (d, J=7.8 Hz, 1H), 4.23 (m, 2H), 2.92 (s, 2H),
2.45 (s, 2H), 2.08 (s, 2H). MS: 583 (M+1).sup.+.
2-(2-chlorophenyl)-4-((S)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidin-2-yl)-N--
(3,3-difluorocyclobutyl)-3-(2-fluoropyridin-4-yl)-4-oxobutanamide--Compoun-
d 303
##STR00455##
[0619] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.76-8.70 (m, 1H),
8.59-8.49 (m, 1H), 8.17-8.04 (m, 1H), 7.43-7.27 (m, 3H), 7.24-6.95
(m, 3H), 6.44-6.25 (m, 1H), 6.10-6.5.96 (m, 1H), 4.94-4.75 (m, 3.1
Hz, 1H), 4.34-4.18 (m, 1H), 3.03 (m, 1H), 2.93-2.81 (m, 2H),
2.65-2.09 (m, 5H). MS: 582.1 (M+1).sup.+.
##STR00456##
[0620] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.77-8.45 (m,
2H), 8.46-7.84 (m, 2H), 7.61 (m, 1H), 7.31-7.22 (m, 2H), 7.09 (m,
1H), 6.89 (d, J=4.3 Hz, 2H), 6.46 (d, J=5.7 Hz, 1H), 6.07 (m, 1H),
4.86 (m, 1H), 4.34 (d, J=6.1 Hz, 1H), 3.19-2.76 (m, 3H), 2.63-2.08
(m, 4H), 1.93 (m, 1H). MS: 605.1 (M+1).sup.+.
(S)--N--((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(7-fluoroquinolin-5-yl)-5-oxopyrrolidine-2-c-
arboxamide--Compound 305
##STR00457##
[0622] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.98 (s, 1H),
8.89 (s, 1H), 8.31 (m, 3H), 7.46 (s, 3H), 7.21-7.06 (m, 3H), 6.31
(s, 1H), 6.13 (s, 1H), 5.04 (d, J=6.9 Hz, 1H), 4.86 (d, J=6.5 Hz,
1H), 4.37 (s, 2H), 2.51 (m, 5H), 2.24 (s, 1H). MS: 633.2
(M+1).sup.+.
Example 26
Preparation of
(2S)--N-(1-(2-chlorophenyl)-2-(3,3-difluorocyclobutyl
amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(3-fluoro-5-(pyridin-4-yl)ph-
enyl)-5-oxopyrrolidine-2-carboxamide--Compound 306
[0623] Compound 306 was prepared according to the following scheme,
using the following protocol.
##STR00458##
Step A:
(2S)--N-(3-bromo-5-fluorophenyl)-N-(1-(2-chlorophenyl)-2-(3,3-dif-
luoro-cyclobutylamino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidin-
e-2-carboxamide
[0624] 3-Bromo-5-fluoroaniline (189 mg, 1 mmol),
2-chlorobenzaldehyde (140 mg, 1 mmol),
(S)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2-carboxylic acid (231
mg, 1 mmol) and 1,1-difluoro-3-isocyanocyclobutane (118 mg, 1 mmol)
were used in the general UGI reaction to give the desired product.
MS: 660.1 (M+1).sup.+.
Step B: Compound 306
[0625] A mixture of
(2S)--N-(3-bromo-5-fluorophenyl)-N-(1-(2-chlorophenyl)-2-(3,3-difluorocyc-
lobutylamino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2-carbo-
xamide (150 mg, 0.23 mmol), pyridin-4-ylboronic acid (42.4 mg, 0.35
mmol), Cs.sub.2CO.sub.3 (224 mg, 0.69 mmol), Pd.sub.2(dba).sub.3
(16.2 mg, 0.023 mmol) and Xant-Phos (27 mg, 0.046 mmol) in
1,4-dioxane (5 mL) was stirred under N.sub.2 at 100.degree. C.
overnight and then filtered. The filtrate was concentrated under
reduced pressure and the residue was purified by a standard method
to give the desired products. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.81-8.57 (m, 3H), 8.56-8.37 (m, 1H), 8.06-7.92 (m, 1H),
7.46-7.36 (m, 3H), 7.24-7.12 (m, 3H), 7.12-6.93 (m, 2H), 6.98-6.01
(m, 2H), 4.98-4.86 (m, 1H), 4.37-4.18 (m, 1H), 3.15-2.63 (m, 4H),
2.53-2.4 (m, 2H), 2.32-2.26 (m, 2H). MS: 659.1 (M+1).sup.+.
[0626] The following analogs were synthesized via the procedures
set forth above, using the appropriate aldehyde, amine, carboxylic
acid, isocyanide and boronic acid using the reagents and solvents
set forth above or similar reagents and solvents thereof, and
purified via standard methods.
(S)--N--((R)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(3-fluoro-5-(pyridin-4-yl)phenyl)-5-oxopyrro-
lidine-2-carboxamide--Compound 307
##STR00459##
[0628] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.76-8.58 (m,
3H), 8.47 (m, 1H), 8.08 (s, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.49-7.38
(m, 1H), 7.35-7.24 (m, 2H), 7.16 (m, 3H), 7.06-6.91 (m, 2H), 6.71
(m, 1H), 6.44 (m, 1H), 4.97 (dd, J=9.2, 3.0 Hz, 1H), 4.32 (m, 1H),
3.14-2.75 (m, 3H), 2.36 (m, 4H), 2.15-1.66 (m, 3H). MS: 659.1
(M+1).sup.+.
(2S)--N-(1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-1--
(4-cyanopyridin-2-yl)-N-(3-fluoro-5-(pyridin-3-yl)phenyl)-5-oxopyrrolidine-
-2-carboxamide--Compound 308
##STR00460##
[0630] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.56-7.98 (m,
4H), 7.83-7.36 (m, 2H), 7.35-7.26 (m, 2H), 7.21-6.89 (m, 5H),
6.47-6.17 (m, 2H), 4.99-4.87 (m, 1H), 4.36-4.16 (m, 1H), 3.12-2.67
(m, 4H), 2.51-2.36 (m, 2H), 2.31-2.19 (m, 2H). MS: 659.1
(M+1).sup.+.
(S)--N--((S)-1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxo-ethy-
l)-1-(4-cyanopyridin-2-yl)-N-(3-fluoro-5-(isoxazol-5-yl)phenyl)-5-oxopyrro-
lidine-2-carboxamide--Compound 309
##STR00461##
[0632] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.77-8.32 (m,
4H), 7.79 (m, 1H), 7.59 (m, 2H), 7.42 (m, 3H), 7.25-6.92 (m, 3H),
6.71 (d, J=6.7 Hz, 1H), 6.45 (m, 1H), 4.98 (dd, J=9.1, 3.4 Hz, 1H),
4.35 (s, 1H), 3.10-2.74 (m, 3H), 2.64-2.19 (m, 4H), 2.17-2.00 (m,
1H), 1.91-1.73 (m, 1H). MS: 659.1 (M+1).sup.+.
(S)--N--((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(3-fluoro-4-(pyridin-4-yl)phenyl)-5-oxopyrro-
lidine-2-carboxamide--Compound 310
##STR00462##
[0634] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.74-8.51 (m,
3H), 7.85 (s, 1H), 7.68-7.63 (m, 1H), 7.54-7.45 (m, 2H), 7.36-7.35
(m, 2H), 7.20 (m, 2H), 7.03-6.98 (m, 2H), 6.45 (m, 1H), 6.17-6.16
(m, 1H), 4.94-4.95 (m, 1H), 4.34 (m, 1H), 3.0-2.84 (m, 3H),
2.6-2.26 (m, 4H), 2.07 (m, 1H). MS: 659.1 (M+1).sup.+.
(S)--N--((R)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(3-fluoro-4-(pyridin-3-yl)phenyl)-5-oxopyrro-
lidine-2-carboxamide--Compound 311
##STR00463##
[0636] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.65 (m, 4H),
7.79 (d, J=7.9 Hz, 1H), 7.36 (m, 5H), 7.25-7.03 (m, 3H), 6.46 (s,
1H), 6.29 (s, 1H), 4.93 (m, 1H), 4.15 (s, 1H), 3.10-2.70 (m, 3H),
2.57 (m, 1H), 2.38-1.99 (m, 4H). MS: 659.1 (M+1).sup.+.
(S)--N--((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(3-fluoro-4-(pyridin-3-yl)phenyl)-5-oxopyrro-
lidine-2-carboxamide--Compound 312
##STR00464##
[0638] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.80-8.46 (m,
4H), 7.96-7.73 (m, 2H), 7.35 (dd, J=7.8, 4.9 Hz, 3H), 7.24-6.92 (m,
5H), 6.46 (s, 1H), 6.27 (d, J=5.4 Hz, 1H), 4.98 (dd, J=9.3, 3.2 Hz,
1H), 4.35 (m, 1H), 3.01 (m, 2H), 2.95-2.82 (m, 1H), 2.64-2.17 (m,
5H). MS: 659.1 (M+1).sup.+.
Example 27
(S)--N--((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxo-et-
hyl)-1-(4-cyanopyridin-2-yl)-N-(3-fluoro-4-(pyridin-2-yl)phenyl)-5-oxopyrr-
olidine-2-carboxamide--Compound 313
[0639] Compound 313 was prepared according to the following scheme,
using the following protocol.
##STR00465##
Step A: 1-(4-Cyano-pyridin-2-yl)-5-oxo-pyrrolidine-2-carboxylic
acid
[(2-chloro-phenyl)-(3,3-difluoro-cyclobutylcarbamoyl)-methyl]-[3-fluoro-4-
-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide. To a
solution of
(S)--N-(4-bromo-3-fluoro-phenyl)-N--((S)-1-(2-chlorophenyl)-2-((3,3-diflu-
orocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidine--
2-carboxamide (500 mg, 0.758 mmol) in 1.4-dioxane (10 mL) was added
Pd(dppf)Cl.sub.2 (110.8 mg, 0.152 mmol), CH.sub.3COOK (185.6 mg,
1.90 mmol), and bis(pinacolato)diboron (384.7 mg, 1.516 mmol). The
mixture was stirred at 80.degree. C. overnight and filtered. The
filtrate was evaporated under reduced pressure and the residue was
purified by a standard method to give the desired product. MS:
708.2 (M+1).sup.+.
Step B: Compound 313
[0640] To a solution of
1-(4-cyano-pyridin-2-yl)-5-oxo-pyrrolidine-2-carboxylic acid
[(2-chloro-phenyl)-(3,3-difluoro-cyclobutylcarbamoyl)-methyl]-[3-fluoro-4-
-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (650
mg, 0.919 mmol) and 2-bromo-pyridine (159.7 mg, 1.01 mmol) in
1.4-dioxane/H.sub.2O (7 mL/3 drops) was added Pd(dppf)Cl.sub.2
(67.3 mg, 0.092 mmol), Cs.sub.2CO.sub.3 (449.5 mg, 1.38 mmol). The
mixture was stirred at 95.degree. C. for 3 hr and filtered. The
filtrate was evaporated under reduced pressure and the residue was
purified by a standard method to give the desired product. .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 8.71 (d, J=11.6 Hz, 2H), 8.51
(s, 1H), 7.99-7.64 (m, 4H), 7.32 (s, 2H), 7.10 (m, 4H), 6.45 (m,
1H), 6.15 (m, 1H), 4.95 (d, J=6.8 Hz, 1H), 4.34 (m, 1H), 3.09-2.81
(m, 3H), 2.61-2.20 (m, 4H), 2.12-2.00 (m, 1H). MS: 659.1
(M+1).sup.+.
[0641] The following analog was synthesized via the procedures set
forth above, using the appropriate aldehyde, amine, carboxylic
acid, isocyanide and halo-substituted-aromatic ring or
heteroaromatic ring using the reagents and solvents set forth above
or similar reagents and solvents thereof, and purified via standard
methods.
(2S)--N-(1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-1--
(4-cyanopyridin-2-yl)-N-(3-fluoro-5-(pyridin-2-yl)phenyl)-5-oxopyrrolidine-
-2-carboxamide--Compound 314
##STR00466##
[0643] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.84-8.64 (m,
3H), 8.65-8.24 (m, 1H), 8.03-7.60 (m, 3H), 7.53-7.31 (m, 3H),
7.26-6.95 (m, 3H), 6.80 (m, 1H), 6.43 (m, 1H), 5.12-4.85 (m, 1H),
4.28 (m, 1H), 2.85 (m, 3H), 2.67-1.98 (m, 5H). MS: 659
(M+1).sup.+.
Example 28
(S)--N--((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxo-et-
hyl)-1-(4-cyanopyridin-2-yl)-N-(3-fluoro-5-(isoxazol-5-yl)phenyl)-5-oxopyr-
rolidine-2-carboxamide--Compound 315
[0644] Compound 315 was prepared according to the following scheme,
using the following protocol.
##STR00467## ##STR00468##
Step A: 3-(dibenzylamino)-5-fluorobenzonitrile
[0645] A mixture of 3-amino-5-fluoro-benzonitrile (13.6 g, 0.1
mol), K.sub.2CO.sub.3 (62.1 g, 0.3 mol), BnBr (51.4 g, 0.3 mol) in
CH.sub.3CN (150 mL) was stirred at 78.degree. C. overnight. The
mixture was filtered and the filtrate was concentrated under
reduced pressure. The residue was purified by a standard method to
give the desired product. MS: 317.1 (M+1).sup.+.
Step B: 1-(3-(dibenzylamino)-5-fluorophenyl)ethanone
[0646] To a mixture of 3-(dibenzyl-amino)-5-fluorobenzonitrile (16
g, 0.05 mol) in anhydrous THF (150 mL) at room temperature was
dropwise added CH.sub.3MgBr (1 N solution in THF, 60 mL, 0.06 mol).
The resulting mixture was stirred at 80.degree. C. for 4 hr and
then cooled down. The mixture was poured into 2 N HCl (68 mL),
followed by addition of methanol (68 mL). The mixture was
concentrated and the residue was extracted with EtOAc (3.times.100
mL). The combined organic layers were washed with brine (100 mL),
dried over anhydrous Na.sub.2SO.sub.4 and then concentrated in high
vacuum. The residue was purified by a standard method to give the
desired product. MS: 334.1 (M+1).sup.+.
Step C:
(E)-1-(3-(dibenzylamino)-5-fluorophenyl)-3-(dimethylamino)prop-2-e-
n-1-one
[0647] A mixture of 1-(3-(dibenzylamino)-5-fluorophenyl)ethanone (2
g, 6 mmol), DMF-DMA (860 mg, 7.2 mmol) in toluene (30 mL) was
stirred at 120.degree. C. for 8 hr. The mixture was concentrated in
high vacuum and the residue was purified by a standard method to
give the desired product. MS: 389.2 (M+1).sup.+.
Step D: N,N-dibenzyl-3-fluoro-5-(isoxazol-5-yl)aniline
[0648] A mixture of
(E)-1-(3-(di-benzylamino)-5-fluorophenyl)-3-(dimethylamino)prop-2-en-1-on-
e (1.5 g, 3.86 mmol), hydroxylamine hydrochloride (534 mg, 7.73
mmol) and pyridine (611 mg, 7.73 mmol) in ethanol (20 mL) was
stirred at 78.degree. C. overnight. The resulting mixture was
evaporated under reduced pressure and the residue was purified by a
standard method to give the desired product. MS: 359.1
(M+1).sup.+.
Step E: 3-Fluoro-5-isoxazol-5-yl-phenylamine
[0649] 10% Pd/C (360 mg) was added to a solution of
dibenzyl-(3-fluoro-5-isoxazol-5-yl-phenyl)-amine (200 mg, 0.559
mmol) in a mixed solvent composed by EtOAc (36 mL), MeOH (15 mL)
and H.sub.2O (7.5 mL). 6 drops of aq. HCl (6 N) was then added into
the above suspension and the resulting reaction mixture was stirred
at 25.degree. C. for 1 hr. The mixture was filtered through Celite.
The filtrate was evaporated under reduced pressure and the residue
was purified by a standard method to give the desired product. MS:
179.0 (M+1).sup.+.
Step F:
(2S)--N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-ox-
oethyl)-N-(3-fluoro-5-(isoxazol-5-yl)phenyl)-5-oxopyrrolidine-2-carboxamid-
e
[0650] 2-Chlorobenzaldehyde (104 mg, 0.74 mmol),
3-fluoro-5-isoxazol-5-yl-phenylamine (132 mg, 0.74 mmol),
(S)-5-oxopyrrolidine-2-carboxylic acid (95 mg, 0.74 mmol) and
1,1-difluoro-3-isocyanocyclobutane (87 mg, 0.74 mmol) were used in
the general UGI reaction to afford the desired product. MS: 547.1
(M+1).sup.+.
Step G: Compound 315
[0651]
(2S)--N-(1-(2-chloro-phenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoe-
thyl)-N-(3-fluoro-5-(isoxazol-5-yl)phenyl)-5-oxopyrrolidine-2-carboxamide
(200 mg, 0.37 mmol), 2-bromopyrimidine (102 mg, 0.56 mmol),
Cs.sub.2CO.sub.3 (240 mg, 0.74 mmol), Pd.sub.2(dba).sub.3 (37 mg,
0.04 mmol) and Xant-Phos (22 mg, 0.03 mmol) in 1,4-dioxane (15 mL)
were stirred under N.sub.2 at 80.degree. C. overnight and then
filtered. The filtrate was concentrated under reduced pressure and
the residue was purified by a standard method to give the desired
product. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.69-8.17 (m,
3H), 7.80-7.28 (m, 3H), 7.25-6.93 (m, 5H), 6.63-6.30 (m, 3H),
4.96-4.92 (m, 1H), 4.37-4.34 (m, 1H), 3.06-2.83 (m, 3H), 2.58-2.21
(m, 4H), 2.08-2.02 (m, 1H). MS: 649.1 (M+1).sup.+.
Example 29
(2S)--N-(1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-1--
(4-cyanopyridin-2-yl)-N-(3-fluoro-5-(oxazol-5-yl)phenyl)-5-oxopyrrolidine--
2-carboxamide--Compound 316
[0652] Compound 316 was prepared according to the following scheme,
using the following protocol.
##STR00469##
Step A: 5-(3-fluoro-5-nitrophenyl)oxazole
[0653] To a solution of 3-fluoro-5-nitrobenz-aldehyde (340 mg, 2.0
mmol) and 2-tosylacetonitrile (430 mg, 2.2 mmol) in MeOH (25 mL)
and DME (25 mL) was added Amberlyst A26 OH-resin (3.7 g). The
mixture was heated under reflux for 1 hr and cooled to r.t. The
resin was filtered and rinsed with MeOH. The filtrate was
concentrated under reduced pressure to give the crude product which
was used directly in the next step. MS: 209.1 (M+1).sup.+.
Step B: 3-fluoro-5-(oxazol-5-yl)aniline
[0654] To a solution of 5-(3-fluoro-5-nitrophenyl)-oxazole (400 mg,
2.0 mmol) in TFA (10 mL) was added Zn powder (380 mg, 6.0 mmol).
The mixture was stirred at room temperature for 2 hr and poured
into ice. The resulting mixture was neutralized with
NH.sub.3.H.sub.2O to pH=10 and then extracted with EtOAc
(3.times.20 mL). The combined organic layers were washed with brine
(50 mL), dried over anhydrous Na.sub.2SO.sub.4 and then
concentrated in high vacuum. The residue was purified by a standard
method to afford the desired product. MS: 179.0 (M+1).sup.+.
Step C: Compound 316
[0655] 2-Chlorobenzaldehyde (104 mg, 0.74 mmol),
3-fluoro-5-(oxazol-5-yl)aniline (132 mg, 0.74 mmol),
(S)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2-carboxylic acid (171
mg, 0.74 mmol) and 1,1-difluoro-3-isocyanocyclobutane (87 mg, 0.74
mmol) were used in the general UGI reaction to afford the desired
product. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.63 (m, 2H),
8.12-7.82 (m, 1H), 7.78-7.30 (m, 2H), 7.26 (t, J=7.4 Hz, 2H), 7.15
(m, 2H), 7.12-6.83 (m, 2H), 6.70-6.16 (m, 2H), 5.03-4.74 (m, 1H),
4.24 (m, 1H), 2.93 (m, 2H), 2.63 (m, 2H), 2.20 (m, 3H). MS: 649.1
(M+1).sup.+.
[0656] The following analog was synthesized via the procedures set
forth above, using the appropriate aldehyde, amine, carboxylic
acid, isocyanide and halo-substituted-aromatic ring or
heteroaromatic ring using the reagents and solvents set forth above
or similar reagents and solvents thereof, and purified via standard
methods.
(S)--N--((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(3-fluoro-5-(oxazol-5-yl)phenyl)-5-oxopyrrol-
idine-2-carboxamide--Compound 317
##STR00470##
[0658] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.68 (s, 1H),
8.60-8.45 (m, 1H), 8.06-7.68 (m, 2H), 7.43 (s, 1H), 7.34-7.10 (m,
4H), 7.04-6.93 (m, 2H), 6.54 (d, J=6.9 Hz, 1H), 6.43 (d, J=11.5 Hz,
1H), 4.95 (t, J=6.5 Hz, 1H), 4.35 (m, 1H), 3.11-2.74 (m, 3H),
2.66-2.14 (m, 4H), 2.09-1.97 (m, 1H). MS: 649.1 (M+1).sup.+.
Example 30
(2S)--N-(1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxo
ethyl)-1-(4-cyanopyridin-2-yl)-N-(3-fluoro-5-(oxazol-2-yl)phenyl)-5-oxopy-
rrolidine-2-carboxamide--Compound 318
[0659] Compound 318 was prepared according to the following scheme,
using the following protocol.
##STR00471##
Step A: 2-(3-fluoro-5-nitrophenyl)oxazole
[0660] A mixture of 3-fluoro-5-nitrobenz-aldehyde (51 mg, 0.3 mmol)
and 2,2-dimethoxyethanamine (32 mg, 0.3 mmol) was stirred at
110.degree. C. for 2 hr and cooled to give a crude intermediate of
(E)-N-(3-fluoro-5-nitrobenzylidene)-2,2-dimethoxyethanamine. A
solution of 20 mg of the above intermediate in 0.5 mL of
H.sub.2SO.sub.4 was added into a mixture of 18 mg of P.sub.2O.sub.5
in 0.1 mL of H.sub.2SO.sub.4. The resulting mixture was heated to
180.degree. C. for 20 min, cooled down and neutralized with
NH.sub.4OH to give the crude product which was used directly
without further purification. MS: 209.1 (M+1).sup.+.
Step B: 3-fluoro-5-(oxazol-2-yl)aniline
[0661] To a solution of 2-(3-fluoro-5-nitrophenyl)-oxazole (380 mg,
1.8 mmol) in TFA (10 mL) was added Zn powder (358 mg, 5.5 mmol).
The mixture was stirred at r.t. for 2 hr and poured into ice. The
resulting mixture was neutralized with NH.sub.3.H.sub.2O to pH=10
and then extracted with EtOAc (3.times.20 mL). The combined organic
layers were washed with brine (50 mL), dried over anhydrous
Na.sub.2SO.sub.4 and then concentrated in high vacuum. The residue
was purified by a standard method to afford the desired product.
MS: 179.0 (M+1).sup.+.
Step C: Compound 318
[0662] 2-Chlorobenzaldehyde (104 mg, 0.74 mmol),
3-fluoro-5-(oxazol-2-yl)aniline (132 mg, 0.74 mmol),
(S)-1-(4-cyanopyridin-2-yl)-5-oxopyrrolidine-2-carboxylic acid (171
mg, 0.74 mmol) and 1,1-difluoro-3-isocyano cyclobutane (87 mg, 0.74
mmol) were used in the general UGI reaction to afford the desired
product. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.70 (m, 2H),
8.56-7.83 (m, 1H), 7.65 (m, 2H), 7.47-7.27 (m, 2H), 7.25-7.09 (m,
2H), 7.10-6.91 (m, 2H), 6.76-6.18 (m, 2H), 5.06-4.71 (m, 1H), 4.25
(m, 1H), 3.12-2.64 (m, 3H), 2.43 (m, 3H), 2.09 (m, 2H). MS: 649.1
(M+1).sup.+.
[0663] The following analog was synthesized via the procedures set
forth above, using the appropriate aldehyde, amine, carboxylic
acid, isocyanide and halo-substituted-aromatic ring or
heteroaromatic ring using the reagents and solvents set forth above
or similar reagents and solvents thereof, and purified via standard
methods.
(S)--N--((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoeth-
yl)-1-(4-cyanopyridin-2-yl)-N-(3-fluoro-5-(oxazol-2-yl)phenyl)-5-oxopyrrol-
idine-2-carboxamide--Compound 319
##STR00472##
[0665] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.82-8.26 (m,
2H), 7.94-7.46 (m, 3H), 7.38-6.81 (m, 6H), 6.44 (m, 1H), 6.20 (dd,
J=14.9, 6.9 Hz, 1H), 4.94 (m, 1H), 4.36 (m, 1H), 3.15-2.70 (m, 3H),
2.62-1.86 (m, 5H).
Example 31
(2S)--N-((1S)-1-(2-chlorophenyl)-2-(6,6-difluorospiro[3.3]heptan-2-yl
amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxo-
pyrrolidine-2-carboxamide--Compound 320
[0666] Compound 320 was prepared according to the following scheme,
using the following protocol.
##STR00473##
Step A: N-(6,6-difluorospiro[3.3]heptan-2-yl)formamide
[0667] To a suspension of 6,6-difluorospiro[3.3]heptan-2-amine
hydrochloride (500 mg, 2.73 mmol) in HCOOEt (5 mL) was added
Et.sub.3N (552 mg, 5.47 mmol). The resulting mixture was stirred
first at room temperature for 30 min in a sealed tank and then
heated to 85.degree. C. overnight. The mixture was concentrated and
followed by addition of EtOAc (10 mL). The resulting suspension was
stirred at room temperature for 30 min and filtered. The filtrate
was concentrated under reduced pressure and the residue was
purified by a standard method to afford the desired product.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.06 (s, 1H), 5.71 (s,
1H), 4.42 (m, 1H), 2.74-2.45 (m, 8H).
Step B: 2,2-difluoro-6-isocyanospiro[3,3]heptanes
[0668] A solution of N-(6,6-difluorospiro[3.3]heptan-2-yl)formamide
(390 mg, 2.23 mmol), PPh.sub.3 (642 mg, 2.45 mmol), CCl.sub.4 (339
mg, 2.23 mmol), and Et.sub.3N (225 mg, 2.23 mmol) in DCM (10 mL)
was heated at 45.degree. C. overnight. The mixture was concentrated
under reduced pressure. The residue was suspended in Et.sub.2O (10
mL) and filtered. The filtrate was concentrated under reduced
pressure and the residue was purified by a standard method to
afford the desired product. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 4.01-3.85 (m, 1H), 2.80-2.37 (m, 8H).
Step C:
(2S)--N-(1-(2-chlorophenyl)-2-(6,6-difluorospiro[3.3]heptan-2-ylam-
ino)-2-oxoethyl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide
[0669] 2-Chlorobenz-aldehyde (104 mg, 0.74 mmol),
5-fluoropyridin-3-amine (83 mg, 0.74 mmol),
(S)-5-oxopyrrolidine-2-carboxylic acid (95 mg, 0.74 mmol) and
2,2-difluoro-6-isocyanospiro[3.3]heptane (116 mg, 0.74 mmol) were
used in the general UGI reaction to afford the desired product. MS:
521 (M+1).sup.+.
Step D
[0670] Compound 320 was synthesized via the general procedure for
Buchwald reaction set forth above. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.97 (s, 0.5H), 8.70 (s, 1H), 8.48 (d, J=4.6
Hz, 1H), 8.41-8.22 (m, 1.5H), 8.15 (d, J=8.7 Hz, 1H), 7.31 (d,
J=7.1 Hz, 1H), 7.25 (d, J=4.9 Hz, 1H), 7.19 (t, J=7.4 Hz, 1H), 7.03
(t, J=7.3 Hz, 1H), 6.91 (m, 1H), 6.42 (m, 1H), 6.05 (m, 1H), 4.83
(m, 1H), 4.38 (m, 11H), 2.97-2.75 (m, 1H), 2.68-2.11 (m, 8H),
2.10-1.82 (m, 3H). MS: 623.1 (M+1).sup.+.
Example A
In Vitro Assays for IDH1m (R132H or R132C) Inhibitors
[0671] A test compound is prepared as 10 mM stock in DMSO and
diluted to 50.times. final concentration in DMSO, for a 50 .mu.l
reaction mixture. IDH enzyme activity converting
alpha-ketoglutarate to 2-hydroxyglutaric acid is measured using a
NADPH depletion assay. In the assay the remaining cofactor is
measured at the end of the reaction with the addition of a
catalytic excess of diaphorase and resazurin, to generate a
fluorescent signal in proportion to the amount of NADPH remaining.
IDH1-R132 homodimer enzyme is diluted to 0.125 .mu.g/ml in 40 .mu.l
of Assay Buffer (150 mM NaCl, 20 mM Tris-Cl pH 7.5, 10 mM
MgCl.sub.2, 0.05% BSA, 2 mM b-mercaptoethanol); 1 .mu.l of test
compound dilution in DMSO is added and the mixture is incubated for
60 minutes at room temperature. The reaction is started with the
addition of 10 .mu.l of Substrate Mix (20 .mu.l NADPH, 5 mM
alpha-ketoglutarate, in Assay Buffer) and the mixture is incubated
for 90 minutes at room temperature. The reaction is terminated with
the addition of 25 .mu.l of Detection Buffer (36 .mu.g/ml
diaphorase, 30 mM resazurin, in 1.times. Assay Buffer), and is
incubated for 1 minute before reading on a SpectraMax platereader
at Ex544/Em590.
[0672] Compounds are assayed for their activity against IDH1 R132C
following the same assay as above with the following modifications:
Assay Buffer is (50 mM potassium phosphate, pH 6.5; 40 mM sodium
carbonate, 5 mM MgCl.sub.2, 10% glycerol, 2 mM b-mercaptoethanol,
and 0.03% BSA). The concentration of NADPH and alpha-ketoglutarate
in the Substrate Buffer is 20 .mu.M and 1 mM, respectively.
[0673] Representative compounds of formula I set forth in Table 1
were tested in this assay or a similar assay and the results are
set forth below in Table 3. As used in Table 3, "A" refers to an
inhibitory activity against IDH1 R132H or IDH1 R132C with an
IC.sub.50.ltoreq.0.1 .mu.M; "B" refers to an inhibitory activity
against IDH1 R132H or IDH1 R132C with an IC.sub.50 between 0.1
.mu.M and 0.5 .mu.M; "C" refers to an inhibitory activity against
IDH1 R132H or IDH1 R132C with an IC.sub.50 between 0.5 .mu.M and 1
.mu.M; "D" refers to an inhibitory activity against IDH1 R132H or
IDH1 R132C with an IC.sub.50 between 1 .mu.M and 2 .mu.M.
TABLE-US-00004 TABLE 3 Inhibitory Activities of Representative
Compounds of formula I IDH IDH R132C R132H HT1080 U87MG Cpd IC50
IC50 IC50 IC50 No (uM) (uM) (uM) (uM) 1 A A A B 2 D B 3 B B B 4 A A
A A 5 A A A B 6 A B B 7 A A A A 8 B C 9 A A A A 10 B B 11 B B 12 A
B B 13 C C 14 A A A B 15 A A B B 16 B B B C 17 B B C D 18 A A A A
19 B C 20 A A B B 21 A A A B 22 B B 23 A B B B 24 C D 25 B C 26 A B
B 27 A A 28 A B A 29 A A A 30 A A B 31 A B C 32 B D 33 A A A B 34 A
B C 35 A B B 36 B B 37 A A A A 38 C D 39 C D 40 A A B B 41 A B C 42
B C 43 A A A A 44 B B 45 A A B B 46 C D 47 A A A B 48 A A B B 49 A
A B B 50 C D 51 A B B B 52 A A 53 A A A A 54 B B 55 A A A A 56 A A
57 B C 58 A A A A 59 B C 60 B B 61 B B 62 A B 63 A A A A 64 A A A A
68 A A A A 69 A A A A 70 A A A A 71 A A A A 72 A A A A 73 A A A A
74 A A A A 75 A A A A 76 A A A A 77 A A A A 78 A A A A 79 A A A A
80 A A A A 81 A A A A 82 A A A A 83 A A A A 84 A A A B 85 A A A A
86 A A A A 87 A A A A 88 A A A A 89 A A A A 90 A A A A 91 A A A A
92 A A A A 93 A A A A 94 A A A A 95 A A A A 96 A A A A 97 A A A A
98 A A A A 99 A A A A 100 A A A A 101 A A A A 102 A A A B 103 A A A
B 104 A A A A 105 A A A A 106 A A A A 107 A A A A 108 A A A A 109 A
A A B 110 A A A A 111 A A A A 112 A A A A 113 A A A A 114 A A A A
115 A A A A 116 A A A B 117 A A A A 118 A A A A 119 A A A B 120 A A
A B 121 A A A A 122 A A A B 123 A A A A 124 A A A A 125 A A A A 126
A A A B 127 A A A A 128 A A A A 129 A A A A 130 A A A A 131 A A A A
132 A A A A 133 A A A A 134 A A A A 135 A A A A 136 A A A A 137 A A
A A 138 A A A A 139 A A A A 140 A A A A 141 A A A A 142 A A A A 143
A A A A 144 A A A A 145 A A A A 146 A A A A 147 A A A A 148 A A A A
149 A A A A 150 A A A A 151 A A A A 152 A A A A 153 A A A A 154 A A
A A 155 A A A A 156 A A A A 157 A A A A 158 A A A A 159 A A A A 160
A A A A 161 A A A A 162 A A A A 163 A A A A 164 A A A A 165 A A A
166 A A A A 167 A A A 168 A A A A 169 A A A 170 A A A 171 A A A 172
A A A 173 A A A 174 A A A A 175 A A A A 176 A A A A 177 A A A A 178
A A B A 179 A A A A 180 A A A A 181 A A A A 182 A A A A 183 A A A
184 A A A A 185 A A A A 186 A A A A 187 A A A A 188 A A A A 189 A A
A 190 A A A A 191 A A A A 192 A A A 193 A A A A 194 A A A 195 A A A
196 A A A 197 A A A A 198 A A A A 199 A A A A 200 A A A A 201 A A A
A 202 A A A 203 A A A 204 A A A A 205 A A A A 206 A A A 207 A A A A
208 A A A A 209 A A A A 210 A A A A 211 A A A A 212 A A A A 301 A A
302 A A
Example B
Cellular Assays for IDH1m (R132H or R132C) Inhibitors
[0674] Cells (HT1080 or U87MG) are grown in T125 flasks in DMEM
containing 10% FBS, 1.times. penicillin/streptomycin and 500 ug/mL
G418 (present in U87MG cells only). They are harvested by trypsin
and seeded into 96 well white bottom plates at a density of 5000
cell/well in 100 ul/well in DMEM with 10% FBS. No cells are placed
in columns 1 and 12. Cells are incubated overnight at 37.degree. C.
in 5% CO.sub.2. The next day test compounds are made up at 2.times.
the final concentration and 100 ul are added to each cell well. The
final concentration of DMSO is 0.2% and the DMSO control wells are
plated in row G. The plates are then placed in the incubator for 48
hours. At 48 hours, 100 ul of media is removed from each well and
analyzed by LC-MS for 2-HG concentrations. The cell plate is placed
back in the incubator for another 24 hours. At 72 hours post
compound addition, 10 mL/plate of Promega Cell Titer Glo reagent is
thawed and mixed. The cell plate is removed from the incubator and
allowed to equilibrate to room temperature. Then 100 ul of Promega
Cell Titer Glo reagent is added to each well of media. The cell
plate is then placed on an orbital shaker for 10 minutes and then
allowed to sit at room temperature for 20 minutes. The plate is
then read for luminescence with an integration time of 500 ms.
[0675] The IC.sub.50 for inhibition of 2-HG production
(concentration of test compound to reduce 2HG production by 50%
compared to control) in these two cell lines for various compounds
of formula I is set forth in Table 2 above. As used in Table 2, "A"
refers to an IC.sub.50 for inhibition of 2-HG production
.ltoreq.0.1 .mu.M; "B" refers to an IC.sub.50 for inhibition of
2-HG production between 0.1 .mu.M and 0.5 .mu.M; "C" refers to an
IC.sub.50 for inhibition of 2-HG production between 0.5 .mu.M and 1
.mu.M; "D" refers to an IC.sub.50 for inhibition of 2-HG production
between 1 .mu.M and 2 .mu.M.
Example C
Metabolic Stabilities of Compounds of Formula I
[0676] Metabolic stabilities of compounds of formula I can be
tested with the following assay and species specific liver
microsomes (LM) extraction ratio (Eh) can be calculated:
1. Buffer A: 1.0 L of 0.1 M monobasic Potassium Phosphate buffer
containing 1.0 mM EDTA; Buffer B: 1.0 L of 0.1 M Dibasic Potassium
Phosphate buffer containing 1.0 mM EDTA; Buffer C, 0.1 M Potassium
Phosphate buffer, 1.0 mM EDTA, pH 7.4 by titrating 700 mL of buffer
B with buffer A while monitoring with the pH meter. 2. Reference
compounds (Ketanserin) and test compounds spiking solution: 500
.mu.M spiking solution: add 10 .mu.L of 10 mM DMSO stock solution
into 190 .mu.L CAN; 1.5 .mu.M spiking solution in microsomes (0.75
mg/mL): add 1.5 .mu.L of 500 .mu.M spiking solution and 18.75 .mu.L
of 20 mg/mL liver microsomes into 479.75 .mu.L of Buffer C. 3.
NADPH stock solution (6 mM) is prepared by dissolving NADPH into
buffer C. 4. Dispense 30 .mu.L 1.5.times. compound/liver microsome
solution in 96-well plate and immediately add 135 .mu.L ACN
containing IS before adding 15 .mu.L Buffer C to prepare real 0
minute samples. 5. Add 15 .mu.L of NADPH stock solution (6 mM) to
the wells designated as Time 30, and start timing. 6. At the end of
incubation (0 min), add 135 .mu.L of ACN containing the internal
standard Osalmid) to all the wells (30 min, and 0 min). Then add 15
.mu.L of NADPH stock solution (6 mM) to the wells designated as
Time 0. 7. After quenching, centrifuge the reaction mixtures at
3220 g for 10 min. 8. Transfer 50 .mu.L of the supernatant from
each well into a 96-well sample plate containing 50 .mu.L of ultra
pure water (Millipore) for LC/MS analysis.
* * * * *