Note: Descriptions are shown in the official language in which they were submitted.
I
Inhibitors of Transglutaminases
Description
The invention relates to novel inhibitors of transglutaminases, in particular
transglutaminase 2, methods for their synthesis and to their use for the
prophylaxis and
treatment of diseases associated with transglutaminases, in particular
transglutaminase
2.
Background of the invention
Transglutaminases are part of the class of transferases and according to EC
nomenclature they are correctly designated as "protein-glutamine: amine y-
glutamyl
transferases" (EC 2.3.2.13). They link the E-amino group of the amino acid
lysine and
the y-glutamyl group of the amino acid glutamine forming an isopeptide bond
while
ammonia is released. In
the absence of suitable amines and/or under certain
conditions, deamidation of the glutamine may occur resulting in the
corresponding
glutamic acid.
Additionally, transglutaminases play an important role in many therapeutic
areas such
as the cardiovascular diseases (thrombosis and atherosclerosis), autoimmune
diseases
(celiac disease, Duhring-Brocq-disease, gluten ataxia), neurodegenerative
diseases
(Alzheimer's disease, Parkinson's disease, Huntington's disease),
dermatological
diseases (ichthyosis, psoriasis, acne) as well as in wound healing and
inflammatory
diseases (e.g. tissue fibrosis) (J.M. Wodzinska, Mini-Reviews in medical
chemistry,
2005, 5, 279 - 292).
Celiac disease, a gluten intolerance, however, is one of the most important
indications.
Celiac disease is characterized by a chronic inflammation of the mucosa of the
small
intestine. In susceptible patients, the intestinal epithelium is successively
destroyed
after ingestion of gluten-containing food resulting in reduced absorption of
nutrients
which again has massive impact on the patients affected and is for example
associated
with symptoms such as loss of weight, anemia, diarrhea, nausea, vomiting, loss
of
appetite and fatigue.
Due to these findings, there is a large demand for the
development of a medicament for the treatment of celiac disease as well as of
other
diseases associated with tissue transglutaminase (transglutaminase 2, TG2,
tTG). The
tissue transglutaminase is a central element during pathogenesis. The
endogenous
enzyme catalyses the deamidation of gluten/gliadin in the small intestinal
mucosa and
thus triggers the inflammatory response.
Therefore inhibitors of tissue
transglutaminase are suitable to be used as active agents for medication.
Date Recue/Date Received 2024-03-07
2
Another very important group of indications for tissue transglutaminase
inhibitors are
fibrotic disorders. Fibrotic disorders are characterized by the accumulation
of cross-
linked extracellular matrix proteins.
Diabetic nephropathy, cystic fibrosis, idiopathic
pulmonary fibrosis, kidney fibrosis as well as liver fibrosis belong to the
most important
fibrotic disorders to be addressed with the compounds disclosed.
US 9,434,763 B2 discloses pyridinone derivatives having a warhead comprising
at least
one acceptor-substituted double bond, such as a Michael System, as
irreversible
transglutaminase inhibitors. Alkylacetamido and arylacetamido pyridinones
showed
inhibitory activity regarding tissue transglutaminase TG2 in nanomolar range
(IC50).
Tse et al. (J. Med. Chem. 2020, 63, 11585-11601) report on replacement of
phenyl
residues by non-classical bioisosteres, such as cubane and
bicyclo[1.1.1]pentane
(BCP), in anti-malarial triazolopyrazine compounds in order to alter compound
solubility
and metabolic stability. The authors further evaluated in vitro antiplasmodial
activity of
bioisosteric modified triazolopyrazines against the 3D7 strain of P.
falciparum.
Replacement of phenyl by bioisosteric saturated heterocyclic residues resulted
in
complete loss of activity. Adamantyl residues as well as other hydrocarbon-
caged
derivatives led to potency up to 2-9 times lower than the corresponding phenyl
triazolopyrazine compounds. In contrast, higher potencies were achieved by
replacing
phenyl with closo-1,2- and 1,7-carborane isomers. The authors concluded that
the
effect of non classical bioiostere replacement on biological properties cannot
be
predicted accurately and that a considerable range of possible bioisosteres
has to be
tested first in order to identify a suitable replacement leading to the
desired properties of
.. a given molecule.
Subbaiah et al. (J. Med. Chem. 2021, 64, 19, 14046-14128) report on
bioisosteres of
the phenyl ring in lead optimization and drug design. It is noted that
bioisosteric phenyl
ring replacement with heterocyclic and carbocyclic moieties can lead to
enhanced
potency, solubility, and metabolic stability while reducing lipophilicity,
plasma protein
binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes
and the
hERG channel.
However, this effect depends strongly on the properties of the
compound itself and the addressed target.
US 11,072,634 B2 discloses reversible transglutaminase inhibitors comprising
an
aldehyde, a ketone, an a-ketoaldehyde, an a-ketoketone, an a-ketoacid, an a-
ketoester,
an a-ketoamide or a halogenmethylketone as warhead. The inhibitors showed
inhibitory activity regarding tissue transglutaminase TG2 in nanomolar and
micromolar
range (IC50).
Date Recue/Date Received 2024-03-07
3
The objective of the present invention is to provide novel, most probably
reversible
inhibitors of transglutaminases, in particular transglutaminase 2 and methods
for the
synthesis of said inhibitors as well as several uses of these inhibitors.
Said objective is solved by the technical teachings of the independent claims.
Further
advantageous embodiments, aspects and details of the invention are evident
from the
dependent claims, the description and the examples.
Surprisingly, it has been found that reversible inhibitors having a chemical
warhead as
disclosed herein inhibit effectively transglutaminases including tissue
transglutaminase
called transglutaminase 2 or TG2. Herein these terms are used synonymous.
Preferably, such chemical warhead moiety is particularly selected from
reversible
warheads such as a-ketoamides. The compounds of the present invention act as
selective inhibitors of transglutaminase 2.
In order to prove inventiveness of the compounds of the present application,
reference
compounds were synthesized and tested in comparison to the most similar
compounds
of the present application. A skilled person might notice compound A8 from our
patent
US 9,434,763 B2 which we introduce as Ref. 3 to highlight the inventive and
preferred
features of the claimed compounds. From US 9,434,763 B2, it is clear, that
aromatic
moieties (C-terminal) restrict the efficacy of those compounds (compare to Al,
A8, A37,
A44, A47). In sharp contrast, branched alkyl moieties are highly preferred as
indicated
by more potent compounds (A28, A29, A59, A61, A63, A67, A68, A79).
To illustrate the advantage of branched alkyl moieties over aromatic moieties,
we refer
to reference compounds Ref. 2 (ZED1227, US 9,434,763 B2) and Ref. 3 (A8,
ZED1047).
Inhibition data were determined using the classical fluorescent
transamidation assay (dansylcadaverine incorporation into methylated casein,
DCC-
assay) as described [Bach Id, C.; HiIs, M.; Gerlach, U.; Weber, J.; Pelzer,
C.; Heil, A.;
Aeschlimann, D.; Pasternack, R. Features of ZED1227: The First-In-Class Tissue
Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of
Celiac
Disease. Cells 2022, //, 1667. https://doi.org/10.3390/cells11101667]. Casein
is one of
the best known high molecular weight (24 kDa) protein substrates for
transglutaminases.
Please note, the ICso value of Ref. 3 (A8) published in US
9,434,763 B2 cannot be compared to the present data, relying on a fluorogenic
isopeptidase assay. Measured in the DCC-assay, Ref. 2 (ICso = 53 nM) is 80-
fold more
potent compared to Ref. 3 (ICso = 4,268 nM).
Date Recue/Date Received 2024-03-07
4
Accordingly, a person skilled in the art of medicinal chemistry would choose
branched
alkyl moieties as lead structures, such excluding aromatic moieties, e.g. the
phenyl
group. It is of common knowledge, that bridged cycloalkyl groups are non-
classical
bioisosters of the phenyl group. By replacement of the phenyl group in A8 by
e.g. an
adamantane group, a skilled person would expect similar physico-chemical or
biochemical properties excluding to invest efforts. Since aromatic moieties
are clearly
not preferred, bridged cycloalkyl groups would not be considered improving the
compounds.
This is further supported by additional reference compounds. ZED3641 (Ref. 1,
as
disclosed in US 11,072,634 B2; reversible acting a-ketomethylamide analogue to
Ref.
2, ZED1227) is about 10-fold more potent compared to Ref. 6 (compare table 1).
Ref. 6
is analogous to compound A8 disclosed in US 9,434,763 B2 with respect to the
backbone proving again superiority of branched alkyl moieties compared to
aromatic
derivatives in combination with reversible acting warheads.
However, surprisingly, replacement of the preferred branched alkyl moieties by
bridged
cycloalkyl groups further significantly improve the potency of the compounds
as shown
in table 1. Therefore, we credit bridged cycloalkyl groups as disclosed
with an
outstanding inventive manner.
In summary, the inventive compounds rated "A" show efficacies of about 100-
fold higher
compared to Ref. 3 (A8, compare to table1).
Further, compounds with activities rated "B" or "C" are still preferred (lower
ICso values)
to Ref. 3 (A8). These compounds can also be considered inventive, since
peripheric
ligands affect physico-chemical or biochemical properties. Therefore, also
less potent
compounds might be of high value, depending on the application.
Thus, the present invention relates to compounds of the general formula (I):
R1
0 0
H
NJNI- R3 (I)
R2,1 1
1
wherein
L represents ¨L1¨ or ¨L1-L2¨; preferably ¨1_1-L2¨;;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NR141¨, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRN1CH(CH3)¨,
Date Recue/Date Received 2024-03-07
5
0
R1 represents
o =
,
R2 represents
RN RN
0 Ra R11 0 R8 __ _ S R8 R11 S R8 _ _ N
Ra R11 N Ra
_ N _
R10 R9 /
' R9 R10 rµD9 9 R10 9 9
RN RN RN RN RN
R11 N R11 N,N _ _ N Ri 1 N RN
R11 N R8
I __ t - _ II R8
r
R10 µs / R9 R10 9 R10 R10
; ,
' R10
R10 ,
R11 0
R11 0 - 0 Ra
R8 .-- R8
- , R10 R11 S
4\1 _-
-
(32\i_Z 1
R10 R10 R9 si\r¨ = R8 R10
= ,
,
RN RN RN
S Ra
R11 S 8
i R _ .õ ,N,N
1 t N RiN 1
----- N N'--- R10
p10 N pN
" --- N -
¨
\_
N
Rio Rio
,
,
RN R12 R12 R12 R12
R13 17-(:1 R13 r __ /':1 R13 N
R13
_
1!...õ. \ N LJ
-ni N=N ------ R14 NIRia N - - R14
N- Ria
RN
R12 R12 RN
R12
oo12 N R12
N rµ 0 ./ ... S ./ ,... 13
Ri6 - - - ¨R
\ ,i)R --
4 1 TR
\R14 R14 14 N 14
-----\R
N'14 10 10 10 ,
R13 RN
R12 R12 RN
\
R13 s N 71õ,,,N,õ:7._ R14
N R8 N R9
co
\7R (
iRio
D14 -'---'-'¨'--%. 14 10--lc-) S ____ - -\ /-------
D10
_
' s " , "
RN
R8 R8
1\1 R9
D__119 R9 S , -
,
_ NY \ I - -
)''''''r/
-,---, Ri.. <õ,-, N-, ---, R ..
, - .. ---------' R8
-- R8
,
S,- ' R8
NI NIL s , N , - N , - 0
R8N 1\1 N6'. - R8--<1 R8--(/0 I
- -
R8
H'
N 0 S S
i , ,
Date Recue/Date Received 2024-03-07
6
N N
---NNH ---NNH
---( 1 ----N3
V V (
8 7 N
z 6
, ,
-_,NH -- "NNH
N N
N , N j N
_ N N'-eN0
--(IV ---(3
N V N
0 6 z 6
H S
cNr1-
-
--, --o------$ _s
-S H H
H
N
,
0 N
N-N-0
0- ----7
H H
,
,
õ N
,
I I
IV
/ Nr
-, N -, -,
N
,
N õ N
N
1\1 1\1
,
N .
., .,
N N
Nle LL LJ 1\1
,
., . N N
\ \! .'-!NN
- N I
N'
,
. N
N I I
1\1 1\1
N -' ---,
1\1 1\1N Nle
,
Date Recue/Date Received 2024-03-07
7
N ,
-'r
I\ N 1\IN
,
., N N . N N
N le NI
N I\IN
, ,
,
. N N . N N
NN
NI 1 '1 '
-N -N
-re-le
. N N . N N , N N
'-! 'T '
N -.õ, õ ,
1
N
, N N ., N N
I
NI I
\%\j
N N ,
, N N , N
,'-!- '-!
I I j '-r N
, N , N ., N
I I
N I\IN N,KI
. N ., N- ., N
I If
Nle le 'Nr
' N , NN,
., ., N
1=1 1=1 ''=
N I
1=1
'
NN
I
NN
. N N N
'1
'''
N Nle N le
,
N ''N
--'r
il
'N N'
I
NN i\INI NNI
.,
N'N Ni\IN N
. . . N
N
NI N
I 'N-'-% 'Nfe IVIV
H
,, NH
H H ,
,
Date Recue/Date Received 2024-03-07
8
_
.
N NH ,
H H , NH , ,
N 0 N=N N N
¨ \I
-\I
¨ \I
0 -- __
, , ,
,
N__ N_ ' N N
N
\/71 1¨Nj
)\1
¨)\1
N \
N N
_
N / \\¨N
N=N N=N NN N=N N=N
- N -- 11 /T\ - - -\q -- --,
, , ,
, ,
-S
N_ \I N N \I ¨ N)\1 ¨ N
)\1
I
I
N_ N_ N N N __ '
---si
N __ /
, , ,
N N N N /__N '
---,\,\ /1\1 --- /N
-- ..\\ /1`,1
L /5
_____
,
' ,
'
N /¨N ___N N __N '
--
,
, ,
Date Recue/Date Received 2024-03-07
9
\I \N
/S -- /c __ -- \\ /( \ N -- ls\ii
-\1
N //
iv \
-Ki -1<1 ; N /
, or
wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of
the
substituents R6 - R14 and R" ; and preferably with 1 to 3 of the substituents
R11 - R13;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,
bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl,
bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl,
bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl,
diamantyl,
hexamethylenetetraminyl and the afore-mentioned residues optionally contain
one or
more C=C double bond(s) and/or are optionally substituted by one or more of
Ra, Rb,
Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -
Br,
-CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3,
-COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CON F12, -CONHCH3,
-CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2,
-CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5,
-NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2,
-NHSO2CF3, -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3,
-CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3,
-CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3,
-cyclo-C3H5, -cyclo-C4H7, -cyclo-05H9, -cyclo-C6H11, -CH2-cyclo-C3H5,
-CH2-cyclo-C4H7, -CH2-cyclo-05H9, -CH2-cyclo-C6H11, -Ph, -CH2-Ph,
-CH2OCH3, -CH2OCH2CH3, -
CH2CH2OCH3, -CH2CH2OCH2CH3,
-CH2CH2NHCH3, -CH2CH2N(CH3)2,
- -N
or -NR6R7 is -N(C2H5)2, _ _N - -Nn
or
, \ __ =
\---' ,
R6, R6, R10, R11, R12, R13, and R14 represent independently of each other -H, -
F, -Cl,
-Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9,
Date Recue/Date Received 2024-03-07
10
-CH2-CH (CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5,
-CH2OH, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F,
-CH2-CH F2, -C H2-C F3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3,
-0C21-15, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCHF2, -0CF3,
-OCH2CF3, -0C2F5, -OCH2OCH3, -0-cyclo-C3H5, -OCH2-cyclo-C3H5,
-0-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -00C2H5, -00C3H7,
-COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7,
-COOCH (CH3)2, -COOC(CH3)3, -
00C-CH3, .. -00C-CF3, -00C-C2H5,
-00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC2H5,
-NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2,
-N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5,
-NHCOC3H7, -N HCOCH (CH3)2, -NHCOC(CH3)3,
-CON H2, -CON HCH3,
-CONHC2H5, -CONHC3H7, -
CON HCH (CH3)2, -CON H-cyclo-C3H5,
-CON HC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2,
-CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7,
-SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -
SO2NHC(CH3)3, -SO2N(CH3)2,
-SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3,
-NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -N HSO2CH (CH3)2, -NHSO2C(CH3)3,
-CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3,
-CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph,
N. N(
- -NO ------------------------------------- r r r rN
rN r r . Y L . L __ . -N NH --N _
_N
N_
'a' `o' , or \ ___ ;
or R8 and R9 or R9 and R1 can form together one of the following five-
membered or
six-membered rings:
0
,0 _N
-CY
, or ''-%N ;
or R12 and R13 or R13 and R14 can form together one of the following five-
membered
or six-membered rings:
0
0 0 ,0
'
H or I
Date Recue/Date Received 2024-03-07
11
R" represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C41-19, -CH2-CH(CH3)2,
-CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -
cyclo-C4H7, -cyclo-CsHo,
-CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-05Fl9, -CH2F, -CHF2, -CF3,
-CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2; -CF12-CF3, -CH2-CH2CI,
-CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3,
-00C2H5, -00C3H7, -COCH(CH3)2, -
00C(CH3)3, -CO-cyclo-C3H5,
-CO-cyclo-C4H7, -CO-cyclo-CsFlo, -COOCH3, -CO0C2H5, -CO0C3H7,
-COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C2H5,
-S02C3H7, -S02CH(CH3)2, -S02-cyclo-C3H5, or -S02C(CH3)3;
RNI represent -H, -CH3, or -CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of
enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically
acceptable salt
thereof.
The inventors have found that the reversible inhibitors of formula (I)
disclosed herein
having a bridged bicyclic residue R3 exhibit increased potency over the
compounds of
the prior art. Particularly, it is demonstrated herein, that the inventive
compounds have
an improved inhibitory activity compared to the known compounds bearing
aromatic
moieties R3 instead of bridged bicyclic residues. In order to prove
inventiveness of the
compounds of the present application, known compounds from US 9,434,763 B2 and
US 11,072,634 B2 (Reference 1 (E16 from US 11,072,634 B2), Reference 3 (A8
from
US 9,434,763 B2), and Reference 6) were synthesized and tested as reference
compounds in comparison to the most similar compounds of the present
application.
To this extent, inhibition data were determined using the classical
fluorescent
transamidation assay (dansylcadaverine incorporation into methylated casein,
DCC-
assay) as described in Buchold et al. [Buchold, C.; Nils, M.; Gerlach, U.;
Weber, J.;
Pelzer, C.; Heil, A.; Aeschlimann, D.; Pasternack, R. Features of ZED1227:
The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical
Evaluation for
the Treatment of Celiac Disease. Cells 2022, 1/,
1667.
https://doi.org/10.3390/cells11101667]. Casein is one of the best known high
molecular
weight (24 kDa) protein substrates for transglutaminases. Inhibition data of
the inventive
compounds was compared with inhibition of compounds disclosed in US 9,434,763
B2,
particularly, compound A8, which is denoted herein as Reference 3. It is
noteworthy that
the ICso values of compounds A8 published in US 9,434,763 B2 and E16 from
US 11,072,634 B2 cannot be compared to the present data, relying on a
fluorogenic
isopeptidase assay.
Date Recue/Date Received 2024-03-07
12
Thus, the inventive compounds of formula (I) rated "A" showed efficacies of
about
100-fold higher compared to Ref. 3 (A8). The same argumentation applies to
Ref. 6
which is except of the phenylethyl group identical to compound 11-111. Ref. 6
is more
than 25-times less potent in comparison to compound 11-111 as evident from
Table 1.
This finding was particularly surprising as a skilled person would not have
expected an
improved inhibitory activity of the inventive compounds bearing a bridged
bicyclic
residue over the compounds of the prior art bearing aromatic residues since it
is
common knowledge that bridged bicyclic groups or bridged cycloalkyl groups are
non-
classical bioisosters of the phenyl group, such that a skilled person would
only expect to
obtain a compound having similar physico-chemical and biological properties,
including
inhibitory activity, when replacing a phenyl group with a bridged bicyclic
group. As
aromatic moieties showed lower potency, bridged cycloalkyl groups would not be
considered improving the physico-chemical and biological properties of the
compounds.
The residues bicyclo[1.1.1]pentyl,
bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,
bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl,
bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl,
bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl,
diamantyl, and
hexamethylenetetraminyl used herein, have the following parent structures
respectively:
bicyclo[1.1.1]pentyl bicyclo[2.1.1]hexyl bicyclo[2.2.1]heptyl
- - -
bicyclo[3.1.1]heptyl bicyclo[2.2.2]octyl bicyclo[3.2.1]octyl
- -
- -
bicyclo[3.2.2]nonyl bicyclo[3.3.2]decyl bicyclo[3.3.3]undecyl
4-homoisotwistyl adamantyl diamantyl
hexamethylenetetraminyl
N
-1\11
N
and the afore-mentioned residues optionally contain one or more C=C double
bond(s)
such as bicyclo[2.2.1]hept-5-enyl (s. 11-97) and/or are optionally substituted
by one or more
of Ra, Rb, Rc, Rd, and R.
Date Recue/Date Received 2024-03-07
13
The unsubstituted bicyclic residues which can be substituted with 1 to 5 of
the
substituents R9 ¨ R14 and RN; have the following structure and the
substituents R9 ¨ R14
and RN have the meanings as defined herein:
R11
RN R11 R11 R11
1\1 R12 0 R12 S R12
Rio \ ___________ Rio \I ( Rio \
\
R13 R13 R13
R13 S
ii Ria , R R14
Ria
R12
,
R11 R11
RN N R11 N R11
- -( - - -- _________ - - -
N __
\I.NrLRi i R137 7 R12 S\\I
R137
R12 R13
R12 , , R12 ;
,
R11 R11 R11 R11
N-
RN
' -eS
i\l3, 1
, R 2 _ R13 j:' 6l, R12
,,õ-4, Ri2
R "' N , R13 R12
R11 R11
N R11 N R11 R11
---( r ---( N ----e0 ----- -e0
N N
R130 6 7 R12 \\I v __ ( 1\13_
N R12
R12 R13 R13/Ni.. \)-- 12
N R
R12 , R13
RN R11 R11 R11
iv Ri2
o Ri2 s R12
--4 --- --
N R13 N R13 -
N R13
R14 R14 R14
RN R11 R11 R11
iv R12 o Ri2 s R12
-- \ - - \ -- \
R13 R13 R13
1-I.
10 10 A
R14 R14 R i
;
N s R1 1 ;
RN R13 R11 R12
,
1\1 s R13 R12 __ ___T- R12 -- / \ __ R13
11 12
, 11 RN 13 RN
'
R11 R13 R11 R12
SN
R13 N
-_N¨-- - - _T- R12
------11 %N12
N
11 R12 S-N------- S-N
13 )s13
;
;
Date Recue/Date Received 2024-03-07
14
R13 RN\ R13
R11 R12 N 0
S N
- - R13 R12
- _-\__R12
. 1\
-N 0 N / R13
11 12 -0
11
,
,
R11 R11 R12 R11
0____NI
---?14¨R13 N
--f-- ___R12 N-N R12 - - R13
_ N
R12
RN 13 RN' , 13
R11
0NI R13 R11 R12
_______ N 0
_-___N-----1R13 N 12 ____ - -__Tir R12
- - /
R13
11 12 0- -N _N /
, 13 11 'N
,
,
R14 R10 R11 R9 R14
., N R13 . R12 õ R13
. ,
1 ====. --., --.,
I 1 NI
/ R12 R9 N- R13 ---"" R12
R9
R10 R11 R14 R10 R11
, , =
R14 R14 R9 R14 R9
N R9 R10., ., -.
N
/ Rlo Rlo
R R13 R13
13
R12 R11 R12 R11 R12 R11
R12 R11 R14 R13
R1c,
-, , N R13 ., N R12
--.,
1 If
R13 N R9 Rio
N Ri2 ---- Ri i
Ria Ri i Rio
,
R10 R11 R14 R14
R12 NN N R9
--, .,
-.., .
y
-Nr R13 R12 ...,.. R9
R12
R14 R11 R10 R11 R10
W4 R14 R9 R14 R9
N R9 .,
---:-.--- N N
NI
N----",Rio R10
R12 R12 R12
R11 R11 R10 R11
R11 R10 R13
. N N R13
R9 .,
--.,
1 ., ,NN
R12 1
R13 N - R10 R11 R9 R12
R14 , R10 R11
Date Recue/Date Received 2024-03-07
15
R13 R13 R10
, N R12 . N R12 N R11
1 ,
N 1 __,
R9rR9---y---- N-:"-", R11 R9-----N-----,-r" R12
R10 R11 R10 R13
R10 R11 R10 R11
R10 R11
N R12 R12
' .
..., ..., ,
1
R9---- N-----..,,H" R12 R9 N( N 1
R9- N1\1 R13
R13 R13 ,
R9 R9 R11 R9 R11
Nr1\1 R11 . R12
õ ,
''--(N -.., -..,
NI
-..(\i--------- ---- R12 . . . . , r --- - . . . õ ri ---- - - R1.2
1\1N
R10 R13 R10 R13 R10 R13
R9 R13
. N N R12 . N N R12
12 õ 'Tr <--.-.---'" --'--.-----
ifr-rN
-,...õ. -..,
NI R N
R10 10 R11
R10
,
R12
. N N R12
f
õ N N . N N R12 ' ----; -=:-.---- --.1----
1 I ,
i\j/\1 R11 wol\I-N
N R11 R10v
R11
R10 ,
,
,
, N N . N N R12 . N N R12
'--! N ' ---; --.--.-.--- ==1---
I,õ .y. 1 ,
R9 R9 r N - ----" R12 R9 ------õr N---- R11
R10 R11 R10 R11 R10
,
R12
, N N R13 õ N N R13
.,,NN
w o' NI" w 2 N
...,--r%\i--------- R12 1 NI
R9..
R11 R10 R11
R10 R11
,
R12 R13 R13
.,,NN ,NN ,,,NN
R9 1 Nr.... R1.. Ri o' I\1 R12 R10-'-'' N-.--m-,:"
R12
R10 R11 R11
R12 N R12 R11 R13
. N R11 õ N R12
. T--, N. -,....
1
,1 ,N r\ir.r N
R9 N-- N Rio wo N R10 R11
,
Date Recue/Date Received 2024-03-07
16
R13 R13 R14
N R12
., N R12 . N R13
.
1 NJ N'l
-.õ-r---N-:;---wi 'Nr R12
R1cN-N--2-----R11
i
R10 R11
R13 R13 R12
..., NN . , NN ., NI, N
N R1 NI- R9
R12 R12 R11
R11 R10 R11 R10
R12 R13 R10
N R10 , ,N R11
R9 R12 NI- R9 NI- N
R11 R10 R11 R12
R10 R10
R10
-, 1\,1 R11 N R11
N R11
N r-rN ' -- ----k---, ---.-:-..---
I õ NI
-,..(------" N-2--- R12
R9"-- N------- N-:%---- RI 2
R9 R12 , R9
R10 R11 R10 R11 R10
N R11 ., .,
N '' ---, N
-N w-.2-y-----" R12 2 1\i ''N
R12---N NI -----y--
R13 R13 R9
R10 R11 R10 R11
R10 R11
.,
N r-rN N--- R ._ 1,
-y-----
R9---- N------- N-.)--- w 2
R9 R12 , R9
R10 R11 R10 R11
R10 R11
R12
R12
.,
-ri N .
NJ -N-:2----,r1---" R12 1 N'r'e
R13.1\1N--N
R13 , R9
, ,
wo R11
R12 R1 R11 R11
-,
-....õ --.., R12
,
., ,N,N
N 'NN
NI 1 õ
' N N R13 w o---- N------ N"--J--- R12
R13
,
R14 R13 R12 R13
R14 RN R14 R9
I N R9 ,
. .
RN- R11 Rii -RN R1 Rlo RN
R13 Rlo
3
R12 R11 R12 R4I 4 I
R9 10 R10 9
Date Recue/Date Received 2024-03-07
17
R14 R13 R12 R13
R12 R11 R12 R11
R12 R14 R10 R10
-,
R9 R11 Ri 1 R9 N R9 R13 N
'RN
N R14 RN R14 R9
RN/
RN R10
R9 0 R9 R9
N __ ( __
N i4 _ 1\,\-- 0
R NN
-- \ / R9 N=1
__ \ z Rto
Ri 1_,\I lik (1\1 Ri 1 R14
R11 \
R14 R11
R11 R13 \ /
-(R12 .13 R12 R12 , R12 13 R12 13
,
R9 R9 R9 R9 R9
N N N N
\ R10 __ R10 R10
R13 D11 R13
N?_Rio \ R11 R11 R11 R11
\ / ' s /
R12 12 R13 12 R13 12 R12 13
R10 R9 R10 R10 R9 R10 Ro
H\1
\__N/ R9
__ \ / R10 R9
R11 D13 R11 R13 / R13 R11 R114 1¨R13
\ 1\/' s
R12 12 R11/ 12 R12 13 R12
R10 R9 R11 R12
R10 R9 R11 R13 R10 R11 R12 R11 R12
¨
R13 R13
R9
12 R9 /(IR10
R11 12 \R10 R9
'
R11 R12 R11 R12 R10 R10
R11 R12
c
N _ N __ c
- R13
R13 - - R13 -
/ - - -
R10
R9
R10 R11
R9 R10 \\ / 1\/
\ /
/c1 R12
¨N , 9 R12 1
NN NN N=N N=N NN
io Rio
Rio
- - \ N
\ / - - \ /)R __ -
\
R11 R14 Ri 3 R13 R11 11
R10 R13 \ / R
\ /R11
R12 13 R12 11 R12 12 R13 12
Date Recue/Date Received 2024-03-07
18
R10 R10 R10 R10 R9
N_c _ N_c N_
Rio
/
R13 D13 D11 R13 R11 R11 R12
\ / '' \ / __ ''
N
Ri2 ii R12 12 R13 12 R11
R9 R9 R9 R9
9
NI_ N__R10 _ 10 N_ R N__ N R10 _ R10
- ___________________ --R
___\I /R1C) - - - \ /
R11 R11
-N
-\1_/ /c R12 R11
's \ / 's
)R11 R12 11 , R.,,, . 12
, ,
R10 R10 R10 R10 R9
N N N N _N
N N IV IV
- -_ _______________ / -- \ / - - \ / -- ____ R10
\ (
R13 \ / R13 \ i\¨R11 Ri3 \ / R11
\ / R11 R12
\ Ki
R12 12 , 11 R12 R13 12 R11
R9 R9
R9 R9 R9
_NJ _NI _NI _NI
N R10 -- _______________________________________ R10 _ R10
R12
_ i
__ \ i_ / - \ /
1\,:R11 R11
R12 N)_R11
¨/c11 /(R Is\I /
R12 11 , R12 12
,
R9 R10 R9 R10 R9 R10 R9 R10
(N 2¨c c Rs R10
__\1_,
- (N
R12 c
R1-2-- /c - ___________________
/ R12 \ / R11
R11 ¨c11 R12 (R 11 ; R12
R9 R10 R11 R12 R11 R12
R11 R12 R11 R12
_
R13 R13
- - \ / R13 R13
R11
R10
\ ./, ___ Ki i\i4 >_R10
12 ¨N ; Rlo kio or N- .
One embodiment is directed to compounds of the general formula (I):
R'l
0 0
H
N L (i)
R2 hi 1 NY R3
1
wherein
Date Recue/Date Received 2024-03-07
19
L represents -L1- or _L12 2¨
L , preferably -L1-L2-;
L1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2C0-, or -CH2CH2C0-;
o
R1 represents
,
R2 represents
RN RN
0 Rs R11 0 R8 __ _ S R8 R11 S R8 _ _ N
R8 R11 N R8
R10 R9 , R9 R10 R9 9 R10 9 9
RN RN R10
R11 NR11 1\1 R11 0
-- R11 0 R8 - _ ),--0 R10
R8 - - " 0)
R8
N µN---
Rio ss 9 R10 R10 R8 \N----- = , , , ,
, ,
,
RN
, RN RN
, R10 R11 S il 1
_ R11 S
CD ISI.___ R8 - - ,cc- -N RN N,
N Rio
2 I 1-
1 /
)\ N N sN--- 0
R. R10 Rio R10 , __
,
,
RN R12 R12 R12
Rio N RN
----- 'N-- N N N -------------------------- r'1/21 R13
) )
..,. R13
'ND -' '
NA LI NI
\,:j
---------\R14 R13
- Ria
N. R14
RN
R12 R12 R12
R12 N R12 0 ./ 13 S ./ N
N R13
R13 --'3_R -- \ 1 R13
R14 \R14 -\R14
N Ria N. R14 Ib0 10
RN R13
R12
R12 R12 RN
,
/') R13 R13 N\--N R14
4 j \¨,j
-----\I ,õ,\--J
(.11 R9
N
R14 R14 --"--------"--;-"- \R14 _____________ R10 N'; -
\__,-----.R10
RN RN
R8
il R9
N R9
R9 N/
_ r -/_, Rio
R10 ,1\1. -/-Ri o -/-
-, D 10 )''''--/- - -
N ¨.,
)
o \\IR8
--
R8 S R8
N/ N - N
- -
- -
S)- ---- R8
R8 1\I 74 N'p\; R8 --_< '''' R8---(/0
N ,
H
N 0 S
S
\ \ \
N
i ,
,
N N
- --eNNH -- cNH
----\"- J
N1
---N3 N
/ _______________________________________________________________ \\J
N __ c
S z
Date Recue/Date Received 2024-03-07
20
N N
N , N j N
_ N N'-eN0
N
0 6 z 0 NI j
H cNr1-j S
-
_s
-S H H
- N /..
S---/
,
H
S-N
N
,
0 N
-cNr1-- N-N-0
0- ---7
H H
'
N /
,
,
õ N
i -
I I
IV
-, N -, -,
N
,
N õ N
N
NI 1=1
'
N .
., .,
N N
LL Il LJ
N 1=1
,
., . N N
\ --! .'-!NN
- N I
N'
. N
--! '-! -----,
N I I
N 1\1-
,
'' ---, N
I I I
1=1 I\IN Nle
N .
1\1N
N N , N N
-11
N NI
N NI N
,
Date Recue/Date Received 2024-03-07
21
, N N . N N
.--rNN
N
--!
I
N Nr ---- --<.--- ---.1
1
I\IN
, N N . N N , N N
'-! N T ' 1
N
N
, N N ., N N . N
'-! N
1
I\ I
1\1 \%\KI
N
,
, . N
--! N '-! N .,,rNN
I I
1=1 1=1 I\Iõ ,
. N . N õ N
I I ,r
N I\IN N,N
. N ., N- , N
'-!
I If If
Nle le -Nr
, N , ,
., N
1=1 N '', NN
Il I
1=1 1=1 ,
N
'--1
'---,
I
NN
. N N , N
'1\11
N I NI
N Nr
, N , ,
-,
N '' ---N
N , N 1 Ki
1=1
-N NV
I
NN Ni\I Nii\I
'-r
N
N'N i\IN N
N
. . . N
--r -,
'-! N
I
r\I-NN 1\i'lele
H
, NH
H H ,
,
.,
N NH
H
H ,
NH , ,
,
Date Recue/Date Received 2024-03-07
22
N
_0 NN N N
\I
LJ
,
N N ___ ' N N
N
1 - - -- \ / -- __
/¨ \I
---1 - __
Lt=
,
14 \
\ ,
,_ ,
______________________________________________ ..
, / \\¨N NN N=N N=N NN NN
- N -- /T\ ---
11 -- ___________________________________ --
, , ,
, ,
N N
\. N N N
_\1
1\1
¨ ¨\1
\ _________________________________________________________ N
,
N_ N __ '
¨N_ii --'N __________ N____ '
--_/1\ N __ /
, , , ,
__ __ NI/A\I N N N __N
'
K N K N
\I\
N /N __N ' N __________ N '
-- //
\ - \1¨)
is1 \ - \J
___ Il - ) \ K 1 , ,
, , ,
Date Recue/Date Received 2024-03-07
23
iv \
-14 , , -1<i ; ts\i/ or /
,
wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of
the
substituents R6- R14 and R" ; and preferably with 1 to 3 of the substituents
R11- R13;
wherein
i) L2 represents a bond, -NRN1CH2-, -NRN1CH2CH2-, or -NRN1CH(CH3)-; and
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,
1-bicyclo[3.1.1]heptyl, 3-bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl,
bicyclo[3.2.1]octyl,
bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-
homoisotwistyl,
diamantyl, hexamethylenetetraminyl and the afore-mentioned residues optionally
contain one or more C=C double bond(s) and/or are optionally substituted by
one or
more of Ra, Rb, Rc, Rd, and Re; or
ii) L2 represents a bond, -NRI41-, -NRN1CH2CH2-, or -NRN1CH(CH3)-; and
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,
bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl,
bicyclo[3.3.2]decyl,
bicyclo[3.3.3]undecyl, 4-homoisotwistyl, 2-adamantyl,
diamantyl,
hexamethylenetetraminyl and the afore-mentioned residues optionally contain
one
or more C=C double bond(s) and/or are optionally substituted by one or more of
Ra,
Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -
Br,
-CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3,
-COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C21-13, -CON H2, -CONHCH3,
-CON(CH3)2, -CONHC2H3, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H3, -CH2CON H2,
-CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H3, -NHCOCH3, -NHCOC21-13,
-NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-13, -NHSO2CHF2,
-NHSO2CF3, -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3,
-CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3,
-CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3,
-cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -
cyclo-C6H11, -CH2-cyclo-C3H3,
-CH2-cyclo-C4H7, -CH2-cyclo-C31-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph,
-CH2OCH3, -CH2OCH2CH3, -
CH2CH2OCH3, -CH2CH2OCH2CH3,
-CH2CH2NHCH3, -CH2CH2N(CH3)2,
Date Recue/Date Received 2024-03-07
24
- -N -
or -NR8R7 is -N(C2H5)2, - Or __ - )
R8, R9, R", R11, R12, R13, and R14 represent independently of each other -H, -
F, -CI,
-Br, -I, -OH, -
CN -NO2, -CH3, -C2F15, -C3H7, -CH (CH3)2, -C4H9,
-CH2-CH (CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5,
-CH2OH, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F,
-CH2-CH F2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3,
-0C21-15, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3,
-0C H2CF3, -0C2F5, -OCH2OCH3, -
O-CYCIO-C3H5, -OCH2-CYCIO-C3H5,
-0-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7,
-COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7,
-COOCH (CH3)2, -COOC(CH3)3, -
00C-CH3, -00C-CF3, -00C-C2H5,
-00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC2H5,
-NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2,
-N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5,
-NHCOC3H7, -N HCOCH (CH3)2, -
NHCOC(CH3)3, -CON H2, -CON HCH3,
-CONHC2H5, -CONHC3H7, -
CON HCH (CH3)2, -CON H-cyclo-C3H5,
-CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2,
-CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7,
-SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -S02N(CH3)2,
-SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3,
-NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -N HSO2CH (CH3)2, -NHSO2C(CH3)3,
-CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3,
-CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph,
N( r N
r r
rN r r Y --N NH --N _N
N-
\ , or \ ___ ;
or R8 and R9 or R9 and R1 can form together one of the following five-
membered or
six-membered rings:
0 N
- ---? , ,
. . N ' N m
- N
, or ;
Date Recue/Date Received 2024-03-07
25
or R12 and R13 or R13 and R14 can form together one of the following five-
membered
or six-membered rings:
()
-N
or I
R" represents -H, -CH3, -C2F15, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2,
-CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3F15,
-cyclo-C4H7, -cyclo-051-19,
-CH2-cyclo-C3F15, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2F, -CHF2, -CF3,
-CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -CH2-CF3, -CH2-CH2C1,
-CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3,
-00C21-15, -00C3H7, -COCH(CH3)2, -
00C(CH3)3, -CO-cyclo-C3F15,
-CO-cyclo-C4H7, -CO-cyclo-051-19, -COOCH3, -CO0C2H5, -CO0C3H7,
-COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-15,
-S02C3H7, -S02CH(CH3)2, -S02-cyclo-C3H5, or -S02C(CH3)3;
KNI represent -H, -CH3, or -CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of
enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically
acceptable salt
thereof.
In one embodiment the herein disclosed inventive compounds, the moiety -L-R3
is not
N H
or
In one embodiment of the herein disclosed inventive compounds, L represents -
L1-L2-;
L1 represents -CH2-, or -CH2C0-; and
L2 represents a bond, -NH-, -NHCH2-, -NHCH2CH2-, or -NHCH(CH3)-.
In one embodiment of the herein disclosed inventive compounds, L represents -
CH2-,
-CH2CO-NH-, -CH2CO-NH-CH2-, or -CH2CO-NH-CH(CH3)-.
In preferred embodiments of the inventive compound of formula (I), R2
represents
Date Recue/Date Received 2024-03-07
26
RN RN
0 Ra Ril 0 R8 __ _ S R8 R11 S R8 R8
R11 1\1 R8
R10 R9 / ,-,9 D10 09 9
R10 9 9
M , '' rµ
RN RN RN Rlo
i 1 N R11 N N D11 0 0 08
¨r 'N --1 ;N --- 'N
R , -, , I._ _ _ R1:_!.0Ra - -
)-- i.
R10 sµ ,/---\R9 R10 9 R10 , ./ , R10 R8
; ,
RN RN
R1 ,
N 10 R11 S
_ _ R11 S
R8 R8 -- _ S R8 R11 N
R
0)r (3)\IZ --1 i." ---Q---- --$'
_________________________________________________________________________ Ni
\N---- , Rs R10 R10 R10
,
RN
RN R12 R12
NI' KI Rio R10 N RN
N N R13 i-r-
1 R13
'N¨
N=Ni -----\R14.
N'14
,
p 12 p 12
R12 R12 N R12 0 ./s R13
_ _
N 1 ./)s
ri.... R13 -------------------- R13 k1 R13 \ i _ _ _
R13
N14 1\1\11114.\-)
N14\-)
N14 10 \R14.
\R14
5 , RN
R12 RN
iv
I \
1 0
R14 iv ___ :/..,
R12
' - I 13
- - 1\ ,TR
----\iR14 R12
'/'\T) R13
R12
R13
13
4N
L j 7 R
R14
R14
R13 RN RN RN
` R9 N R
N 7 ii R9
. 1õ,,..._ R14.
N9
r--- - i R1c, N . ,
I __ s ( r--- -71 Rio ,...õ ---,--, R
in
..
Rio------4N--- - - ------ R10 )
0 ,
;
R8 R8 S , - R8
R9 S ,-
Na / II
R8
dli - - S)- - - ---Ni S
Ri,-
N
<...; Nr_ , n u1
- - IN R8 .._ 4\1,-_-_N R8 0---N
N , - N , - 0
R8-1\1 R8-1)
- -
N
H
N 0 S S
, , N
, , , ,
,
'
N N
- ---NNH ----CNN
N7 ---( ---(NN3
V V
6 j z ( \\I
----Cs ----Cs ----NH - - -CNN
N N
'
Date Recue/Date Received 2024-03-07
27
_ N N
- -(1V ______ ----(NN3
,
N
0 a Z 0 Nj
H S
-/cNr1- ___[-----
__ N, --o------$ _s
-S H H
S- ---/
H
S-N
N
,
O N
N--N-0
0- ---7
H H
,
--Nr--/ - 0
-N t
0N -- -N
,
,
õ N
i
I I
N
N -, -,
N
,
N õ N
N
NI 1=1
N .
. .,
N N
LL Il
N Lk 1=1
,
' ., . N N . N
\ --! '-! N
- N I
N -
,
. N
--! '-! -----,
N I I
N
,
N
I I I
I\IN Nle
N ,
1\1N
,
N N , N N
-11
N NI
N I\JN
. N , N N . N N
'- N
N
--!
I
NN
Date Recue/Date Received 2024-03-07
28
, N N . N N , N
-T
N _N
,
1
N
, N N ., N N . N
--! '-! N
I
I
1\1- \%\j
'
N N
,
, , N N N
--! --!
I I ''-r N
N I\IN KIN
,
'
N ., N- ., N
I If If
Nle , le -Nr
'
1=1 1=1 '-, NN
N I
1=1
, N N
'--1 NN
''--,
I
N N--N I\IN
. N N , N
'1\11 I
N Nle N le
' N -,
N, ''N,
--'r
N ,N
1=1
-N N'
I
NN , i\INI NNI
,
N'N i\IN-'N N
N
. . . N
--r --r
'-! N
I
r\I-NN
,
H
-, NH
H H ,
,
.,
N NH
H'
H NH , ,
,
N ___ \ 0 NN N NI_
N
-- \\ /c -\I
//
-- \ / \ /\1
0
,
Date Recue/Date Received 2024-03-07
29
N N N N
--- N
/1\ 1K)
--- ' , ___________ /IN,
-K-)\1
---___/ \ --
-1 _______________________________ / , __ (
, ,
-)\1
14 \
N N
\ / /
c
N / \\-N
____________________________________________________________ , ,
N=N N=N NN NN N=N
- N --- /T\ ---\1
lik --- _________________________________ --
N __ \I' ,
N ________________________________ ,
N ,
N N __ ,
\I
1 ics1
\ __ 14
N_ N_ ' N __ ' N N____ '
---1 --,-1 --_/1\ -- 1/\ --,
,
/__N N N N
--8 - r\ __ 2\51 1
,
N N __N ' N N '
)\1
i\l¨ =
Or
Date Recue/Date Received 2024-03-07
30
wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of
the
substituents R9 ¨ R14 and RN; and preferably with 1 to 3 of the substituents
R11 ¨ R13
and the substituents R9 ¨ R14 and RN3 have the meanings as defined herein.
In even more preferred embodiments, R2 represents:
RN RN
0 Ra Ri 1 0 R8 __ _. S R8 Ri 1 S R8 _
_ N Ra R11 N Ra
- r ir lr -\___--
Rio _______ R9 , D9 R10 09 9 R10 9 9
RN RN RN RN RN RN
R11 ii R11 N,N N R11 Ki _ R11 il R8 _N
R8
_
--1 jt1
I I l(
Rio µs // R9 R10 9 R10 R10
' ,
" R10
R10 '
R11 0 0 p8 - ' R1
R10 0 R11
S
R11 0 R8 - -1,- , .
19)4\1Z- ICI)R8
1 _________________________________________________________________________ I--
-- -
R10 R8 4\r--- = (342\i-Z
R..,s,
Rio
, , = , ,
RN
RN RN
R11 S R8 S R8 -__ _KI,N Rii N
N N
, Rio Rlo N RN
I i--- --1 __________ I--- N ----- N
----- ' N-
\_
N
Rio Rio ,
,
RN R12 R12 R12 R12
N N N-R x ri -1 1k) R13 1.1.: R13 f
R13 N/.)
R13
--,kN
Lt, j \-)
N-N N=N1 ----- R 1 4
, N Ri4 N Ri4 N'
R14
RN
R12 R12 R12 RN
N R12 0 A 13 1\1
S 1 A p 13 1 A R13 1\1.: R12
R -- \ 1 - -- \ 1
X) 13
-
\-) \R14 R14 \R14 N --
---\14
N Ri4 10 10 10
R13
RN
R12 R12 RN
.
-,7"-------- K 13 \ NykrR14 II
R9
I I R13 L i R r--
- "ii Rio
- id s (KI R9
R14 R.. RioN-') - \___,-----
...R10
RN
R8 R8
il R9
_ r Yr Rio
p 1 0 o N/¨
R9
--/--. 10 )'''''-r- S)-
\õ ¨,. N ¨1-= ?\1 c R8
S,- ' R8
N'.___Nil S- . N - N ,-
R8 , 1\ d'Il- R8 ,
--__< R8-__c) II
R8
' ' ' '
H
N 0
\ \ \ N \(
, N
, , , ,
,
Date Recue/Date Received 2024-03-07
31
---NH - - -CO S N s
- - -N
,
-,
,
I 1 N N
/
. , N N .
- 1 -r
N --<
N N
H ,
N NH
, H ,
---t/N
or
,
wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of
the
substituents R9 ¨ R14 and RN; and preferably with 1 to 3 of the substituents
R11 ¨ R13
and the substituents R9 ¨ R14 and RN have the meanings as defined herein.
Thus, the present invention relates to compounds of the general formula (I):
R*I
0 0
II1N7LR3 (I)
R2 hi 1
1
wherein
L represents ¨L1¨ or _L1-L2¨; preferably ¨L1-L2¨;
L1 represents ¨CH2¨, or ¨CH2C0¨;
L2 represents a bond, ¨NH¨, ¨NHCH2¨, ¨NHCH2CH2¨, or ¨NHCH(CH3)¨,
o
R1 represents
,
R2 represents
RN RN
0 _______________ R8 Ri 1 0 R8 __ _ S R8 Ri 1 S R8 _ _ N R8 Ri 1 N R8 r
1 r 1 r -\___--
Rio _____ R9
/ R9 Ri 0 09 9 WO g 9
RN RN RN RN
Ri"1 1 N t1 R N N N R8 Ri 1 0
_ _ Ri 1 N R8 - _ Ri 1 0 Rs
j
Rio µs Rio Rio Rio
Date Recue/Date Received 2024-03-07
32
R10
R19 .
--101_1R8
,o)--i Rto R11 S ii S 8
1R8
c,
Rio R8 Rõ Rio
,
RN RN
S Rs Rii N RN R12
Rio
'N N ---
NI \-1C1 p10 N, _ppN
's '--- N 's
-N N
--- 'N fr...1 R13
u _\,,,j
Rio N-I\i' -."-
------\R14
R12 ,
R12 R12 R12 N R12 0 ./
...
N/ --- \ i IRli l Ri3 ir-'1 R13 R13 rr /-'1 Ri 3
N\-114. \N
N Ri4\-)
N14 N\-114 10 R14
RN
R12 R12 RN
S i A p13 1\1 1 'Al p 13 /' s 1, - 7------../
p12
R12 R12
- - \ 1 \T- -- \ 1 - R''-' i R13
r/1 R13
_......_
-\ in
10 ' RN 14 ,
\R N ----\\;14 \-----) R4., ,,
id /\\-'
pp . .
,
RN
RN R8
II R9
\......:R:
7/Rio N'\
R8
S/- - --N R8 S , ____I\IN ,
R8-1\1 I N R8 - R8--co
or ---
N
R3 represents bicyclo[1.1.1]pentyl,
bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,
10 bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,
bicyclo[3.2.2]nonyl,
bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl,
diamantyl,
hexamethylenetetraminyl and the afore-mentioned residues optionally contain
one or
more C=C double bond(s) and/or are optionally substituted by one or more of
Ra, Rb,
Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -
Br,
-CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3,
-COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H5, -CONH2, -CONHCH3,
-CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2,
-CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5,
-NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2,
-NHSO2CF3, -NHSO2CH2CF3;
R4 represents -NR6R7;
Date Recue/Date Received 2024-03-07
33
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3,
-CH(CH3)2, -CH2CH2CH2CH3, -
CH2CH2CH2CH2CH3, -CH2CH(CH3)2,
-CH2CH=CH2, -
CH2CH=CH (CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3,
-cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -cyclo-C6H11, -CH2-cyclo-C3H5,
-CH2-cyclo-C4H7, -CH2-cyclo-051-19, -
CH2-cyclo-C6H11, -CH2OCH3,
-CH2OCH2CH3, -
CH2CH2OCH3, -CH2CH2OCH2CH3,
-CH2CH2NHCH3, -CH2CH2N(CH3)2,
--N --
or -NR6R7 is -N(C2F15)2, --N NO Or
--K ) .
R6, R6, R10, R11, R12, R13, and R14 represent independently of each other -H, -
F, -Cl,
-Br, -OH, -CN, -NO2, -CH3, -C2F15, -C3H7, -CH(CH3)2, -C4H9,
-CH2-CH (CH3)2, -CH (CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5,
-CH2OH, -CH2F, -CHF2, -CF3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F,
-CH2-CH F2, -C H2-C F3; -CH2-CH2CI, -CH2-CH2Br, -CH2-CH21, -OCH3,
-0C21-15, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -0CF3,
-OC H2CF3, -0C2F5, -OCH2OCH3, -
0-cyclo-C3H5, -OCH2-cyclo-C3H5,
-0-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7,
-COCH(CH3)2, -00C(CH3)3, -COOK -COOCH3, -CO0C2H5, -CO0C3H7,
-COOCH (CH3)2, -COOC(CH3)3, -00C-CH3, -00C-
CF3, -00C-C2H5,
-00C-C3H7, -00C-CH(CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC2H5,
-NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2,
-N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5,
-NHCOC3H7, -N HCOCH (CH3)2, -NHCOC(CH3)3, -
CON H2, -CON HCH3,
-CONHC2H5, -CONHC3H7, -CON
HCH (CH3)2, -CON H-cyclo-C3H5,
-CON HC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2,
-CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7,
-SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -
SO2NHC(CH3)3, -SO2N(CH3)2,
-SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3,
-NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -N HSO2CH (CH3)2, -NHSO2C(CH3)3,
-CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -CECH, -CEC-CH3,
-CH2-CECH, -Ph, -0-Ph, -0-CH2-Ph,
H
N H H
1\( N N
r N
- ---- -. -NO
L---)r- - N N
,
N H
N
N
r ):,--Ni NH--Ni \I- I\Y \I __ \
- _
0 0 \ __ / , \ / , or \ /
\ ;
,
Date Recue/Date Received 2024-03-07
34
or R8 and R9 or R9 and R1 can form together one of the following five-
membered or
six-membered rings:
0
_0 __N '
_
'1\1 , or ;
or R12 and R13 or R13 and R14 can form together one of the following five-
membered
or six-membered rings:
_0,
''N
0 or
R" represents -H, -CH3, -C2F13, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2,
-CH(CH3)-C2H3, -C(CH3)3, -cyclo-C3H3, -
cyclo-C4H7, -cyclo-C31-19,
-CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-C31-19, -CH2F, -CHF2, -CF3,
-CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2; -CF12-CF3, -CH2-CH2CI,
-CH2-CH2Br, -CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3,
-00C21-13, -00C3H7, -COCH(CH3)2, -00C(CH3)3, -
CO-cyclo-C3H3,
-CO-cyclo-C4H7, -CO-cyclo-C31-19, -COOCH3, -COOC2H3, -CO0C3H7,
-COOCH (CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3, -S02C21-13,
-S02C3H7, -S02CH(CH3)2, -S02-cyclo-C3H3, or -S02C(CH3)3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of
enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically
acceptable salt
thereof.
Preferred are the compounds of the formula (lb):
0
0
zrIJ N-R6
0 714 0
R2AN NAL
(Ib);
and L, R2, R3, R8, R7 have the same meanings as defined in the formula (I)
Preferred are the compounds of the formula (lb):
Date Recue/Date Received 2024-03-07
35
o
o
N - R6
0 714 0
H
R2 AN NNI'L'R3
H
(lb)
wherein
L represents ¨L1¨ or ¨1_1-L2¨; preferably ¨1_1-L2¨;;
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NRI41¨, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRN1CH(CH3)¨;
R2 represents
RN RN
0 Ra R11 0 R8 __ _ S R8 R11 S R8 _
_, N R8 R11 N R8
_
- lr \ , lr -\__
R10 _______ D9 /
' R9 D10 __ R9 9 R10 9 9
rµ ; , 's
RN RN RN R1
R11 N R11 k N
N - ---- 'N
R1,1 .,0 _ _ R11 0 R8 - _
)c(:).__ R8
3\ d i __ ,---
R10 µs / __ R9 R10 \R9 R10
R10 R9
; ; ;
RN RN
Rio ,
, Rio R11 S N
R8 _ _ Ri i S R8 - __ ),S1,..__Ra - _ _
,,,,, Ri i N,
(21) (32 "
ni' \
N
NI
IV¨ 10 , \N----
R8 Rlo Rio Rio ,
,
RN'
RN R12 R12
Rio N N RN N Rio N ----- ' - N' --- N
D N ir-1/21 R13 R13
-'`
\ u \-)
, V ¨ii \I=N1 , ----
---\R14 N Ru
,
,
R12 ,
R12 R12 N R12 0 R12 A 13 S A
13
R13 N/.) R13 r R13 -- \ 1 TR -
- \ 1 R
N\11114 \-)
N. Ru N. Ru 10 -\.i-R14
-\;j14
RN
R12 RN
1\1 A 13 RN R12
R12
- - ._ S
---3C,\TR II R9 R1-.3
- - 1
N----- 14\'R
,
R13 RN
R12
H,
1\1)-- Du R9
' '
N
N¨S
_ r %1 R10
\R14 R10----NI S Nj
RN
H
il R9 .N. _).:(..7: ir, R9
_ r -/Rio
\ / / 4_/_,
R ¨ / m _Rio
,' , , -
, ,
Date Recue/Date Received 2024-03-07
36
S
\ N/\
-Nr R8
R8 R8;
S - N
R8
R81\111- NV 7,
b-N
or
N -
R8-1)
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,
bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl,
bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl,
bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl,
diamantyl,
hexamethylenetetraminyl, and the afore-mentioned residues optionally contain
one or
more C=C double bond(s) and/or are optionally substituted with one or more of
Ra, Rb,
Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -
Br,
-CN, -OH, -CH3, -
CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3,
-CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H3, -CONH2,
-CONHCH3, -CON(CH3)2, -CONHC2F13, -CH2CO2H, -CH2CO2CH3,
-CH2CO2C2H3, -CH2CONH2, -
CH2CONHCH3, -CH2CON(CH3)2,
-CH2CONHC2H3, -NHCOCH3, -NHCOC21-13, -NHCOCF3, -NHCOCH2CF3,
-NHSO2CH3, -NHSO2C21-13, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3, -CH2CH2CH3,
-CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3,
-CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3,
-cyclo-C3H3, -cyclo-C4H7, -cyclo-C31-19, -cyclo-C6H11, -CH2-cyclo-C3H3,
-CH2-cyclo-C4H7, -CH2-cyclo-C31-19, -CH2-cyclo-
C6H11, -Ph, -CH2-Ph,
-CH2OCH3, -CH2OCH2CH3, -
CH2CH2OCH3, -CH2CH2OCH2CH3,
-CH2CH2NHCH3, -CH2CH2N(CH3)2,
or -NR6R7 is -N(C2F13)2, - - -
or
R" represents -H, -CH3, -C2E-13, -C3H7, -CH(CH3)2,
-C4H9,
-CH2-CH(CH3)2, -CH(CH3)-C2H3, -
C(CH3)3, -cyclo-C3H3, -cyclo-C4H7,
Date Recue/Date Received 2024-03-07
37
-cyclo-051-19, -CH2-cyclo-C3F15, -CH2F, -CHF2, -
CF3, -CH2CI, -CH2Br,
-CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br,
-CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-15,
-00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOCH3, -CO0C2H5, -CO0C3H7,
5 -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -S02CH3, -S02CF3,
-S02C21-15, -S02C3H7, -S02CH(CH3)2, or -S02C(CH3)3;
RNi represent -H, -CH3, or -CH2CH3;
and R8- R14 have the meanings as defined above for formula (I);
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of
enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically
acceptable salt
thereof.
Preferably, R2 represents
RN RN
0 R8 Ril 0 R8 ___ S R8 W 1 S R8 _ _ NI R8 Rii NI
R8 \ , lr i___--- -\___--
R10 _____ D9 /
' R9 D10 n9 9 R10 9 9
RN RN RN Rio
Ri i N Rii NI NI 0 0 D s
-1 jt1 I ;(1\ I - - == ' N - ------Y - - Ri
i 01,____ R8 - - )-- i . 0 --,. - -
____________________________ q \ 1 \ 1
\NI--
Rio µs ,/ R9 Rio \R9 Rio Rio 0
RN RN
Rio ' N
, Rio RS i S
R8 RS R8 - _ 3õ-SI____ R8
Rii N,N
- -
102 N-
R8
Rio Rio Rio / \ N
,
= , , , ,
' ,
RN
RN Ri2 Ri2
N
, NI Rio o IAio N,NIA
04N
NI N D N ir..1 R13 R13
\---- NI
- - -L 'N.1 - - 'N-' ' N -
=NI 44
z' ,
R12 R12
R12 R12 N R12 0 A 13 S A
13
ri.....:1 R13 N/.) R13 IR) ,) R
N N N \11S14 \')
. R14 \-)
. R14. io - 14
10
\R14
RN
Ri2 RN
R12
i\j---/ 1 13 R12 R12 \i,....---://,,,
-- -_\TR --4 i -R R13
\J 13 R 1
L j R3
Filo - =R14 NI ------\R14 R14 -'----"--
----,----\1:z14
Date Recue/Date Received 2024-03-07
38
R13 RN RN
N
. R9
% µ
14 R ii R9 Ni
r 1 r /I
Rio--)c R
-) ___________ s (II,R9
Rio -,- Rio 7
0 S
R9 1\1
Ri.n Rio ,
_/_, N'\ 1 N - S).- - .. / m
\N
R8
,-
- 8 ----.. -
R8 --1\1 I N_ R -1\1 -1) --i\i
, b-N , , or R8
Preferably, -NR6R7 of the formula (lb) represents -NH2, -NHCH3, -N(CH3)2,
-NHCH(CH3)2, -NHCH2CH2CH3, -NH-CH2CH=CH2, -NHCH2CH2CH2CH3,
-NHCH2CH(CH3)2, -NHC(CH3)3, -NHCH2CH2CH2CH2CH3, -NH-cyclo-C3H6,
-NH-cyclo-C4H7, -NH-cyclo-C6I-16, -NH-cyclo-C6Hii, -NHCH2-cyclo-C3H6,
-NHCH2-cyclo-C4H7, -NHCH2-cyclo-C6I-16, -NHCH2-cyclo-C6H11, -NHCH2-Ph,
-NHCH2OCH3, -NHCH2OCH2CH3, -NHCH2CH2OCH3, -NHCH2CH2NHCH3,
-NHCH2CH2N(CH3)2,
--N --N - -NO ___ or --K )
.
In some embodiments, the present invention relates to the compound of the
formula (I),
R1
0 0
H 1- (I)
2N N7 R3
R H 1
wherein
L represents -L1- or -L1-L2-; preferably -L1-L2-;;
L1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2C0-, or -CH2CH2C0-;
L2 represents a bond, -NR'-, -NRNICH2-, -NRN1CH2CH2-, or -NRN1CH(CH3)-;
0
R1 represents ' NR6
eL
H .
,
R2 represents
Date Recue/Date Received 2024-03-07
39
RN RN
0 Ra R11 0 R8 ___ S R8 W1 S R8 ___ NI R8 R11 N R8
-_
Rlo R9 / rµ ri, rµ
9 R10 n9 9 R10 9 9
'
RN RN RN Iwo
R11 N w 1 NI NI p11 0 0 D8 . -
I ;t1 -1 --- 'N ----1 i.-- R1:_ilOrr R8 -
_. ,$, ..
)\
N¨
R1c, sµ ,//¨\R9 R10 \R9 R10 R10 R8
; '
RN
wo ,
, lo R11 S R11 S R8 -- S R8 _ _
NI
0)r R8 (32\IZR R8
N---- , R8 R10 R10 R10
RN RN RN
NI NI RN
R11 N R10 N RN , R
-- '--- :N
N -- 'N- N
-
'
)` __________________ nf )¨Ni
Rio , NA
R12 ' R12 ' R1.2
,
R12 '
N R12 '
R13 ) 1.1.-- R13 fl R13 N
------------------------------------------------------- _1 R13 r /-
) R13
\i \-)
-------\Ri4 N R14 N R14 Ni14. N R14
5 , , , , '
RN
R12 R12 Ri2 RN
__:cS xiR 13 _ _ RN
R12
...
13 N
I ¨R 1 R13
Rh' __
\ ,\ 9II R - -4 1
I
R14 R14
1\\\-)
R14 r_ N----14
10 10 10 ----\___/-------R10
R13
R12 R12
S H , ________ N
vN___Ri4
R13
S
R14 -'"-----"- -'---="\R- 14 R10 __ N
RN RN
H
il N R9 N
R10 _ I R9
r -/Rio c2iJTi1
c-NJ (21) i
, 1_9 R9
10 1\_/_., 1 1
¨R N
I\I
- 1 ,-.
' R8 R8 S
,-
, S , - NI
10
N
NI\ I )ri.-- S)---
N) NN \N R8 \S-N `N-_,-N R8
, ,
, '
' R8 ,
S , - . N , - N
R81\I 11 -
N6- ./
b-N R8-1\I R8¨/0 11
, , , or
R3 represents bicyclo[1.1.1]pentyl,
bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,
bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl,
bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl,
Date Recue/Date Received 2024-03-07
40
bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl,
diamantyl,
hexamethylenetetraminyl, and the afore-mentioned residues optionally contain
one or
more C=C double bond(s) and/or are substituted with one or more of Ra, Rb, Rc,
Rd, and
Re;
R6 represents ¨H, ¨CH3, ¨CH2CH=CH2, ¨cyclo-C3H3, ¨CH2CH2CH2CH2CH3;
and R8 ¨ R14, Ra; Rb; Rc; Rd; Re; rµ mni,
and RN1 have the meanings and preferred
meanings as defined herein.
Also preferred are compounds of the general formula (I),
R1
0 0
H L (I)
R2N N Nv R3
H 1
wherein
L represents ¨L1¨ or
L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, ¨CH2CH2C0¨;
L2 is a bond, ¨NR'¨, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRN1CH(CH3)¨;
0
R1 represents .
' ieLR4 =
,
R2 represents
RN RN
N 8 R8 R11 S ii 8 -R- N R8
o R8 Rii o R __ _ R8 R S R -- _
1 _______ r ,--- i ____ r \ ,
Ri0 R9 / __ m9 Ri 9 // R9 D10 R9 / R9
RN RN RN
R11 N, N RN Rii 0 Ril 0 R8 ----- 1 t
1 r----
Rio µµ / R9 Rio 9 R10 R10
RN RN
N RN
R11 S R11 S R8
--- 'N Rii N
N -----
---N i
---- 'N
NA
Rio Rio Rio
R12 R12 R12 R12 N R12
N RN /-1 R13 R13 R13 N r 4)
1
R13
- - -N--
.%\-414 \-) R13
\-)
N=N N Rizt 'N Rizt N Rizt N Rizt , , ,
Date Recue/Date Received 2024-03-07
41
RN
R12 R12 R12 RN
0 A _ i.<13
___
\R14 S ./) _ i.<13
--
10 \R14 N
-- I }R13
\
io i.g14 R12
--
I\L----/') 13
N------\\-R14
R13 RN
R12 R12 RN
,
U13 r-.7- 13 Ri4 K1 R9 TR L i
R3 N r,\! (riR9 r -/i
- sR14
R14 R10---N) - \ -R _
Rio
RN
K1 R9 R9
DFin, 9
N. _r '/1 RW e-/IRI N Ri 0
o) ,- , or
5 R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl,
bicyclo[2.2.1]heptyl,
bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl,
bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl,
bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl,
diamantyl,
hexamethylenetetraminyl, and the afore-mentioned residues optionally contain
one or
more C=C double bond and/or are substituted one or more of Ra, Rb, Rc, Rd, and
Re;
Ra, Rb, Rc, Rd, and Re represents independently of each other -H, -F, -Cl, -
Br,
-CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3,
-CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C2H3, -CONH2,
-CONHCH3, -CON(CH3)2, -CONHC2F13, -CH2CO2H, -CH2CO2CH3,
15 -CH2CO2C2H3, -CH2CONH2, -CH2CONHCH3, -
CH2CON(CH3)2,
-CH2CONHC2H3, -NHCOCH3, -NHCOC21-13, -NHCOCF3, -NHCOCH2CF3,
-NHSO2CH3, -NHSO2C21-13, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;
R4 represents -NR6R7;
R6 and R7 represent independently of each other -H, -CH3,
-CH2CH2CH3, -CH(CH3)2, -
CH2CH2CH2CH3, -CH2CH2CH2CH2CH3,
-CH2CH(CH3)2, -C(CH3)3, -
CH2CH=CH2, -CH2CH=CH(CH3),
-CH2CH=C(CH3)2, -CH2CH=CHCH2CH3,
-cyclo-C3H3, -cyclo-C4H7,
-cyclo-C31-19, -cyclo-C6H11, -CH2-cyclo-C3H3, -CH2-cyclo-C4H7, -CH2-cyclo-
C3H9,
-CH2-cyclo-C6H11, -CH2-Ph, -
CH2OCH3, -CH2OCH2CH3,
-CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2,
or -NR6R7 represents - -N, - -N --N
Or -- __ )
\ =
,
Date Recue/Date Received 2024-03-07
42
R" represents -H, -CH3, -C2E-13, -C3H7, -
CH(CH3)2, -C4H9,
-CH2-CH(CH3)2, -CH(CH3)-C2H3, -C(CH3)3,
-cyclo-C3H3, -cyclo-C4H7,
-cyclo-C31-19, -CH2-cyclo-C3H3, -CH2F, -CHF2, -CF3, -
CH2CI, -CH2Br,
-CH21, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CH2Br,
-CH2-CH21, -CH2-CH=CH2, -CH2-CECH, -CHO, -COCH3, -00C21-13,
-00C3H7, -COCH(CH3)2, -00C(CH3)3, -COOCH3, -COOC2H3, -CO0C3H7,
-COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -
S02CH3, -S02CF3,
-S02C21-13, -S02C3H7, -S02CH(CH3)2, or -S02C(CH3)3;
RI" represent -H, -CH3, or -CH2CH3;
or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of
enantiomers, a racemate, a solvate, a hydrate, or a pharmaceutically
acceptable salt
thereof.
Also preferred are compounds of the formula (I) or (lb), wherein
I-1 represents -CH2-, or -CH2C0-;
L2 represents a bond, -NR'-, -NRNICH2-, or -NRNICH(CH3)-;
R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl,
bicyclo[2.2.1]heptyl,
bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 4-homoisotwistyl, adamantyl, or
diamantyl, and
the afore-mentioned residues optionally contain one or more C=C double bond(s)
and/or are substituted by one or more of Ra, Rb, Rc, Re', and Re; and
Ra, Rb, Rc, Rd, Re and RNI have the same meanings as defined herein.
Preferably, R2 of the formula (I) or (lb) represents
R10
R10
Ri R8
- 1 _______ r i 0
\ , R s R8 ii 0
i r )--
0).-yR8
Rio R9 .
/ R9 Rio __ R9
/ R9 R8 sN-----
'
RN RN
', Rio Rii S Rii S 0r8 -., S R8 -- 11 R8
102 1 ----- -1 i -c\___Ir
\N---- N
R8 Rio Rio Rio Rio
RN RN
Riz Riz
R11 N N N' R10 pp10 NN - , _ ppN
N
- --f _
- D N f) R13 R13
N-"
\ --- '
\-)
// ; \I=N1 ; ------- Ria N Ria
Date Recue/Date Received 2024-03-07
43
RN
R12 R12 R12 RN
R12 N R12
S A 13
iv
0 A
_......,
L( % R13 - - \ 1 gR13 R - - \ 1 --/'\ R13 - - 4 1
,JR13
N14 10 R14
R14
10 R14 N -----\\fR14
R13 RN RN
R RN
12 s il R9 '
s N R9 ,
N N. "
N R9 r -,, r 71 Rio
;¨ ( __ Rio
R14 Rio N -
R8 R8 S , -
' ,
% R9 S -
Ni_II S
NI/ , -
I
/ " ,1\1 --/--, R10 , _Z Nri . S)-
R8--/
\\NI 11
" R8 \S-N `N,-_- N R8
R8
N , - N
1\d'i. - R8-1\1 ''' R8// 1
or
5 and R8 ¨ R14
and R" have the meanings as defined in formula (I) or (lb).
Preferred are compounds having any one of the formulae (IV-a) ¨ (IV-o) and
(V-a) ¨ (V-d):
o o
1 R6
- R6
N 0 Nii__f
0 c)-(:"H 0 0 c 0 RC
R2 N L Ra JNH
H 1 1 2
N L NI-1N,L--L Rb
) N 2 Rb Fe"
H
0
Ra
(IV-a)
(IV-b)
o o
(: N-R6 0
N-R6
H Rb Ra
0 j)"H 0 0 0
H H Rc
N A ni N N L2
R2A N )-Li N I-2 R2 I =I
H
Ra H Rd
Rc b
(IV-d)
(IV-c)
o o
Rb Ra
N-R6 (21
Rb Ra
0 :cA H 0 ) -L H 0
NR 6 RC
711' N c H H
H NI'') L2 R A N L2
Rd
R2 N R2 N )-Li N
H
(IV-e) (IV-f)
Date Recue/Date Received 2024-03-07
44
o Rd o
o
N - R6
-
0 oil NH
R6 H R
o H Rb Ra
0 0
H H R
R2A HN 0
c
o
1\1AN L2 N
R2AHN N L2
Rd
(IV-g) (IV-h)
o o
o
N - R6 Ra N - R6
H
Rb H
0 0 0 :c)Fi 0
H Rc
N N L2 Am N L2
R2A HN R2 IN N
Rd H
(IV-i) (IVA)
0 0
0 0
N-R6 (7t) N-R6
H H
0 7
H H 0 0 0 2
R2Am N N
IN N L2
R2A HN N L2
H
(IV-k) (IV-I)
o o
o I
NI-r6
NH
0 0 0 c 0
NH,)-L 1 2
R2j.LNH
, J1 Nr- R2iLNH NFOLNrl-2
0 0 0 0
(IV-m) (IV-n)
o o
ol Ni4R6 o
N - R6
H
0 C 0 0 il 0
2&NH NH 1 0
N N N 1-2"- R
R3
-r-N-----L2
R8
I \ 1 H 8
o o
R9 Rio
(IV-o)
(V-a)
o o
)-LC)
N - R (:)6
NI- R6
0 j H H 0 0 H H 0
S R8 N R3 R8 NI N- le L2l 'AV
-1'4 I H
R10 R10
R9
(V-c)
(V-b)
Date Recue/Date Received 2024-03-07
45
o
0 )-LCI H 0
H
Rii 0
N N.AN L2-R3
R13 ¨
(V-d)
and R2, R3; R6, R8; Rs; R10, R11, R12, R13, Ra; R13, Rc; Rd and L2 have the
same
meanings as defined herein, preferably as defined in formula (I) or (lb).
Also preferred are the compounds of any of the formula (IVa-1),
0
()-L
N - R6
0 ) H 0
H H Rb
R2 11 -)-LI\IN
H
Ra
(IVa-1)
wherein
R6 represents ¨H, ¨CF13, ¨CH(CH3)2, ¨CH2CH2C1-13,
¨CH2CH=CH2,
¨CH2CH2CH2CH3, ¨CH2CH(CH3)2, ¨C(CH3)3, ¨CH2CH2CH2CH2CH3, ¨cyclo-C3H5,
¨cyclo-05H8, ¨cyclo-C8H11 or ¨CH2¨cyclo-C3H5.
and R2, Ra, and Rb have the same meanings as defined above.
Preferably, in the compounds of formula (I) or (lb), Ra and Rb represent
independently
of each other ¨H, ¨F, ¨Cl, ¨Br, ¨OH, ¨CN, ¨CF13, ¨C2H5, or ¨0O2Me.
Preferably, in any of the formula (I), (lb), (IV-a) ¨ (IV-o), or (IVa-1):
R2 represents
o o
-_
0 Br ; ____________________ _o Br o
r - 13r --Ior Fi2Ni 1
Br
,
-- ,s _._. Br S
Br
S CI --pB
- - --p -- --, , _s 13r
Br
S
Br
CI Br ; Br ; --CI Me() Br /
.-- 0
- --
S 01 CI ---_y SCI BrS_____ Br -- HN
NC
---ON--- H2N N
Date Recue/Date Received 2024-03-07
46
Me ____//N õ - .----
o'N)
--ON1 -
-<
0 / Oil Br N--
---N
S-Br S ci S Br -iStCI
BrSBr
CISCl
--it. -.
a
S rs...,E S Br
- -IsCI - \ SCF3
---)- , 3 --)" - - \ st. OMe
CI _________________________________ , Br __
'I
S S -., S
/1 ) C
r
N '7-- \\ I \ 0 ON HN N
\__-=-----N
,
H H H
IV
N
1 N N N
N"N ',N 'N N' N' N, ----,
N / 1,1=1
, CO2Me N-
,
NO2 ,-0O2H .,CO2Me . N
N 1
N N N 1
'A N
,
' , N H '
0 H H
N7--- i
N
N_--
r- _-
N ---- HN -'- N -
--- --
...--
Nv- G-- L Br - . HN__.'=
' 0
\ \ ,
0
__ -- \
---- N.--- N-----1--S _______ S.----N -- \
,
0 1
- - 0
\ 0 ,
-- \ 0 -
---- \ I cc, 0
/ I
õ CI r
' , ',
F '
,
H \
S
S S N N
-- \ -- \ Br
H H N
N H S
4 _ _
N N
, OH '
_________________ .- H õ-
F3C-0 -"
N HN 1 I ,N
, N N-
,-- N, 1 Sõ-
-
I I N N7Th----
NN N N) \s_li s,/--IN___N- Nal
N-
Date Recue/Date Received 2024-03-07
47
S õ--
s N 1
S -
N/ 1\1\\ \\ N\\
IV N N H N
N\r\\I"
H2N
---
N ,-
b-N N/).11 --____c3 I
, Or and
R6 represents ¨H, ¨CH3, ¨CH(CH3)2, ¨CH2CH2CH3,
¨CH2CH=CH2,
¨CH2CH2CH2CH3, ¨CH2CH(CH3)2, ¨C(CH3)3, ¨CH2CH2CH2CH2CH3, ¨cyclo-C3H3,
¨cyclo-C31-19, ¨cyclo-C6H11 or ¨CH2¨cyclo-C3H3.
Due to the specially selected substituents R2 on the N-terminal side and
substituents R3
on the C-terminal side and of the inventive compound according to the
invention the
steric dimension can be adjusted very precisely, so that a binding pocket of a
desired
target molecule may be addressed with highly matching measurements.
Preferred, are the compound of any of the formulae (I), (lb), (IV-a) ¨ (IV-o),
and
(V-a)¨ (V-d), wherein
R3 represents
,
,
,
----- ----- ''
,
, ,
,
,
'
, õs-
,
. ., ., .,
'
F Br CI OH
. CN
'- '= '= . 0 ..
N
CO2H CONH2 CONMe2 H
;
CO2Me CO2H Br OH
.,
.,
CF3 -- -- -- i 1
Date Recue/Date Received 2024-03-07
48
F
F
F jzcI ZCF3 ZOH jZco2Me
or .
Surprisingly, it was found that the inventive compounds bound to the
transglutaminase 2
.. reversibly and inhibit the transglutaminase effectively. The electrophilic
warheads in
combination with the preferred embodiment specifically react with highly
nucleophilic
thiols in the active site of the transglutaminase 2. Accordingly, it was found
that potential
unspecific reactions with off-targets are reduced.
In one embodiment, the present invention refers to the compound selected from
the
.. group consisting of:
o
11-2: (S)-2-(benzofuran-2-carboxamido)-
N1-(1-
N
(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-
O c)-LCI H 0
H 1,2-dihydropyrid in-3-y1)-N6-
methy1-5-
0 N NIANINEI
1 H IIIII oxohexanediamide
o
11-3: (S)-N1-(1-(2-(2-adamantylamino)-2-
N
oxoethyl)-2-oxo-1,2-dihydropyrid in-3-y1)-
O :c)LI-1 0
H ii H N6-methy1-2-(3-methylbenzofuran-2-
0
N NN-)111
1 H TIII carboxamido)-5-oxohexanediamide
o
11-4: A N (S)-2-(3-chlorobenzofuran-2-
carboxamido)-N1-(1-(2-(2-
O c. H 0
H II H
0
N r\j-7-ncN adamantylamino)-2-oxoethyl)-2-oxo-1,2-
1 H dihydropyridin-3-y1)-N6-methy1-5-
a
oxohexanediamide
o
11-5: (S)-2-(4-bromobenzofuran-2-
NV
carboxamido)-N1-(1-(2-(2-
O cA E I 0
H H adamantylamino)-2-oxoethyl)-2-oxo-
1,2-
0 N r\jANIN
i H dihydropyridin-3-y1)-N6-methyl-5-
oxohexanediamide
r
Date Recue/Date Received 2024-03-07
49
o
11-6: 01\J (S)-2-(4-bromobenzofuran-2-
H carboxamido)-N1-(1-(2-(2-
o 0
H H H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
8 1
s N 1\1NN H dihydropyridin-3-y1)-N6-methyl-5-
oxohexanediamide
0
11-7: 0 N (S)-2-(benzo[b]thiophene-2-
carboxamido)-
V
H
N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-
o 0
H H H 2-oxo-1,2-dihydropyridin-3-yI)-N6-
methyl-
s s1N NNN
H
8 5-oxohexanediamide
B
0
11-8: 1\1 (S)-2-(5-bromobenzo[b]thiophene-2-
carboxamido)-N1-(1-(2-(2-
O H 0
H dihydropyridin-3-y1)-N6-methyl-5-
H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
N r\jANIN
H
oxohexanediamide
0
11-9: 0 N (S)-2-(1H-indole-2-carboxamido)-N1-(1-
(2-
(2-adamantylamino)-2-oxoethyl)-2-oxo-
O H 0
H H H H 1,2-dihydropyridin-3-y1)-N6-methyl-5-
8 1
N N Ncr\iNa H oxohexanediamide
o
11-10: A(3N (S)-2-(4,5-difluoro-1H-indole-2-
H 0
H H II H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
N 0
Nc Nj-7.n carboxamido)-N1-(1-(2-(2-
fN
I H dihydropyridin-3-y1)-N6-methyl-5-
oxohexanediamide
o
11-11: c) (S)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
o )-L H le 0
H Nc H II N H N6-methy1-2-(3-methy1-1H-indole-2-
N
(II
1µ1-7-iN
I H carboxamido)-5-oxohexanediamide
o
11-12: o N (S)-2-(1H-benzo[d]imidazole-2-
carboxamido)-N1-(1-(2-(2-
O c)Fi
H H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
Yc r\jAN-rN
11 i\J H 6 dihydropyridin-3-y1)-N6-methy1-5-
oxohexanediamide
o
11-13: (S)-2-(2,3-dihydro-1H-indene-2-
le
H carboxamido)-N1-(1-(2-(2-
O 0
H II H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
N NIµVIN
H dihydropyridin-3-y1)-N6-methy1-5-
oxohexanediamide
Date Recue/Date Received 2024-03-07
50
o
11-14: (S)--(2-bromo-4-methylth iazole-5-
NV
carboxamido)-N1-(1-(2-(2-
0 cA I-1 0
H H H
s)-Nj N-cr\v-IN adamantylamino)-2-oxoethyl)-2-oxo-1,2-
Br-li I H dihydropyridin-3-y1)-N6-methy1-5-
oxohexanediamide
o
11-15: (S)-N1-(1-(2-(2-adamantylamino)-2-
o
O)Are
H oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-
0
H H H
s__Aõ, N6-methyl-2-(4-methyl-2-
F3C1\ j 1 ill u
IIJ (trifluoromethyl)thiazole-5-
carboxamido)-5-
oxohexanediamide
o
11-16: (S)-2-(4-bromo-2-
(trifluoromethyl)thiazole-
o
ON
F3C H 5-carboxamido)-N1-(1-(2-(2-
0
H H H
m N-c,,,IN adamantylamino)-2-oxoethyl)-2-oxo-1,2-
_1\ j 1
Br H
'' 1.,,)
dihydropyridin-3-y1)-N6-methy1-5-
oxohexanediamide
0
11-17: (S)-2-(2,4-dichlorothiazole-5-
Ore
H carboxamido)-N1-(1-(2-(2-
o 0
H H H
s_IAN 1\1><NIN adamantylamino)-2-oxoethyl)-2-oxo-1,2-
ci_iq 1 H
dihydropyridin-3-y1)-N6-methy1-5-
a
oxohexanediamide
o
11-18: )-L (S)-N1-(1-(2-(2-adamantylamino)-2-
N
o
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-
c H 0
H H H
s)-L N 1\1>-cNN (2-methoxy-4-methylthiazole-5-
Me -i\ j I H giII carboxamido)-N6-methy1-5-
oxohexanediamide
o
11-19: (S)-N1-(1-(2-(2-adamantylamino)-2-
0re
H oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-
0 0
H H H
SJiNJN,>-CNN,a, N6-methyl-2-(4-methyl-2-phenylthiazole-5-
H
carboxamido)-5-oxohexanediamide
\ I 8
0
11-20: (S)-2-(2,4-dimethylthiazole-5-
N
carboxamido)-N1-(1-(2-(2-
o :c AEI 0
H H H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
-1
)-LN Ncre-IN 1 I H dihydropyridin-3-y1)-N6-methy1-5-
oxohexanediamide
o
11-21: (S)-2-(5-bromo-3-methylthiophene-2-
N
carboxamido)-N1-(1-(2-(2-
o :cAEI 0
H II H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
S N
Br \ 1 HN N Nr1 dihydropyridin-3-y1)-N6-methy1-5-
oxohexanediamide
Date Recue/Date Received 2024-03-07
51
o
11-22: (S)-2-(3,5-dibromothiophene-2-
le
carboxamido)-N1 -(1 -(2-(2-
O H 0
H II H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
S N NNIIµl
Br \ I H Br d ihydro pyrid in-3-y1)-N6-methy1-5-
oxohexanediamide
o
11-23: (S)-2-(5-bromothiophene-2-carboxamido)-
le
Ni -(1 -(2-(2-adamantyl amino)-2-oxoethyl)-
O c)-LC) H 0
H 1µ1 II N H 2-oxo-1,2-dihydropyridin-3-y1)-N6-
methyl-
S
N IN
Br \ I H 5-oxohexanediamide
o
11-24: (S)-2-(5-chlorothiophene-2-
carboxamido)-
le
Ni -(1 -(2-(2-adamantyl amino)-2-oxoethyl)-
O c)-LC) H 0
H N II N H 2-oxo-1,2-dihydropyridin-3-y1)-N6-
methyl-
S
N IIµl
CI \ I H 5-oxohexanediamide
o
11-25: (S)-2-(5-bromo-3-methylfuran-2-
le
carboxamido)-N1 -(1 -(2-(2-
O H 0
H II H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
0
N NNIIµl
Br \ I H di hydro pyrid in-3-y1)-N6-methy1-5-
oxohexaned iamide
o
11-26: (S)-2-(5-ch lorofura n-2-carboxamido)-
N1 -
le
(i -(2-(2-ada mantylami no)-2-oxoethyl)-2-
O H 0
H II H
0 N oxo-1,2-dihydropyridin-3-y1)-N6-methy1-
5-
oxohexanediamide
o
11-27: (S)-2-(5-chlorothiophene-3-
carboxamido)-
O E1
le
Ni -(1 -(2-(2-adamantyl amino)-2-oxoethyl)-
0
H H 2-oxo-1,2-dihydropyridin-3-y1)-N6-
methyl-
Nyjr N
5-oxohexanediamide
0
11-28: o 0 (S)-2-(2,5-dichlorothiophene-3-
re
H carboxamido)-N1 -(1 -(2-(2-
0
H H H
CI / N 1\12-cNiN adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
I H g d ihydro pyrid in-3-y1)-N6-methy1-5-
a
oxohexanediamide
o
11-29: c2 (S)-2-(2,5-dibromothiophene-3-
le
carboxamido)-N1 -(1 -(2-(2-
11
O c)LI-1 o -\LANH
N adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
Br / N
I H d ihydro pyridi n-3-y1)-N6-methy1-5-
Br
oxohexanediamide
Date Recue/Date Received 2024-03-07
52
o
11-30: (S)-2-(5-bromothiophene-3-carboxamido)-
0
le
N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-
O H H 0
H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-
Br / 1 HN N)-LNI N
i 1 5-oxohexanediamide
o
11-31: (S)-2-(2-chloro-5-methylthiazole-4-
H
N
carboxamido)-N1-(1-(2-(2-
O O
C;)1.-Li ll
1µ1 H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
AN N-crµi
H N
dihydropyridin-3-y1)-N6-methy1-5-
oxohexanediamide
o
11-32: (S)-2-(2,5-dichlorothiazole-4-
N
H carboxamido)-N1-(1-(2-(2-
O F-Li O
fL ll H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
NN Nriµ
N-cl
Hjj dihydropyridin-3-y1)-N6-methyl-5-
8
CI
oxohexanediamide
o
11-33: (:) (S)-2-(2,5-dibromothiazole-4-
N
H carboxamido)-N1-(1-(2-(2-
O )1.-Li 011
H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
Br-__
N___fLN N-cre-rN
H dihydropyridin-3-y1)-N6-methyl-5-
8
Br
oxohexanediamide
o
11-34: (S)-2-(2-bromo-5-methylthiazole-4-
NV
carboxamido)-N1-(1-(2-(2-
o cA H 0
NN 1-1\1 NH adamantylamino)-2-oxoethyl)-2-oxo-1,2-
i 1
dihydropyridin-3-y1)-N6-methy1-5-
oxohexanediamide
o
11-35: (S)-2-(2-bromothiazole-4-carboxamido)-
N
N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-
o cA H 0
NDAN IAN 2-oxo-1,2-dihydropyridin-3-yI)-N6-methyl-
i 1
5-oxohexanediamide
o
11-36: 0 (S)-2-(2-chlorothiazole-4-carboxamido)-
N
N1-(1-(2-(2-adamantylamino)-2-oxoethyly
O ),.., H 0
- N II 2-oxo-1,2-dihydropyridin-3-yI)-N6-
methyl-
i -LN NN
5-oxohexanediamide
o
11-37: (S)-2-(2,5-dimethylfuran-3-
carboxamido)-
o N
N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-
0 H 'Ill
H 2-oxo-1,2-dihydropyridin-3-yI)-N6-methyl-
NcNIN
5-oxohexanediamide
Date Recue/Date Received 2024-03-07
53
o
11-38: (S)-2-(4, 5-dimethylth iazole-2-
carboxamido)-N1 -(1 -(2-(2-
0 c)-LC)I\1 El 0
H H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
sAN r\IANN
dihydropyridin-3-y1)-N6-methy1-5-
oxohexanediamide
o
11-39: fe (S)-2-(4-bromothiazole-2-carboxamido)-
Ni -(1 -(2-(2-adamantylamino)-2-oxoethyl)-
0
H H 2-oxo-1,2-dihydropyridin-3-y1)-N6-
methyl-
p
s N f\JAN{N H 8 5-oxohexanediamide
B
0
11-40: N (S)-2-(4-bromothiophene-2-carboxamido)-
Ni -(1 -(2-(2-adamantyl amino)-2-oxoethyl)-
o
H II H 2-oxo-1,2-dihydropyridin-3-y1)-N6-
methyl-
S
N NI\VIN
\ I H 5-oxohexanediamide
B
0
11-41: (S)-2-(4-bromo-3-methylth iophene-2-
NI
carboxamido)-N1 -(1 -(2-(2-
o :cAI-1 0
H f\I N H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
S AIN
N
\ I H dihydropyridin-3-y1)-N6-methyl-5-
oxohexanediamide
B
0
11-42: (S)-2-(3-bromothiophene-2-carboxamido)-
I\V
N1 -(1 -(2-(2-adamantylamino)-2-oxoethyl)-
o :(JAI-1 0
H H 2-oxo-1,2-dihydropyridin-3-y1)-N6-
methyl-
S N
5-oxohexanediamide
Br
0
11-43: (S)-2-(3-chloro-4-methylth iophe ne-2-
V
carboxamido)-N1 -(1 -(2-(2-
o cA N I-1 0
H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
S
N NNN
\ I H A d ihydro pyrid in-3-y1)-N6-methy1-5-
a oxohexanediamide
o
11-44: (S)-2-(4-bromo-5-chlorothiophene-2-
NV
carboxamido)-N1 -(1 -(2-(2-
0 :cAI-1 0
H H H
1\1><N N adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
dihydropyridin-3-y1)-N6-methy1-5-
B oxohexanediamide
Date Recue/Date Received 2024-03-07
54
o
11-45: (S)-2-(4,5-dibromothiophene-2-
le
carboxamido)-N1 -(1 -(2-(2-
O :c)L1-1 0
H H N H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
Br-___p)-N -Cr\VIN
\ I H dihydropyridin-3-y1)-N6-methy1-5-
B oxohexanediamide
o
11-46: (S)-2-(4, 5-dibromo-3-methoxyth iophe
ne-2-
V
carboxamido)-N1 -(1 -(2-(2-
O C:c)-N 1-1 0
H H Nn H
N adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
BrVN c
\ I H dihydropyridin-3-y1)-N6-methy1-5-
0Me
B oxohexanediamide
o
11-47: N (S)-2-(4-bromofuran-2-carboxamido)-N1-
(1 -(2-(2-ada mantylami no)-2-oxoethyl)-2-
0
H II H oxo-1,2-dihydropyridin-3-y1)-N6-methy1-
5-
0
N NI\VIN
\ I H oxohexanediamide
B
0
11-48: (S)-2-(4,5-dibromofuran-2-carboxamido)-
0
le
N1 -(1 -(2-(2-adamantylamino)-2-oxoethyly
:c)L1-1 0
H H H 2-oxo-1,2-dihydropyridin-3-yI)-N6-
methyl-
Br-___;____YN N-Cr\VIN
\ I H 5-oxohexanediamide
B
0
11-49: (S)-2-(4,5-dichlorothiophene-2-
le
carboxamido)-N1 -(1 -(2-(2-
r\j N
O C2c)L1-1 0
H H
N adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
S N AI
CI \ I H d ihydro pyrid in-3-y1)-N6-methy1-5-
CI oxohexanediamide
o
11-50: ())-L (S)-2-((S)-1-acetyl pyrrol id i ne-2-
NJ
H carboxamido)-N1 -(1 -(2-(2-
o
o 1.i o
H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
N4
-----Ai N)cN
dihydropyridin-3-y1)-N6-methy1-5-
oxohexanediamide
o
11-51: (S)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-oxo-1 ,2-d ihydropyrid in-3-yI)-
0 :cA N I-1 0
H N6-methyl-2-(1-methy1-1 H-1 ,2,3-triazole-5-
N/Yc NN-INI carboxamido)-5-oxohexanediamide
H
Date Recue/Date Received 2024-03-07
55
o
11-52: (S)-N1-(1-(2-(2-adamantylamino)-2-
I-1
N
oxoethyl)-2-oxo-1,2-dihydropyrid in-3-y1)-
0 c)-LCI 0
H N6-methy1-5-oxo-2-(2H-tetrazole-5-
N
HN"NV IN carboxamido)hexanediamide
NN
0
11-53: (S)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyrid in-3-y1)-
O :c)L N I-1 0 Ni N6-methyl-5-oxo-2-
(pyrazine-2-
H
N)-L NAN8
il carboxamido)hexanediamide
N
0
11-54: (S)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
H
O :cA N H 0 N6-methyl-2-((S)-1 -methylpyrrolidine-2-
Er\l)L
NIN carboxamido)-5-oxohexanediamide
o
11-55: 0 (S)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyrid in-3-y1)-
O jA N 1-1 0 H N6-methyl-5-oxo-2((S)-
pyrrolidine-3-
H
N NI NVIN carboxamido)hexanediamide
H
--:)-
o
11-56: (S)-2-((2S,4S)-4-bromopyrrolidine-2-
N carboxamido)-N1-(1-(2-(2-
ILANo :cAI-1 o adamantylamino)-2-
oxoethyl)-2-oxo-1,2-
NN H N
j dihydropyridin-3-y1)-N6-methyl-5-
H
oxohexanediamide
Be
o
11-58: (S)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyrid in-3-y1)-
O :c)L N
H 1-1 0 N6-methyl-5-oxo-2((S)-piperidine-2-
H H
1\1)-LNI NNIN carboxamido)hexanediamide
= H
0
11-59: -L (S)-N1-(1-(2-(2-adamantylami no)-2-
V oxoethyl)-2-oxo-1,2-dihydropyrid in-3-
y1)-
0 j)N H 0
H N6-methyl-5-oxo-2-((R)-piperidine-3-
HNN NncN
carboxamido)hexanediamide
H
Date Recue/Date Received 2024-03-07
56
o
11-60: (S)-N1-(1-(2-(2-adamantylamino)-2-
N oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-
o AI-1 o
H N6-methyl-24(R)-((R)-3-
H H
N)AN N
ANN carboxamido)-5-oxohexanediamide
:c
H 8
0
0
11-61: :c (S)-N1-(1-(2-(2-adamantylamino)-2-
V
H oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-
N
o )-L N 0
N_ H II H N6-methy1-5-oxo-2-(quinuclidine-3-
N NNVIN carboxamido)hexanediamide
H
0
11-62: )-LcsN (S)-methyl 3-(1-(1-(2-(2-
adamantylamino)-
o H 0
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-
c
H II H ylamino)-6-(methylamino)-1,5,6-
02N
N NncN
H trioxohexan-2-ylcarbamoy1)-5-
nitrobenzoate
02Me
0
11-63: (S)-N1-(1-(2-(2-adamantylamino)-2-
o H 0
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
c=Acs 1.4 N
N6-methyl-2-(5-nitronicotinamido)-5-
02NN N)-LI\ j _Ill
1 H g oxohexanediamide
f\J
0
11-64: (S)-5-(1-(1-(2-(2-adamantylamino)-2-
HO2C-LN EI le
oxoethyl)-2-oxo-1,2-dihydropyridin-3-
H H H ylamino)-6-(methylamino)-1,5,6-
N-cr\JN
1
f\V 8 trioxohexan-2-ylcarbamoyl)nicotinic
acid
H
0
11-65: -'c (S)-methyl 5-(1-(1-(2-(2-
adamantylamino)-
Me02C)LN V
H 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-
o
H ?I H
ylamino)-6-(methylamino)-1,5,6-
N-cr\iNa
1 H
g trioxohexan-2-ylcarbamoyl)nicotinate
0
11-66: N (S)-N1-(1-(2-(2-adamantylamino)-2-
H oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-
o
q
H N6-methyl-2-(6-methylimidazo[2,1-
Fiqi NH ;\icN
b]thiazole-5-carboxamido)-5-
oxohexanediamide
o
11-67: )-LC)N (S)-N1-(1-(2-(2-
adamantyl(methyl)amino)-
V
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
0 cEl 0
H II
Ni NN N6-methyl-2-(3-methylbenzofuran-2-
0
N I
i H carboxamido)-5-oxohexanediamide
Date Recue/Date Received 2024-03-07
57
0 ______________________________________________________________________
11-68: 0 N1 (S)-N1-(1-(2-(5-hydroxyadamantane-2-
amino)-2-oxoethyl)-2-oxo-1,2-
O 0
H H H dihydropyridin-3-y1)-N6-methyl-2-(3-
g I
0 N 1\12-cNiN H methylbenzofuran-2-
carboxamido)-5-
OH
oxohexanediamide
0
11-69: (S)-N1-(1-(2-(5-fluoroadamantane-2-
amino)-2-oxoethyl)-2-oxo-1,2-
O :cA N1 FI 0
H II H dihydropyridin-3-y1)-N6-methyl-2-(3-
0
N Nj-7.nfN
I H methylbenzofuran-2-carboxamido)-5-
F
oxohexanediamide
0
11-70: (S)-N1-(1-(2-(5-chloroadamantane-2-
amino)-2-oxoethyl)-2-oxo-1,2-
O :cA N1 FI 0
H H H dihydropyridin-3-y1)-N6-methyl-2-(3-
O N N-cr\JN
I H A methylbenzofuran-2-carboxamido)-5-
a
oxohexanediamide
0
11-71: (S)-N1-(1-(2-(5-bromoadamantane-2-
amino)-2-oxoethyl)-2-oxo-1,2-
O :cA N1 FI 0
H H H dihydropyridin-3-y1)-N6-methyl-2-(3-
O N N-cr\JN
I H g methylbenzofuran-2-carboxamido)-5-
Br
oxohexanediamide
o
11-72: (S)-N1-(1-(2-(5-methyladamantane-2-
le
amino)-2-oxoethyl)-2-oxo-1,2-
O H 0
H 1µ1 II N H dihydropyridin-3-y1)-N6-methyl-2-(3-
0
N -rN
I H methylbenzofuran-2-carboxamido)-5-
oxohexanediamide
0
11-73: :c re (S)-N1-(1-(2-(2-carbonitrileadamantane-
2-
A
H amino)-2-oxoethyl)-2-oxo-1,2-
O 0
H II H CN dihydropyridin-3-y1)-N6-methyl-2-(3-
0
N NN-(1\1
I H methylbenzofuran-2-carboxamido)-5-
oxohexanediamide
o
11-74: (S)-N1-(1-(2-(2-methyl adamantane-2-
O (J I-1
KV
carboxylate-2-amino)-2-oxoethyl)-2-oxo-
:)L 0
H H CO2Me 1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-
O N 1µ1AN{N
I H 8 methylbenzofuran-2-carboxamido)-5-
oxohexanediamide
0
11-87: (S)-N1-(1-(2-(1-adamantylmethylamino)-
2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
O :cA N1 FI 0
H H H N6-methy1-2-(3-methylbenzofuran-2-
0 N 1\12-cNiN
I H g carboxamido)-5-oxohexanediamide
Date Recue/Date Received 2024-03-07
58
0 ______________________________________________________________________
11-88: o,r
(S)-N1-(1-(2-(1-(1-
1,
adamantypethanamino)-2-oxoethyl)-2-oxo-
0 H 1 ,2-di hydro pyrid in-3-y1)-N6-methy1-
2-(3-
o N 1\12-cNiN
I H 8 methylbenzofuran-2-carboxamido)-5-
oxohexanediamide
o
11-90: (S)-N1-(1-(2-((1R,2S,4S)-
bicyclo[2.2.1Theptan-2-ylamino)-2-
O :c)Ei N El OH oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-
o N NNNH
I H 8 N6-methyl-2-(3-methylbenzofura n-2-
carboxamido)-5-oxohexanediamide
o
11-92: (S)-N1 -methyl-5-(3-methylbenzofuran-2-
0,
-N-
H carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-
2-
o o ((1S,2S,4R)-1,7,7-
H
O NA NH trimethylbicyclo[2.2.1]heptan-2-
I 11Cor U" o ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
o
11-94: (S)-N1-(1-(2-((1R,2R,4S)-
bicyclo[2.2.1Theptan-2-ylamino)-2-
O :c)-> N Hi.._ oxoethyl)-2-oxo-1 ,2-
dihydropyrid in-3-y1)-
O N NIA N
I H N6-methy1-2-(3-methylbenzofura n-2-
carboxamido)-5-oxohexanediamide
o
11-95: (S)-N1-(1-(2-(bicyclo[2.2.1Theptan-1-
N ylamino)-2-oxoethyl)-2-oxo-1 ,2-
O H H 0 dihydro pyridin-3-y1)-N6-
methy1-2-(3-
O N NANI H methylbenzofuran-2-
carboxamido)-5-
1 H oxohexanediamide
o
11-96: (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7-
N ylamino)-2-oxoethyl)-2-oxo-1,2-
o :cAH H OH dihydropyridin-3-y1)-N6-
methyl-2-(3-
o N N 2-cNNH methylbenzofuran-2-
carboxamido)-5-
1 H oxohexanediamide
o
11-97: (S)-N1-(1-(2-(bicyclo[2.2.1]hept-5-en-
2-
N ylamino)-2-oxoethyl)-2-oxo-1 ,2-
O :c)Ei El OH NH dihydropyridin-3-y1)-N6-
methyl-2-(3-
o N N12-cN
I H i 1 8 methylbenzofuran-2-carboxamido)-5-
oxohexanediamide
Date Recue/Date Received 2024-03-07
59
o
11-98: (2S)-N1 -(1 -(2-(bicyclo[2.2.2]octan-2-
V
ylamino)-2-oxoethyl)-2-oxo-1 ,2-
O :cA N EI 0
H dihydropyridin-3-y1)-N6-methy1-2-(3-
o
1 HN NNIN methyl benzofuran-2-carboxamido)-5-
oxohexaned iamide
o
11-99: (S)-N1 -methyl-5-(3-methylbenzofuran-2-
carboxamido)-2-oxo-N6-(2-oxo-1 -(2-oxo-2-
O j)-LC) N El 0
H ((1 R,2R,4R)-1 ,7,7-
0 N Nr\VIN ssµ trimethylbicyclo[2.2.1]heptan-2-
1 1-1 1 1
ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
o
11-100: O (S)-N1 -methyl-5-(3-methylbenzofuran-2-
Ni
H carboxamido)-2-oxo-N6-(2-oxo-1 -(2-oxo-
2-
O 0
H H H ((1 R,2R,3R,5S)-2,6,6-
0 N NNN,,
I H A tri methyl bicyclo[3.1.1 ]heptan-3-
ylamino)ethyl)-1 ,2-dihydropyridin-3-
yl)hexanediamide
o
11-101: o N (S)-N1 -methyl-5-(3-methylbenzofuran-2-
V
carboxamido)-2-oxo-N6-(2-oxo-1 -(2-oxo-2-
O H H 0
H ((1S,2S,3S,5R)-2,6,6-
: I
o N I\JANN
H g tri methyl bicyclo[3.1.1 ]heptan-3-
ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
o
11-103: C))- (S)-N1 -(1 -(2-(4-homoisotwistane-3-
amino)-2-oxoethyl)-2-oxo-1,2-
cLN El 0
H d ihydro pyrid in-3-y1)-N6-methy1-2-(3-
0
0
N NNN methyl benzofuran-2-carboxamido)-5-
1 H oxohexanediamide
o
11-104: A m (S)-N1-(1-(2-(diamantane-1-amino)-2-
-
O oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-
c H 0
H N6-methyl-2-(3-methylbenzofura n-2-
o N Nr\vINH
I H carboxamido)-5-oxohexanediamide
0
11-105: 0 N (S)-N1-(1-(2-(diamantane-4-amino)-2-
V
oxoethyl)-2-oxo-1 ,2-d ihydropyrid in-3-y1)-
0 H 0
H H H N6-methyl-2-(3-methylbenzofura n-2-
0 N Ncr\JN
1 H
8 carboxamido)-5-oxohexanediamide
Date Recue/Date Received 2024-03-07
60
o
11-107: (S)-N1-(1-(1-adamantyl methyl)-2-oxo-
1,2-
1\V dihydropyridin-3-y1)-N6-methy1-2-(3-
O cA H H 0 methylbenzofuran-2-
carboxamido)-5-
II
0
N NN oxohexanediamide
I H
0
11-108: (2S)-N1-(1-((3-hydroxy-1-
N adamantyl)methyl)-2-oxo-1,2-
O JA H H 0 dihydropyridin-3-y1)-N6-
methyl-2-(3-
ii
0
N NN methylbenzofuran-2-carboxamido)-5-
1 H oxohexanediamide
H
0
11-109: o (2S)-N1-(1-((3-bromo-1-
N adamantyl)methyl)-2-oxo-1,2-
O H H 0 dihydropyridin-3-y1)-N6-
methy1-2-(3-
0 N N methylbenzofuran-2-carboxamido)-5-
-ANn7
I H 8
7oxohexanediamide
o
11-110: (S)-N1-(1-(2-adamantylmethy1)-2-oxo-
1,2-
N dihydropyridin-3-y1)-N6-methy1-2-(3-
o :cAFI H 0 methylbenzofuran-2-
carboxamido)-5-
ii
0
N NN oxohexanediamide
I H
0
ii-Ill: (S)-N1-(1-(2-(2-adamantylamino)-2-
N oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-
o c)":) H H N6-methyl-2-(nicotinamido)-5-
ii
N, N f\VIN oxohexanediamide
I H
1\1
0
11-112: (S)-2-(isonicotinamido)-N1-(1-(2-(2-
01\1
H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
o , 0
H dihydropyridin-3-y1)-N6-methyl-5-
N -AN-N
oxohexanediamide
i\I H 8
o
11-113: (S)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
o c)-Lcl N I-1 0
H H N6-methyl-5-oxo-2-(pyridazine-4-
N N-ANIN carboxamido)hexanediamide
NI H
-1\I
Date Recue/Date Received 2024-03-07
61
o
11-114: (S)-N1-(1-(2-(2-adamantylamino)-2-
N oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-
o I-1 H o H N6-methyl-5-oxo-2-(pyridazine-3-
N NNIN
carboxamido)hexanediamide
I H
.1\1
1\1-
0 A
11-115: (S)-N1-cyclopropyl-N6-(1-(2-(2-
oFr,i/--
adamantylamino)-2-oxoethyl)-2-oxo-1,2-
o 0
0
H II H dihydropyridin-3-y1)-5-(3-
N N-ncN
i H methylbenzofuran-2-carboxamido)-2-
oxohexanediamide
o
11-116: (S)-N1-(1-(2-(2-adamantylamino)-2-
N--
oxoethyl)-2-oxo-1,2-dihydropyrid in-3-y1)-2-
0
O :c)L1-1 0
H II H (3-methylbenzofuran-2-carboxamido)-5-
N NNN
I H g oxo-N6-pentylhexanediamide
o
11-117: (S)-N1-allyl-N6-(1-(2-(2-adamantylamino)-
N
1-1 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-
O (-3c)-L 0
H H 5-(3-methylbenzofuran-2-carboxamido)-2-
0 N r\IAN{N
I H 8 oxohexanediamide
o
11-118: (S)-N1-(1-(2-(2-adamantylami no)-2-
NH2 oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-2-
o (--)c)-L 0
H ii H (3-methylbenzofuran-2-carboxamido)-5-
0
N NI\VIN
I H oxohexanediamide
o
11-119: (S)-N1-ally1-5-(benzofuran-2-
N carboxamido)-N6-(1-(2-(2-
o :c)L EI 0
H ii H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
0
N NNIIµi
I H dihydropyridin-3-y1)-2-oxohexanediamide
o
11-120: (S)-2-(benzofuran-2-carboxamido)-N6-
N
isopropyl-N1-(1-(2-(2-adamantylamino)-2-
O (:)E1 0
H ii H oxoethyl)-2-oxo-1,2-dihydropyrid in-3-
y1)-5-
0
N N-ncN
I H oxohexanediamide
o A
11-121: (S)-2-(benzofuran-2-carboxamido)-N6-
oN
H cyclopropyl-N1-(1-(2-(2-
adamantylamino)-
o 0
H ii H 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-
0
N NncN
I H 5-oxohexanediamide
Date Recue/Date Received 2024-03-07
62
11-122: o) c lel (S)-2-(benzofuran-2-carboxamido)-N1 -
(1-
H (2-(2-adamantylamino)-2-oxoethyl)-2-
oxo-
o 0
H H 1 ,2-di hydro pyrid in-3-y1)-5-oxo-N6-
0 N NIAN{N phenyl hexaned iamide
1 H 8
o
11-123: (S)-2-(benzofuran-2-carboxamido)-N6-
H =C))11 N 1::11 benzyl-N1-(1-(2-(2-adamantylamino)-
2-
O H oxoethyl)-2-oxo-1 ,2-dihydropyrid
in-3-y1)-5-
0
N NIµVIN
I H oxohexanediamide
o
11-124: :c (S)-2-(benzofuran-2-carboxamido)-N1 -
(1-
(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-
o A NH2 0
H II H 1 ,2-dihydropyrid in-3-y1)-5-
0
N NNINI
I H oxohexanediamide
o
11-125: (S)-2-(2,5-dichlorothiophene-3-
NH2 carboxamido)-N1 -(1 -(2-(2-
kLAlelH
N adamantylamino)-2-oxoethyl)-2-oxo-1,2-
ci / N
I H dihydropyridin-3-y1)-5-oxohexanediamide
ci
o
11-126: :c (S)-N1-(1-(2-(2-adamantylami no)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-
8
o A NH2 o
11-\LAN11-\1 (4-methyl-2-(trifluoromethyl)thiazole-5-
F3c 1 H carboxamido)-5-oxohexanediamide
1
o
11-127: (S)-N1-(1-(2-(2-adamantylami no)-2-
NH2 oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-2-
0 c)i.- H i o (1 -methyl-1 H-1 ,2,3-triazole-5-
N(AN 1\1-ANIN carboxamido)-5-oxohexanediamide
H
N
\
0
11-128: :c (2S)-N1-(1-(2-((1 R,2R,4S)-
H bicyclo[2.2.1Theptan-2-ylamino)-2-
o )-L le 0
H 11 H A oxoethyl)-2-oxo-1 ,2-dihydropyrid in-
3-y1)-2-
aNrncN_I (2,5-dichlorothiophene-3-carboxamido)-
ci N6-methy1-5-oxohexanediamide
o
11-129: (2S)-N1-(1-(2-((1R,2R,4S)-
ON
H bicyclo[2.2.1]heptan-2-ylamino)-2-
0 H0 H
-L, L oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
sc i\i,,11 N
N
F3C-i\I 1 H i N( N6-methyl-2-(4-methyl-2-
0 0
(trifluoromethyl)thiazole-5-carboxamido)-5-
oxohexanediamide
Date Recue/Date Received 2024-03-07
63
o
11-130: 0 N (2S)-N1-(1-(2-((1R,2R,4S)-
H bicyclo[2.2.1]heptan-2-ylamino)-2-
o o oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-
Nr1-1\1:11.._ N6-methyl-2-(1-methy1-1 H-1 ,2,3-
triazole-5-
s\i_N carboxamido)-5-oxohexanediamide
N
o
11-131: (S)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-oxo-1 ,2-dihydropyrid in-3-yI)-
o :c N
H N6-methy1-5-oxo-2-(2H-1,2,3-triazole-4-
N
NN NHN carboxamido)hexanediamide
\N_ki H a
H
0
11-132: (S)-N1-(1-(2-(2-adamantylamino)-2-
N oxoethyl)-2-oxo-1 ,2-dihydropyrid in-3-
yI)-
0 :c)F1 0
H N N H N6-methyl-5-oxo-2-(1 H-i,2,3-triazole-
4-
N
HNhi carboxamido)hexanediamide
o
11-133: :c)(S)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
-N 1-1 0
H H N6-methyl-2-(1-methyl-1 H-1 ,2,3-
triazole-4-
o
N
¨I\I/h1 N
carboxamido)-5-oxohexanediamide
o
11-134: (S)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-oxo-1 ,2-dihydropyrid in-3-yI)-
o :c)L N 1-1 0
H N6-methyl-5-oxo-2-(1 H-1 ,2,4-triazole-3-
N N NH N
ci_A H j\I carboxamido)hexanediamide
H
0
11-135: (S)-N1-(1-(2-(2-adamantylamino)-2-
N
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
o c)-()
H j_e II H N6-methy1-2-(1-methy1-1 H-1 ,2,4-
triazole-3-
N
N N H N j\I carboxamido)-5-oxohexanediamide
/
o
11-136: (S)-2-(benzofura n-3-carboxamido)-N1 -
(1 -
I\V
(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-
0 , H 0
\I it oxohexanediamide
H 1 ,2-dihydropyrid in-3-y1)-N6-methy1-5-
N leyi H
0
11-137: (S)-2-(benzo[b]thiophene-3-
carboxamido)-
V
Ni -(1 -(2-(2-adamantylamino)-2-oxoethyly
H
0 :c)L N 1-1 0
N NN.rN 2-oxo-1,2-dihydropyridin-3-yI)-N6-
methyl-
I H 5-oxohexanediamide
Date Recue/Date Received 2024-03-07
64
o
11-138 A (S)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
o c H N H 0
J)iH N6-methyl-2-(1-methyl-1 H-pyrazole-3-
/ N NI\VIN
_il H carboxamido)-5-oxohexanediamide
/
o
11-139 A (S)-N1-(1-(2-(2-adamantylamino)-2-
N
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
o J H 0
H H
N N6-methyl-2-(1-methyl-1 H-pyrazole-4-
N NIN
carboxamido)-5-oxohexanediamide
N
/
o
11-140 (S)-N1-(1-(2-(2-adamantylamino)-2-
N
H oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-
o H Oil
H N6-methy1-2-(1-methy1-1 H-pyrazole-5-
-,. N NleIN
\ H carboxamido)-5-oxohexanediamide
_N
\
0
11-141 o (S)-N1-(1-(2-(2-adamantylamino)-2-
N
H oxoethyl)-2-oxo-1 ,2-d ihydropyrid in-
3-yI)-
0
H N6-methyl-2-(4-methyl-1,2,3-thiadiazole-5-
sN 1111ANIN
N"\ 1 H carboxamido)-5-oxohexanediamide
N
0
11-142 o (S)-N1-(1-(2-(2-adamantylamino)-2-
N
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
o H H 0
H N6-methy1-5-oxo-2-(1,2,5-thiadiazole-3-
NN
NV\I HN N
carboxamido)hexanediamide
o
11-143 (S)-2-(4-iodo-1 -methyl-1 H-pyrazole-5-
N
H carboxamido)-N1 -(1 -(242-
I 0 H CI),
H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
--- N NleIN
\ H dihydropyridin-3-y1)-N6-methyl-5-
_N
\ oxohexanediamide
o
11-144 (S)-N1-(1-(2-(2-adamantylami no)-2-
NH2
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-
o cA H (1),
H (1 -methyl-1 H-pyrazole-5-carboxamido)-5-
\ H oxohexanediamide
_N
N
0
11-145 o (S)-N1-(1-(2-(2-adamantylami no)-2-
NH2
oxoethyl)-2-oxo-1 ,2-d ihydropyrid in-3-yI)-2-
0
H (4-methyl-1,2,3-thiadiazole-5-
sN illi N N
N'µ 1 H carboxamido)-5-oxohexanediamide
N
Date Recue/Date Received 2024-03-07
65
o
11-146 (S)-2-(benzofuran-2-carboxamido)-N1 -
(1 -
NH2
(24(1 R,2R,4S)-bicyclo[2.2.1 ]heptan-2-
O 0
N NEIrel%cri_ ylamino)-2-oxoethyl)-2-oxo-1 ,2-
0 N
I H dihydropyridin-3-y1)-5-oxohexanediamide
o
11-147 OVllNH (S)-N1-(1-(2-((1 R,2R,4S)-
bicyclo[2.2.1]heptan-2-ylamino)-2-
O 0
H II oxoethyl)-2-oxo-1 ,2-d ihydropyrid in-
3-yI)-2-
0
N NNVINE1-===IL
I H (3-methylbenzofuran-2-carboxamido)-5-
oxohexanediamide
o
11-148 (S)-2-(benzofuran-2-carboxamido)-N1 -
(1-
NH2
(24(1 S,2R,4R)-bicyclo[2.2.1 ]heptan-2-
o II j-c) NF
ylamino)-2-oxoethyl)-2-oxo-1 ,2-
I H
dihydropyridin-3-y1)-5-oxohexanediamide
o
11-149 c))-L (S)-N1-(1-(2-((1 S,2R,4R)-
NH2
-- bicyclo[2.2.1]heptan-2-ylamino)-2-
o
NH
c 0
H yI)-2-oxo-1,2-dihydropyndin-3-y1)-
2-
jj o N NvI
I H (3-methylbenzofuran-2-carboxamido)-5-
oxohexanediamide
o
11-150 oy(S)-2-(benzofura n-2-carboxamido)-5-oxo-
NH2
N1 -(2-oxo-1 -(2-oxo-2-((1 R,2S,4R)-1 ,7,7-
o 0
0
trimethyl bicyclo[2.2.1]heptan-2-
N NN
I H INH
jj ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
o
11-151 NH2 (S)-2-(3-methyl benzofuran-2-
o N N
carboxamido)-5-oxo-N1-(2-oxo-1-(2-oxo-2-
0
H ((1R,2S,4R)-1,7,7-
o
H NINH
1 trimethylbicyclo[2.2.1]heptan-2-
ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
o
11-152 (S)-N1-(1-(2-((1R,2R,4S)-
bicyclo[2.2.1]heptan-2-ylamino)-2-
o :c)-H 0
H H oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
1-1\11,1/4,c_i_
N6-methyl-2-(4-methyl-1 ,2,3-th lad iazole-5-
iv
carboxamido)-5-oxohexanediamide
Date Recue/Date Received 2024-03-07
66
o
11-153 (S)-N1-(1-(2-((1R,2R,4S)-
H bicyclo[2.2.1]heptan-2-ylamino)-2-
0 :cA N 0
H II oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-
-- N NNI-1\1-'1/4,ciiLl
\ H
N6-methyl-2-(1-methy1-1H-pyrazole-5-
N carboxamido)-5-oxohexanediamide
o
11-154 (S)-N1-(1-(2-((1S,2R,4R)-
N
0 I-1 0 ob xi coy:t1 ho y[ 20. 22. 10] xh oe
pit a2n -d2i h- yyl da rmo ipnyor)i d- 2i n- _ 3 _ y 0 _
S:N 111j-LN NH
F3C¨S4 I H Ji
N6-methyl-2-(4-methyl-2-
(trifluoromethyl)thiazole-5-carboxamido)-5-
oxohexanediamide
o
11-155 o (S)-N1-(1-(2-((1S,2R,4R)-
NV
0 H H 0 bicyctlo h[2 .2.1 Theptan-2-ylamino)-
2. - 1 _2-
N NJc NH Y1 ) 2 i ,2d .hYd.d -3_
PY Y )
CI / 1 H li
(2,5-dich lorothiophene-3-carboxamido)-
a N6-methy1-5-oxohexanediamide
o
11-156 0 (S)-N1-(1-(2-((1 S,2R,4R)-
NV
H bicyclo[2.2.1]heptan-2-ylamino)-2-
H oxoethyl)-2-oxo-1 ,2-d ihydropyrid in-
3-y1)-
0
0 S N RUL NH
N's 1 H jnc N6-methyl-2-(4-methyl-1 ,2,3-th lad
iazo le-5-
N
carboxamido)-5-oxohexanediamide
o
11-157 (S)-N1-(1-(2-((1S,2R,4R)-
o
N
0 H H 0
ob xi Coy:t1h0 y02
[ 2. 2. 10] xh oe pi 2tan-d ih2-yyldarmoipnyor)id-2in-_3_yo-
N
/y_LN N j-N-INH H
N6-methyl-2-(1-methy1-1 H-1 ,2,3-triazole-5-
N carboxamido)-5-oxohexanediamide
o
11-158 T-1
-N (S)-N1-(1-(2-((1 S,2R,4R)-
H 1-- bicyclo[2.2.1]heptan-2-ylamino)-2-
o
N 0
H II oxoethy1)-2-oxo-1,2-dihydropyridin-3-
y1)-
i\vINH
\ H
N6-methyl-2-(1-methyl-1H-pyrazole-5-
_N
\ carboxamido)-5-oxohexanediamide
o
11-159 )-L(3 N (S)-N1 -methyl-5-(4-methyl-2-
0 I-1 0
(trifl uoromethyl)th iazole-5-carboxamido)-2-
j
oxo-N6-(2-0x0-1-(2-oxo-2-((1R,2S,4R)-
SN 111J-N NH
F3C--<1 1 H
II
1 ,7,7-tri methyl bicyclo[2.2.1 ]heptan-2-
ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
Date Recue/Date Received 2024-03-07
67
0 _____________________________________________
0
11-160 (S)-2-(2,5-dichlorothiophene-3-
0
carboxamido)-N6-methy1-5-oxo-N1 -(2-oxo-
jA N FI 0
H H 1-(2-oxo-2-((1R,2S,4R)-1,7,7-
N N-cNi NH
CI / 1 trimethylbicyclo[2.2.1]heptan-2-
H 1 1
CI ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
0
11-161 N (S)-N1-methy1-5-(4-methyl-1,2,3-
th lad iazole-5-carboxamido)-2-oxo-N6-(2-
0 oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-
o H
H H
,S_..)- N N-cNNH
trimethylbicyclo[2.2.1]heptan-2-
N I H
8
Ns ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
0
11-162 0 N (S)-N1 -methy1-5-(1-methy1-1 H-1,2,3-
H triazole-5-carboxamido)-2-oxo-N6-(2-
oxo-
0 0 1-(2-oxo-2-((1 R,2S,4R)-1,7,7-
NH
N/Ahl N trimethylbicyclo[2.2.1]heptan-2-
_N\ ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
0
11-163 (S)-N1 -methyl-5-(1-methy1-1 H-pyrazo
le-5-
N carboxamido)-2-oxo-N6-(2-oxo-1 -(2-oxo-
2-
0 :cAH 0 ((1R,2S,4R)-1,7,7-
H 11
NH
---c.N NNI trimethylbicyclo[2.2.1]heptan-2-
\ H
_IV ylamino)ethyl)-1,2-dihydropyridin-3-
\
yl)hexanediamide
o
11-164 OJiN (2S)-2-(4-tert-butyl-1 H-pyrrole-3-
H carboxamido)-N6-methyl-N1 -(1 -(241 -
o 0
H ill N adamantylamino)ethyl)-2-oxo-1,2-
dihydropyridin-3-yI)-5-oxohexanediamide
¨
o
11-165 c))- (2S)-2-(4-cyano-1 -methyl-1 H-pyrrole-
2-
carboxamido)-N6-methyl-N1 -(1 -(341 -
o cLNI H 0
H
I\IA adamantylamino)propyI)-2-oxo-1,2-
\ N " dihydropyridin-3-yI)-5-
oxohexanediamide
o
11-166 c" (S)-N1-(1-(3-(2-adamantylami no)-3-
0 V
oxopropy1)-2-oxo-1,2-dihydropyridin-3-y1)-
N H 0 0
0?LN ki)-Lre-ANflf 2-(5-methoxyoxazole-2-carboxamido)-N6-
Me0-t i\ j H
H
methyl-5-oxohexanediamide
Date Recue/Date Received 2024-03-07
68
o
11-167 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1 -
NV
ylamino)-2-oxoethyl)-2-oxo-1 ,2-
O cA H El 011
0
N NN H d ihydro pyrid in-3-y1)-N6-methy1-2-(3-
1 H jj JJ methylbenzofuran-2-carboxamido)-5-
oxohexanediamide
o
11-168 o (S)-2-(2-acetyloxazole-4-carboxamido)-
I\V
N1-(1-(2-(bicyclo[1 A .1]pentan-1 -ylamino)-
0 0 IIL.1 ,
H
0 NNI 2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-
N6-methy1-5-oxohexanediamide
o
11-169 (S)-N1 -(1 -(2-(bicyclo[2.1.1 ]hexan-1
-
V
ylamino)-2-oxoethyl)-2-oxo-1,2-
o
N" Ac) H N El oll
H d ihydro pyrid in-3-y1)-N6-methy1-2-(3-
0
NNI N
I H methyl benzofuran-2-carboxamido)-5-
oxohexaned iamide
o
11-170 (S)-N1 -(1 -(2-(bicyclo[2.1.1 ]hexan-1 -
NV
H ylamino)-2-oxoethyl)-2-oxo-1,2-
o o cA E i OH
H d ihydro pyrid in-3-yI)-2-(2-
isopropyloxazole-
_DAN r\i>,<NIN
)----<1 I H 5-carboxamido)-N6-methy1-5-
oxohexanediamide
o
11-171 o (2S)-2-(benzofura n-2-carboxamido)-N1 -
(1 -
NV
O H 0
(2-(bicyclo[3.2.1]octan-8-ylamino)-2-
H H
0 NN oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-
NyNII4)
I H
8 N6-methyl-5-oxohexanediamide
o
11-172 (2S)-N1 -(1 -(2-(bicyclo[3.2.1 ]octan-
8-
0
N
H ylamino)-2-oxoethyl)-2-oxo-1,2-
o m 0
H dihydropyridin-3-y1)-2-(3,5-
N INI-A N
N dimethylisoxazole-4-carboxamido)-N6-
N¨
methy1-5-oxohexanediamide
o
11-173 o (S)-N1 -(1 -(2-(5-carboxy-2-
N
H aminoadamantane)-2-oxoethyl)-2-oxo-1,2-
N o N-An
N 0
H H
d ihydro pyrid in-3-y1)-N6-methy1-2-(4-
-LcNj
N H co2H methylpyrimidine-5-carboxamido)-5-
oxohexanediamide
0
11-174 0 (2S)-N1-(1-(2-(4-aminoadamantane-N,N-
H
0 r
H
0 dimethy1-1-carboxamide)-2-oxoethyl)-2-
H 8
N NNN 1 oxo-1,2-dihydropyridin-3-y1)-N6-
methy1-5-
H
N-- oxo-2-(1,2,3,4-tetrahydronaphthalene-2-
carboxamido)hexanediamide
Date Recue/Date Received 2024-03-07
69
o
11-175 o (S)-2-((S)-1,4-
diazabicyclo[2.2.2]octane-2-
N
H carboxamido)-N6-tert-butyl-N1 -(1 -
(242-
1,1 o 0
H II H
adamantylamino)-2-oxoethyl)-2-oxo-1,2-
H 8 dihydropyridin-3-y1)-5-oxohexanediamide
o
11-176 (S)-N1-tert-buty1-5-(1 H-indole-3-
N
carboxamido)-N6-(1 -(2-(2-
H
0 :cAH 0
H
N NNN dihydropyridin-3-y1)-2-oxohexanediamide
adamantylamino)-2-oxoethyl)-2-oxo-1,2-
6 I H
H
0
11-177 o (S)-N1-tert-butyl-N6-(1-(2-(2-
N
H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
Nbo 0
\IDAN 11)c 11 dihydropyridin-3-y1)-5-(6-
1 H methyl i midazo[2,1 -b]th iazole-3-
carboxamido)-2-oxohexanediamide
11-178
ON)D' (S)-2-(benzo[d]thiazole-2-carboxamido)-
H 2N1 -1(1 -(.4 2)(12S,2R,4thR)-
0132icyclo[21.,22._1]heptan-
o 0
Hno
S,1)-1\1 NNINH
i\J H dihydropyridin-3-y1)-N6-cyclopenty1-5-
oxohexanediamide
11-179 0).0N1.1) (S)-N1-(1-(2-((1S,2R,4R)-
bicyclo[2.2.1 ]heptan-2-ylamino)-2-
0 o
H 1 1 oxoethy1)-2-oxo-1,2-dihydropyridin-3-
y1)-
mN NNINFI
N6-cyclopenty1-2-(imidazo[2,1-b]thiazole-
C
6-carboxamido)-5-oxohexanediamide
sz
11-180 0 Ni0 (S)-N1-(1-(2-((1S,2R,4R)-
OH
H
bicyclo[2.2.1]heptan-2-ylamino)-2-
= 0 0
H H
. 3C0- 1 N NNNH oxoethyl)-2-oxo-1 ,2-d ihydropyrid in-
3-y1)-
H g
1\1 N6-cyclopenty1-2-(4-hydroxy-6-
(trifluoromethoxy)quinoline-3-
carboxamido)-5-oxohexanediamide
11-181
0 N j 0 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-
H ylamino)-2-oxoethyl)-2-oxo-1 ,2-
0 o dihydropyridin-3-y1)-2-(cinnoline-3-
N NE-1AN H carboxamido)-N6-cyclohexy1-5-
N1- oxohexanediamide
Date Recue/Date Received 2024-03-07
70
11-182
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1 -
0 H 0 ylamino)-2-oxoethyl)-2-oxo-1,2-
d ihydro pyrid in-3-y1)-N6-cyclohexy1-2-(3-
0
N N1\11 H
I H ethylbenzofuran-2-carboxamido)-5-
oxohexanediamide
11-183
:c)0-0 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-
H
-L ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-N6-cyclohexy1-2-(1-
----Ai 0
H 0
N N-ANI H
I H ethy1-1H-indole-2-carboxamido)-5-
oxohexanediamide
11-184 )0c,0 0 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-
H ylamino)-2-oxoethyl)-2-oxo-1 ,2-
0 0
H dihydropyridin-3-y1)-N6-cyclohexy1-2-
(2-
N 1\1AN={IFIL
i 1-1 8 methyl-1,8-naphthyridine-3-carboxamido)-
NN 5-oxohexanediamide
o
11-185 N (S)-N1 -(1 -(2-(bicyclo[2.1.1 ]hexan-1-
H ylamino)-2-oxoethyl)-2-oxo-1 ,2-
0 c)-LCI 0
H II H dihydropyridin-3-y1)-N6-methyl-5-oxo-2-
HN NNINe (1 ,2,3,4-tetrahydroquinoline-6-
N
H carboxamido)hexanediamide
0
11-186 0 N (S)-N1 -(1 -(2-(2-carboxy-2-amino-5-
V
0 ,F1 0 (trifluoromethypadamantane)-2-
oxoethyl)-
H H CO2H
0 N N
Nj)L N 2-oxo-1,2-dihydropyridin-3-yI)-N6-
methyl-
H 8
HN CF3 5-oxo-2-(3-oxo-1 ,2,3,4-
tetra hydroisoquinoli ne-6-
carboxamido)hexaned iamide
0
11-187 N (S)-N1-(1-(2-(5-ethyladamantane-2-
V
0 F1
H H H amino)-2-oxoethyl)-2-oxo-1,2-
I\IAN I\1 õ J\I dihydropyridin-3-y1)-N6-methy1-2-(1,6-
rti
naphthyridine-2-carboxamido)-5-
oxohexanediamide
o
11-188 o (S)-N1 -(1 -(2-(bicyclo[2.1.1 Thexan-1
-
N
ylamino)-2-oxoethyI)-2-oxo-1,2-
N 0 H 0
H II 1 N naphthyridine-1 -carboxamido)-5-
H d ihydro pyrid in-3-y1)-N6-methy1-2-
(2,6-
N NN
I N Fl 1 1 8
oxohexanediamide
Date Recue/Date Received 2024-03-07
71
o
11-189 o N (S)-2-(4-amino-1,2,5-oxadiazole-3-
H carboxamido)-N1-(1-(2-
H2N 0
H o (bicyclo[1.1.1]pentan-1-ylamino)-2-
NN N H
H N oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-
b- N6-methy1-5-oxohexanediamide
o
11-190 o (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-
NV
0 H H 0 ylamino)-2-oxoethyl)-2-oxo-1,2-
O N NANyI H dihydropyridin-3-yI)-2-(6-
\N 1 H (dimethylamino)benzofuran-2-
/ carboxamido)-N6-methy1-5-
oxohexanediamide
o
11-191 C:1)- (S)-2-(2-acetamidothiazole-5-
V
carboxamido)-N1-(1-(2-
0 cLN H 0
H ,
SjA,,, Nci\j,H (bicyclo[1.1.1]pentan-1-ylamino)-2-
HNiq 1 p
8 oxoethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-
-1) N6-methy1-5-oxohexanediamide
o
11-192 )LC:1N (S)-N4-(1-(1-(2-(bicyclo[1.1.1]pentan-
1-
V
ylamino)-2-oxoethyl)-2-oxo-1,2-
0 c H 0
H
0 N NN H dihydropyridin-3-ylamino)-6-
H2N H
/ I H (methylamino)-1,5,6-trioxohexan-2-yI)-1H-
pyrrole-2,4-dicarboxamide
0
11-193 0 Li (S)-N1-(1-(2-(1-acetylamino-4-
0 0 aminoadamantane)-2-oxoethyl)-2-oxo-1,2-
0 H H
0 dihY droP yridin-3-y1)-N6-methy1-5-oxo-
2-(5-
:"-OAH N u-INaElj sulfamoylfuran-3-
carboxamido)hexanediamide
0
11-194 (S)-2-(benzofuran-5-carboxamido)-N1-(1
-
"-
H
O 0 H N 0 H (2-(1-acetylamino-4-
aminoadamantane)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
N-i---
H N6-methyl-5-oxohexanediamide
0
11-195 (S)-2-(benzofuran-6-carboxamido)-N1-(1
-
O ZEI le 0 (2-(4-aminoadamantane-1-
carboxamide)-
H II H
o N I\J N 2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-
\ H N 8 NH2
N6-methyl-5-oxohexanediamide
0
11-196 0 õ, (S)-N1-(1-(2-(4-aminoadamantane-1-
0 carboxamide)-2-oxoethyl)-2-oxo-1,2-
0
H H H
.____I\INIF\li NreIN NH2 dihydropyridin-3-y1)-N6-methy1-2-(3-(1-
methylcyclopropyI)-1,2,4-oxadiazole-5-
carboxamido)-5-oxohexanediamide
Date Recue/Date Received 2024-03-07
72
o
11-197 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-
N
ylami no)-2-oxoethyl)-2-oxo-1,2-
o :c) oll dihydropyridin-3-y1)-N6-
methy1-2-(5-
N ,7)-N N2-cNi H
methy1-1,2,4-oxadiazole-3-carboxamido)-
---- H
5-oxohexanediamide
o
11-198 o (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1 -
N
H ylami no)-2-oxoethyl)-2-oxo-1,2-
o H o dihydropyridin-3-y1)-N6-methy1-
5-oxo-2-
NNr H (1 ,2,3-th iad iazole-4-
N-..--.,N a
carboxamido)hexanediamide
o
11-199 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-
N
ylami no)-2-oxoethyl)-2-oxo-1,2-
O HH Oil dihydropyridin-3-y1)-N6-
methy1-5-oxo-2-
S
Nrx eHN N,õN,,H (1 ,2,4-th iad iazole-5-
carboxamido)hexanediamide
o
11-200 (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-
N
ylamino)-2-oxoethyl)-2-oxo-1,2-
o c)-Lc) H N H oll dihydropyridin-3-
y1)-N6-methyl-5-oxo-2-
s N H
<\I N H j\I (1 ,3,4-th iad iazole-2-
carboxamido)hexaned iamide
o
11-201 o (S)-N1-(1-(2-(bicyclo[1 A .1]pentan-1 -
N
ylami no)-2-oxoethyl)-2-oxo-1,2-
o H H o
H d ihydro pyrid in-3-y1)-2-(4-
cyclopropy1-1,2, 3-
N S N N 1 Nr th lad iazole-5-carboxamido)-N6-methy1-5-
I 0
1\1 oxohexanediamide
o
11-202 N (S)-2-(4-cyclopropy1-1,2,3-thiadiazole-
5-
carboxamido)-N1 -(1 -(2-(2-
O cA HHOu
H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
N'S N NN
., N
dihydropyridin-3-y1)-N6-methy1-5-
oxohexanediamide
o
11-203 o N (S)-2-(4-isopropyl-1,2,3-thiadiazole-5-
H carboxamido)-N1 -(1 -(2-(2-
O , o
H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
S N N
di hydro pyrid in-3-y1)-N6-methy1-5-
N
oxohexanediamide
Date Recue/Date Received 2024-03-07
73
o
11-204 N o (S)-2-(4-ethy1-1,2,3-thiadiazole-5-
H carboxamido)-N1 -(1 -(2-(2-
0
H
S2NJjg);.,A adamantylamino)-2-oxoethyl)-2-oxo-1,2-
N
f\r\ 1 H UI
dihydropyridin-3-y1)-N6-methy1-5-
)v
oxohexanediamide
o
11-205 o N (S)-2-(4-formy1-1 ,2,3-th lad iazole-5-
V
H carboxamido)-N1 -(1 -(2-(2-
o 0
H H adamantylamino)-2-oxoethyl)-2-oxo-1,2-
s N N j-Lrey
dihydro pyridin-3-y1)-N6-methy1-5-
H
0 oxohexanediamide
o
11-206 o NI (S)-2-(4-(hydroxymethy1)-1,2,3-
thiadiazole-
H 5-carboxamido)-N1 -(1 -(2-(2-
, 0
SICILN)i\IJLNIN adamantylamino)-2-oxoethyl)-2-oxo-1,2-
1\rµ 1 H di hydro pyridin-3-y1)-N6-methy1-5-
H
tv
H oxohexanediamide
o
11-207 oN (S)-N1-(1-(2-(1-adamantylamino)-2-
o
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
H H o
N6-methyl-2-(1-methyl-1 H-imidazole-5-
NN NNINH
carboxamido)-5-oxohexanediamide
N
0
11-208 o (S)-N1-(1-(2-(((1 S,2R,5S)-6,6-
O NO dimethylbicyclo[3.1.1]heptan-2-
H H
Nyr\J NNI\J-1õ yl)methylamino)-2-oxoethy1)-2-oxo-1,2-
2N H 8 dihydro pyridin-3-y1)-N6-methy1-2-(1-
N
methyl-1 H-imidazole-2-carboxamido)-5-
oxohexaned iamide
o
11-209 : (S)-N1-(1-(2-(((1 R,2R,5R)-6,6-
V
dimethylbicyclo[3.1.1Theptan-2-
0 c)Ei N H OH
HNz''''-'7)-LN N2-N< õ INI Cli yl)methylamino)-2-oxoethyl)-2-oxo-
1,2-
dihydropyridin-3-y1)-2-(1H-imidazole-4-
carboxamido)-N6-methyl-5-
oxohexanediamide
o
(S)-N1-(1-(2-(3,5-dimethyladamantane-1-
N
amino)-2-oxoethyl)-2-oxo-1,2-
11-210 0 :cAI-1 0
dihydropyridin-3-y1)-N6-methy1-2-(1-
zyc NN.(NH
N H
8 methyl-1 H-imidazole-5-carboxamido)-5-
\ oxohexanediamide
Date Recue/Date Received 2024-03-07
74
o _______________________________________________________________________
(S)-N1 -(1 -(2-(3,5,7-tri methyl-1 -
N
adamantylamino)-2-oxoethyl)-2-oxo-1,2-
11-211 0 :c)-1-1 0
H II dihydropyridin-3-y1)-N6-methy1-2-(1-
N
,/yc NN-INH
H
methyl-1 H-imidazo le-5-carboxamido)-5-
N oxohexanediamide
or a pharmaceutically acceptable salt thereof.
Especially preferred are the following compounds:
11-2: (S)-2-(benzofuran-2-carboxamido)-N1 -(1 -(2-(2-ada mantylamino)-2-
oxoethyl)-2-oxo-
1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexaned iamide
11-3: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-
methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-4: (S)-2-(3-chlorobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-5: (S)-2-(4-bromobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-6: (S)-2-(4-bromobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-7: (S)-2-(benzo[b]th iophene-2-carboxamido)-N1 -(1 -(2-(2-ada mantylami
no)-2-oxoethyl)-
2-oxo-1 ,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide
11-8: (S)-2-(5-bromobenzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-9: (S)-2-(1 H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-oxo-
1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-10: (S)-2-(4,5-difluoro-1H-indole-2-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide
11-11: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-
methy1-2-(3-methy1-1H-indole-2-carboxamido)-5-oxohexanediamide
11-12: (S)-2-(1 H-benzo[d]imidazole-2-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-13: (S)-2-(2,3-dihydro-1H-indene-2-carboxamido)-N1 -(1 -(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-14: (S)--(2-bromo-4-methylth iazo le-5-carboxamido)-N1 -(1 -(2-(2-ada
mantylamino)-2-
oxoethyl)-2-oxo-1,2-di hydropyrid in-3-y1)-N6-methyl-5-oxohexaned iamide
11-1 5: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-N6-
methy1-2-(4-methy1-2-(trifluoromethypthiazole-5-carboxamido)-5-
oxohexanediamide
11-16: (S)-2-(4-bromo-2-(trifl uoromethyl)thiazole-5-carboxamido)-N1 -(1 -
(242-
adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-
oxohexanediamide
11-17: (S)-2-(2,4-dichlorothiazole-5-carboxamido)-N1 -(1-(2-(2-
adamantylamino)-2-
Date Recue/Date Received 2024-03-07
75
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-18: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-2-(2-
methoxy-4-methylthiazole-5-carboxamido)-N6-methy1-5-oxohexanediamide
11-19: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-
methy1-2-(4-methy1-2-phenylthiazole-5-carboxamido)-5-oxohexanediamide
11-21: (S)-2-(5-bromo-3-methylthiophene-2-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-22: (S)-2-(3,5-dibromothiophene-2-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-23: (S)-2-(5-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-
2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-24: (S)-2-(5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-
2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-25: (S)-2-(5-bromo-3-methylfuran-2-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-26: (S)-2-(5-chlorofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-
oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-27: (S)-2-(5-chlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-
2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-28: (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-29: (S)-2-(2,5-dibromothiophene-3-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-30: (S)-2-(5-bromothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-
2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-31: (S)-2-(2-chloro-5-methylthiazole-4-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-32: (S)-2-(2,5-dichlorothiazole-4-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-33: (S)-2-(2,5-dibromothiazole-4-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-34: (S)-2-(2-bromo-5-methylthiazole-4-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-35: (S)-2-(2-bromothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-
oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-36: (S)-2-(2-chlorothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-
oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-37: (S)-2-(2,5-dimethylfuran-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-
2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Date Recue/Date Received 2024-03-07
76
11-39: (S)-2-(4-bromoth iazole-2-carboxamido)-N1 -(1 -(2-(2-adamantylami
no)-2-oxoethyl)-2-
oxo-1 ,2-d ihydropyrid in-3-y1)-N6-methyl-5-oxohexanediamide
11-40: (S)-2-(4-bromoth iophene-2-carboxamido)-N1 -(1 -(2-(2-ada mantylami
no)-2-oxoethyl)-
2-oxo-1 ,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexaned iamide
11-41: (S)-2-(4-bromo-3-methylth iophene-2-carboxamido)-N1 -(1 -(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyrid in-3-y1)-N6-methyl-5-oxohexanediamide
11-42: (S)-2-(3-bromoth iophene-2-carboxamido)-N1 -(1 -(2-(2-ada mantylami
no)-2-oxoethyl)-
2-oxo-1 ,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexaned iamide
11-44: (S)-2-(4-bromo-5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-45: (S)-2-(4,5-dibromothiophene-2-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-46: (S)-2-(4,5-d ibromo-3-methoxyth io phene-2-carboxamido)-N1 -(1 -(242-
adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-
oxohexanediamide
11-47: (S)-2-(4-bromofu ran-2-carboxamido)-N1 -(1 -(2-(2-adamantylamino)-2-
oxoethyl)-2-
oxo-1 ,2-d ihydropyridi n-3-y1)-N6-methyl-5-oxohexanediamide
11-48: (S)-2-(4,5-d ibromofuran-2-carboxamido)-N1 -(1 -(2-(2-ada mantylami
no)-2-oxoethyl)-2-
oxo-1 ,2-d ihydropyrid in-3-y1)-N6-methyl-5-oxohexanediamide
11-49: (S)-2-(4,5-dichlorothiophene-2-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-50: (S)-2-((S)-1-acetyl pyrrolidi ne-2-carboxamido)-N1 -(1 -(2-(2-
adamantylami no)-2-
oxoethyl)-2-oxo-1,2-di hydropyrid in-3-y1)-N6-methyl-5-oxohexanediamide
11-51: (S)-N1-(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyrid
in-3-y1)-N6-
methy1-2-(1 -methyl-1 H-1,2,3-triazole-5-carboxamido)-5-oxohexaned iamide
11-53: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-
methy1-5-oxo-2-(pyrazine-2-carboxamido)hexanediamide
11-54: (S)-N1-(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyrid
in-3-y1)-N6-
methy1-24(S)-1 -methylpyrrol id ine-2-carboxamido)-5-oxohexaned iamide
11-55: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-
methy1-5-oxo-24(S)-pyrrolidine-3-carboxamido)hexanediamide
11-56: (S)-24(2S,4S)-4-bromopyrrolidine-2-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-58: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-
methy1-5-oxo-24(S)-piperidine-2-carboxamido)hexanediamide
11-59: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-
methy1-5-oxo-24(R)-piperidine-3-carboxamido)hexanediamide
11-60: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-
methy1-24(R)-morpholine-3-carboxamido)-5-oxohexanediamide
11-61: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyrid
in-3-y1)-N6-
Date Recue/Date Received 2024-03-07
77
methyl-5-oxo-2-(quinuclidine-3-carboxamido)hexanediamide
11-62: (S)-methyl 3-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-
ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate
11-63: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-
methy1-2-(5-nitronicotinamido)-5-oxohexanediamide
11-64: (S)-5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-ylamino)-
6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid
11-65: (S)-methyl 5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-
ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinate
11-68: (S)-N1-(1-(2-(5-hydroxyadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-69: (S)-N1-(1-(2-(5-fluoroadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-
y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-70: (S)-N1-(1-(2-(5-chloroadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-
y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-71: (S)-N1-(1-(2-(5-bromoadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-
y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-72: (S)-N1-(1-(2-(5-methyladamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-
y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-73: (S)-N1-(1-(2-(2-carbonitrileadamantane-2-amino)-2-oxoethyl)-2-oxo-
1,2-
dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-
oxohexanediamide
11-87: (S)-N1-(1-(2-(1-adamantylmethylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-
N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-88: (S)-N1-(1-(2-(1-(1-adamantypethanamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-
y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-90: (S)-N1-(1-(24(1R,2S,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-
2-oxo-1,2-
dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-
oxohexanediamide
11-92: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-
(2-oxo-2-
((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-
dihydropyridin-
3-yl)hexanediamide
11-94: (S)-N1-(1-(24(1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-
2-oxo-1,2-
dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-
oxohexanediamide
11-95: (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-
y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-96: (S)-N1-(1-(2-(bicyclo[2.2.1]heptan-7-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-
y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-97: (S)-N1-(1-(2-(bicyclo[2.2.1]hept-5-en-2-ylamino)-2-oxoethyl)-2-oxo-
1,2-
dihydropyridin-3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-
Date Recue/Date Received 2024-03-07
78
oxohexanediamide
11-05: (2S)-N1-(1-(2-(bicyclo[2.2.2]octan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-
y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-00: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-
(2-oxo-2-
((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-
dihydropyridin-
3-yl)hexanediamide
11-100: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-
1-(2-oxo-2-
((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-
dihydropyridin-3-yphexanediamide
11-101: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-
1-(2-oxo-2-
((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-
dihydropyridin-3-yphexanediamide
11-103: (S)-N1-(1-(2-(4-homoisotwistane-3-amino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-
N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-104: (S)-N1-(1-(2-(diamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-N6-
methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-105: (S)-N1-(1-(2-(diamantane-4-amino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-N6-
methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-107: (S)-N1-(1-(1-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-
methy1-2-(3-
methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-108: (2S)-N1-(14(3-hydroxy-1-adamantypmethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-N6-
methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-100: (2S)-N1-(14(3-bromo-1-adamantypmethyl)-2-oxo-1,2-dihydropyridin-3-
y1)-N6-methyl-
2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-110: (S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-
methy1-2-(3-
methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-111: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-N6-
methy1-2-(nicotinamido)-5-oxohexanediamide
11-112: (S)-2-(isonicotinamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-
oxo-1,2-
dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-113: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-N6-
methy1-5-oxo-2-(pyridazine-4-carboxamido)hexanediamide
11-114: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-N6-
methy1-5-oxo-2-(pyridazine-3-carboxamido)hexanediamide
11-115: (S)-N1-cyclopropyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-
1,2-
dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide
11-116: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-2-(3-
methylbenzofuran-2-carboxamido)-5-oxo-N6-pentylhexanediamide
11-117: (S)-N1-allyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-
5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide
11-118: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-2-(3-
Date Recue/Date Received 2024-03-07
79
methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-119: (S)-N1-ally1-5-(benzofuran-2-carboxamido)-N6-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide
11-120: (S)-2-(benzofuran-2-carboxamido)-N6-isopropyl-N1 -(1 -(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide
11-121: (S)-2-(benzofuran-2-carboxamido)-N6-cyclopropyl-N1 -(1 -(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide
11-124: (S)-2-(benzofuran-2-carboxamido)-N1 -(1 -(2-(2-ada mantylamino)-2-
oxoethyl)-2-oxo-
1,2-dihydropyridin-3-y1)-5-oxohexaned iamide
11-126: (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide
11-126: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-2-(4-
methy1-2-(trifluoromethypthiazole-5-carboxamido)-5-oxohexanediamide
11-127: (S)-N1-(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
dihydropyrid in-3-y1)-2-(1-
methyl-1 H-1 ,2,3-triazole-5-carboxamido)-5-oxohexanediamide
11-128: (2S)-N1-(1 424(1 R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-
oxoethyl)-2-oxo-1 ,2-
dihydropyridin-3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methy1-5-
oxohexanediamide
11-129: (2S)-N1-(1 424(1 R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-
oxoethyl)-2-oxo-1 ,2-
dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-2-(trifluoromethyl)thiazole-5-
carboxamido)-5-oxohexanediamide
11-130: (2S)-N1-(1 424(1 R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-
oxoethyl)-2-oxo-1 ,2-
dihydropyridin-3-y1)-N6-methy1-2-(1 -methyl-1 H-1,2,3-triazole-5-carboxamido)-
5-
oxohexanediamide
11-131: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-N6-
methy1-5-oxo-2-(2H-1,2,3-triazole-4-carboxamido)hexanediamide
11-135: (S)-N1-(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
dihydropyrid in-3-y1)-N6-
methy1-2-(1 -methyl-1 H-1,2,4-triazo le-3-carboxamido)-5-oxohexaned iamide
11-136: (S)-2-(benzofuran-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-
oxoethyl)-2-oxo-
1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-137: (S)-2-(benzo[b]thiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-
2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-138 (S)-N1-(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyrid
in-3-y1)-N6-
methyl-2-(1 -methyl-1 H-pyrazole-3-carboxamido)-5-oxohexa ned iamide
11-139 (S)-N1-(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyrid
in-3-y1)-N6-
methyl-2-(1 -methyl-1 H-pyrazole-4-carboxamido)-5-oxohexa ned iamide
11-140 (S)-N1-(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
dihydropyridin-3-y1)-N6-
methy1-2-(1 -methyl-1 H-pyrazole-5-carboxamido)-5-oxohexa ned iamide
11-141 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-
methy1-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide
Date Recue/Date Received 2024-03-07
80
11-142 (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-
methy1-5-oxo-2-(1,2,5-thiadiazole-3-carboxamido)hexanediamide
11-145 (S)-N1-(1 -(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyrid
in-3-y1)-2-(4-
methyl-1 ,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide
11-146 (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-((1 R,2R,4S)-
bicyclo[2.2.1]heptan-2-
ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide
11-147 (S)-N1-(1 424(1 R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-
2-oxo-1 ,2-
dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-148 (S)-2-(benzofuran-2-carboxamido)-N1-(1-(24(1S,2R,4R)-
bicyclo[2.2.1]heptan-2-
ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide
11-149 (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-
2-oxo-1,2-
dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-150 (S)-2-(benzofuran-2-carboxamido)-5-oxo-N1-(2-oxo-1-(2-oxo-
24(1R,2S,4R)-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
11-151 (S)-2-(3-methyl benzofuran-2-carboxamido)-5-oxo-N1 -(2-oxo-1 -(2-oxo-
2-((1 R,2S,4R)-
1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1 ,2-dihydropyrid in-3-
yl)hexaned iamide
11-152 (S)-N1-(1 424(1 R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-
2-oxo-1 ,2-
dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-
oxohexanediamide
11-154 (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-
2-oxo-1,2-
dihydropyridin-3-y1)-N6-methyl-2-(4-methyl-2-(trifluoromethypthiazole-5-
carboxamido)-5-oxohexanediamide
11-155 (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-
2-oxo-1,2-
dihydropyridin-3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methyl-5-
oxohexanediamide
11-156 (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-
2-oxo-1,2-
dihydropyridin-3-y1)-N6-methyl-2-(4-methyl-1,2,3-thiadiazole-5-carboxamido)-5-
oxohexanediamide
11-157 (S)-N1-(1 -(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-
2-oxo-1 ,2-
dihydropyridin-3-y1)-N6-methy1-2-(1 -methyl-1 H-1,2,3-triazo le-5-carboxamido)-
5-
oxohexanediamide
11-158 (S)-N1-(1 -(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-
2-oxo-1 ,2-
dihydropyridin-3-y1)-N6-methy1-2-(1 -methyl-1 H-pyrazole-5-carboxamido)-5-
oxohexanediamide
11-159 (S)-N1-methy1-5-(4-methyl-2-(trifluoromethypthiazole-5-carboxamido)-
2-oxo-N6-(2-
oxo-1 -(2-oxo-2-((1 R,2S,4R)-1,7,7-trimethyl bicyclo[2.2.1 The ptan-2-
ylamino)ethyl)-1,2-
dihydropyridin-3-yl)hexanediamide
11-160 (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methy1-5-oxo-N1 -(2-
oxo-1 -(2-oxo-2-
Date Recue/Date Received 2024-03-07
81
((1 R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1 ,2-
dihydropyrid in-
3-yl)hexanediamide
11-161 (S)-N1 -methyl-5-(4-methyl-1,2,3-th iad iazole-5-carboxamido)-2-oxo-
N6-(2-oxo-1 -(2-
oxo-2-((1 R,2S,4R)-1,7,7-trimethyl bicyclo[2.2.1]heptan-2-ylamino)ethyl)-1 ,2-
dihydropyridin-3-yl)hexanediamide
11-162 (S)-N1 -methyl-5-(1 -methyl-1 H-1,2,3-triazo le-5-carboxamido)-2-oxo-
N6-(2-oxo-1 -(2-
oxo-2-((1 R,2S,4R)-1,7,7-trimethyl bicyclo[2.2.1]heptan-2-ylamino)ethyl)-1 ,2-
dihydropyridin-3-yl)hexanediamide
11-163 (S)-N1 -methyl-5-(1 -methyl-1 H-pyrazole-5-carboxamido)-2-oxo-N6-(2-
oxo-1 -(2-oxo-2-
((1 R,2S,4R)-1 ,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1 ,2-
dihydropyridin-
3-yl)hexanediamide
11-167 (S)-N1-(1 -(2-(bicyclo[1 .1 .1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1
,2-dihydropyrid in-3-
y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexaned iamide
11-168 (S)-2-(2-acetyloxazole-4-carboxamido)-N1 -(1 -(2-(bicyclo[1
.1.1]pentan-1 -ylamino)-2-
oxoethyl)-2-oxo-1,2-di hydropyrid in-3-y1)-N6-methyl-5-oxohexaned iamide
11-169 (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-
y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
11-170 (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-
y1)-2-(2-isopropyloxazole-5-carboxamido)-N6-methyl-5-oxohexanediamide
11-171 (2S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(bicyclo[3.2.1]octan-8-
ylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-172 (2S)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-
y1)-2-(3,5-dimethylisoxazole-4-carboxamido)-N6-methy1-5-oxohexanediamide
11-173 (S)-N1-(1-(2-(5-carboxy-2-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methy1-2-(4-methylpyrimidine-5-carboxamido)-5-oxohexanediamide
11-174 (2S)-N1 -(1 -(2-(4-aminoad amantane-N,N-d imethyl-1 -carboxamide)-2-
oxoethyl)-2-oxo-
1,2-dihydropyrid in-3-y1)-N6-methy1-5-oxo-2-(1 ,2,3,4-tetra hydro na phtha
lene-2-
carboxamido)hexa ned iamide
11-178 (S)-2-(benzo[d]thiazole-2-carboxamido)-N1-(1-(24(1S,2R,4R)-
bicyclo[2.2.1]heptan-2-
ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopentyl-5-
oxohexanediamide
11-182 (S)-N1-(1 -(2-(bicyclo[1 .1 .1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1
,2-dihydropyrid in-3-
y1)-N6-cyclohexy1-2-(3-ethylbenzofuran-2-carboxamido)-5-oxohexaned iamide
11-183 (S)-N1-(1 -(2-(bicyclo[1 .1 .1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1
,2-dihydropyrid in-3-
y1)-N6-cyclohexy1-2-(1-ethyl-1 H-indole-2-carboxamido)-5-oxohexaned iamide
11-194 (S)-2-(benzofuran-5-carboxamido)-N1-(1-(2-(1-acetylamino-4-
aminoadamantane)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-195 (S)-2-(benzofuran-6-carboxamido)-N1-(1-(2-(4-aminoadamantane-1-
carboxamide)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Date Recue/Date Received 2024-03-07
82
11-198 (S)-N1-(1 -(2-(bicyclo[1 .1 .1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-
1 ,2-dihydropyrid in-3-
y1)-N6-methy1-5-oxo-2-(1 ,2,3-th lad iazole-4-carboxamido)hexanediamide
11-199 (S)-N1-(1 -(2-(bicyclo[1 .1 .1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-
1 ,2-dihydropyrid in-3-
y1)-N6-methy1-5-oxo-2-(1 ,2,4-th lad iazole-5-carboxamido)hexanediamide
11-200 (S)-N1-(1 -(2-(bicyclo[1 .1 .1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-
1 ,2-dihydropyrid in-3-
y1)-N6-methy1-5-oxo-2-(1 ,3,4-th lad iazole-2-carboxamido)hexanediamide
11-201 (S)-N1-(1 -(2-(bicyclo[1 .1 .1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-
1 ,2-dihydropyrid in-3-
y1)-2-(4-cyclopropy1-1 ,2,3-thiadiazole-5-carboxamido)-N6-methy1-5-
oxohexanediamide
11-202 (S)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N1 -(1 -(2-
(2-adamantylamino)-
2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-203 (S)-2-(4-isopropy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide
11-204 (S)-2-(4-ethyl-1,2,3-thiadiazole-5-carboxamido)-N1 -(1 -(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-205 (S)-2-(4-formy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-
adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
11-206 (S)-2-(4-(hydroxymethyl)-1 ,2,3-th iad iazole-5-carboxamido)-N1 -
(1 -(242-
adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-
oxohexanediamide
11-207 (S)-N1-(1 -(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
dihydropyrid in-3-y1)-N6-
methyl-2-(1 -methyl-1 H-imidazo le-5-carboxamido)-5-oxohexaned iamide
(S)-N1-(1 -(2-(3,5-dimethyladamantane-1 -amino)-2-oxoethyl)-2-oxo-1,2-
11-210 dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-imidazole-5-
carboxamido)-5-
oxohexanediamide
(S)-N1 -(1 -(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-
11-211 dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-imidazole-5-
carboxamido)-5-
oxohexanediamide
or a pharmaceutically acceptable salt thereof.
Method for production of inventive compounds
In some embodiments, the present invention relates to a method for the
synthesis of a
compound of formula (I), especially any compound of the formula (lb):
o
0 N_R6
0 1470
H
R21N NAN,LR3
H
(lb)
Date Recue/Date Received 2024-03-07
83
The compound of the formula (lb) can be produced and thus, the present
invention
relates to a method for producing the compound of formula (lb) comprising the
following
steps in the following order:
Step 1B: providing a compound 4b
0
Ac0JJNR6
127
PG3 N OH
-
H
o 4b;
Step 2B: performing coupling reaction of the compound 4b with a compound 5
o
H2NN_L R3
5
to obtain a compound 6b
o
AV 14
NI' R6
H
PG3,N NN_L,R3
H
10 6b;
Step 3B: deprotecting an amino protecting group PG3to obtain a compound 7b
0
Ac0JJNR6
iiz7 0
H
N -Li\i_l_ R3
H2N
7b;
15 Step 4B: performing coupling reaction of the compound 7b with a
carboxylic acid
(R2-CO2H 8) to obtain a compound 9b
0
AcOjN-R6
0 1470
H
R2jC NN-1-123
H 9b;
Step 5B: performing oxidation reaction of the compound 9b to produce the
20 compound of the formula (lb)
Date Recue/Date Received 2024-03-07
84
OrJJ N R6
0 Li 147 0
R2A N N N L R3
H
(Ib);
wherein L, R2, R3, R6 and R7 have the same meanings as defined above in the
formula (lb), and PG3 is an amino protecting group.
AcOA N R6
In the step 5B the chemical warhead precursor
Hmay be firstly converted
HO N R6
to Hunder a basic condition such as treating with K2CO3, and then
HO N R6 OA N -R6
H
is converted to the corresponding chemical warhead H
by an
oxidation method, preferably by using Dess-Martin periodinane (DMP),
iodoxybenzoic
acid (IBX), or hypochlorite/TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) in a
polar
solvent, as described in the chemical examples.
In an alternative route first all protecting groups PG1 and PG2 are
simultaneously
removed and the protecting group PG3 is selectively introduced. Preferably,
PG1 and
PG3 are same.
The term "protecting groups" as used herein refers to commonly used protection
groups
in organic synthesis, preferably for amino and carboxyl groups.
PG1, PG3, and PG5
preferably are suitable protecting groups for amino groups. PG2 and PG4
preferably are
suitable protecting groups for carboxyl groups. Preferably, PG1, PG3, and PG5
may be
selected from the group consisting of or comprising: acetyl, benzoyl,
benzyloxycarbonyl
(Cbz), tert-butylcarbonyl, tert-butyloxycarbonyl (Boc), and
fluorenylmethylenoxy group
(Fmoc). PG2 and PG4 may be selected from the group consisting of or
comprising:
methoxy, ethoxy, isobutoxy, tert-butoxy, benzyloxy; preferably, tert-butoxy
group.
In Step 2B, to promote the coupling reaction with amino group of intermediate
compound, activating reagents are commonly used to activating carboxylic acid
(õPeptide Coupling Reagents, More than a Letter Soup", Ayman El-Faham and
Fernando Albericio, Chemical Reviews, 2011, 111(11), p.6557-6602). The
activation
may be introduced separate reaction or in situ reaction. Preferably, any of
the following
coupling reagent can be used to activate carobxylic acid group: BOP
(Benzotriazole-1-
Date Recue/Date Received 2024-03-07
85
yl-oxy-tris-(dimethylamino)-phosphoniurn hexafluorophosphate), PyBOP
(Benzotriazole-
1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), AOP (7-
(Azabenzotriazol-
1-yl)oxy tris(dimethylamino)phosphonium hexafluorophosphate), PyAOP ((7-
Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate), TBTU
(2-(1H-
Benzotriazole-1-yI)-1,1,3,3-tetramethylaminium tetrafluoroborate), EEDQ (N-
Ethoxycarbony1-2-ethoxy-1,2-dihydroquinoline), Polyphosphoric Acid (PPA), DPPA
(Diphenyl phosphoryl azide), HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-
triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HBTU (0-Benzotriazol-1-
yl-
N,N,N,1\11-tetramethyluronium hexafluorophosphate), HOBt (1-
Hydroxybenzotriazole),
HOAt (1-Hydroxy-7-azabenzotriazole), DCC (N,AP-Dicyclohexylcarbodiirnide), EDC
(or
EDAC or EDCI, 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide), BOP-CI (Bis(2-
oxo-3-
oxazolidinyl)phosphinic chloride), TFFH
(Tetramethylfl uoroformam id ini um
hexafluorophosphate), BroP (Bromo tris(dimethylam ino)
phosphonium
hexafluorophosphate), PyBroP
(Bromo-tris-pyrrolidino-phosphoniurn
hexafluorophosphate) and CI P (2-
Chloro-1,3-dimethylimidazolidinium
hexafluorophosphate), or further, similar acting reagents, providing an
activated
intermediate,or a mixture thereof.
Pharmaceutical Composition & Medical Use
Therefore another aspect of the present invention relates to compounds
according to
the general formula (I) as medicine as well as their use in medicine.
Especially preferred
is the use as inhibitors of transglutaminases, in particular transglutaminase
2 (TG2).
Thus the compounds of formula (I) described herein or according to the present
invention may be administered themselves or in form of a pharmacologically
acceptable
salt.
The compounds of the present invention may form of a pharmacologically
acceptable
salt with organic or inorganic acids or bases. Examples of suitable acids for
such acid
addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric
acid, phosphoric
acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-
aminosalicylic
acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid,
sulfonic acid,
phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid,
gluconic acid,
lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic
acid, benzoic
acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid,
ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid,
ethylenesulfonic acid, p-
toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic
acid, china
acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid,
picric acid,
Date Recue/Date Received 2024-03-07
86
adipic acid, d-o-tolyltartaric acid, tartronic acid, (o, m, p)-toluic acid,
naphthylamine
sulfonic acid, trifluoroacetic acid, and other mineral or carboxylic acids
well known to
those skilled in the art. The salts are prepared by contacting the free base
form with a
sufficient amount of the desired acid to produce a salt in the conventional
manner.
Preferred is the mesylate salt, hydrochloride salt and the trifluoroacetate
salt and
especially preferred is the trifluoroacetate salt and the hydrochloride salt.
In the case the inventive compounds bear acidic groups, salts could also be
formed with
inorganic or organic bases. Examples for suitable inorganic or organic bases
are, for
example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, lysine or arginine
and
the like. Salts may be prepared in a conventional manner using methods well
known in
the art, for example by treatment of a solution of the compound of the general
formula
(I) with a solution of an acid, selected out of the group mentioned above.
Methods of Use
In a further aspect of the present invention, the novel compounds according to
the
general formula (I) are used as pharmaceutically active agent, i.e. the
compound of the
formula (I) is used in medicine.
Furthermore, the present invention relates to a pharmaceutical composition
comprising
at least one compound according to the general formula (I), as an active
ingredient or a
pharmacologically acceptable salts thereof as an active ingredient, together
with at least
one pharmacologically acceptable carrier, excipient and/or diluent.
The compounds according to general formula (I) described herein are especially
suitable for the treatment and prophylaxis of diseases associated with and/or
caused by
transglutaminase 2.
Celiac disease, a gluten intolerance is associated with tissue
transglutaminase (TG 2).
Another very important group of indications for tissue transglutaminase
inhibitors are
fibrotic disorders. Fibrotic disorders are characterized by the accumulation
of cross-
linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis,
idiopathic
pulmonary fibrosis, kidney fibrosis as well as liver fibrosis belong to the
most important
fibrotic disorders to be addressed with the compounds disclosed.
In the biological example B-1, it is proven that the inventive compounds as
reversible
and irreversible TG inhibitors effectively inhibit the activity of TGs,
especially TG2.
Date Recue/Date Received 2024-03-07
87
As used herein the term "inhibiting" or "inhibition" refers to the ability of
a compound to
downregulate, decrease, reduce, suppress, inactivate, or inhibit at least
partially the
activity of an enzyme, or the expression of an enzyme or protein.
Therefore, another aspect of the present invention is the use of the inventive
compounds of the general formula (I), or the pharmaceutical composition
thereof as
described in the treatment or prophylaxis of autoimmune and inflammatory
diseases,
vascular diseases, fibrotic diseases, liver diseases, cholestatic liver
diseases, cancer,
neurodegenerative diseases, ocular diseases, and skin disorders.
Further aspects of the present invention relate to the use of the compounds of
general
formula (I) for the preparation of a pharmaceutical composition useful for
prophylaxis
and/or treatment of autoimmune and inflammatory diseases, vascular diseases,
fibrotic
diseases, liver diseases, cholestatic liver diseases, cancer,
neurodegenerative
diseases, ocular diseases, and skin disorders.
In a further aspect of the present invention, a method for preventing and/or
treating
autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases,
liver
diseases, cholestatic liver diseases, cancer, neurodegenerative diseases,
ocular
diseases, and skin disorders, which method comprises administering to a
subject, in
particular a human, a pharmaceutically effective amount of at least one
compound of
the general formula (I), to prevent and/or treat said autoimmune and
inflammatory
diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic
liver diseases,
cancer, neurodegenerative diseases, ocular diseases, and skin disorders.
Preferred, the autoimmune and inflammatory diseases comprises multiple
sclerosis,
celiac disease, Duhring-Brocq-disease (dermatitis herpetiformis), gluten
ataxia, gluten
neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory
bowel
disease, systemic lupus erythematosus psoriasis, and gingivitis;
the vascular diseases comprise atherosclerosis, thrombosis, vascular
stiffness;
the fibrotic diseases affecting the lung, the kidney, the liver, the skin or
the gut like cystic
fibrosis, kidney fibrosis and diabetic nephropathy, intestinal fibrosis,
idiopathic lung
fibrosis, liver fibrosis;
the liver diseases like alcoholic hepatitis, alcoholic steatohepatitis,
nonalcoholic
steatohepatitis, non-alcoholic fatty liver disease, liver cirrhosis,
autoimmune hepatitis or
liver inflammation;
the cholestatic liver diseases comprise primary biliary cholangitis and
primary sclerosing
cholangitis;
the cancer comprises glioblastoma, melanoma, pancreatic cancer, renal cell
carcinoma,
meningioma, and breast cancer,
Date Recue/Date Received 2024-03-07
88
the neurodegenerative diseases comprise Parkinson's disease, Huntington's
disease,
or Alzheimer's disease,
the ocular diseases comprise glaucoma, cataracts, macular degeneration, or
uveitis;
the skin disorders comprise acne, psoriasis, scarring, and skin aging.
More preferred, the compound of the formula (I), or the pharmaceutical
composition
thereof is useful in the treatment or prophylaxis of celiac disease.
Furthermore, the compounds of the general formula (I), can be administered in
form of
their pharmaceutically active salts, optionally using essentially non-toxic
pharmaceutically acceptable carriers, adjuvants or extenders. Medications are
prepared
in a known manner in a conventional solid or fluid carrier or in extenders and
a
conventional pharmaceutically acceptable adjuvant/expedient in a suitable
dose. The
preferred preparations are provided in an administrable form suitable for oral
application, such as pills, tablets, film tablets, coated tablets, capsules
and powders.
Tablets, film tablets, coated tablets, gelatine capsules and opaque capsules
are the
preferred pharmaceutical formulations. Any pharmaceutical compositions
contains at
least one compound of the general formula (I), and/or pharmaceutically
acceptable salts
thereof in an amount of 5 mg to 500 mg, preferably 10 mg to 250 mg and most
preferred in an amount of 10 to 100 mg per formulation.
Besides, the object of the present invention also includes pharmaceutical
preparations
for oral, parenteral, dermal, intradermal, intragastric, intracutaneous,
intravascular,
intravenous, intramuscular, intraperitoneal, intranasal, intravaginal,
intrabuccal,
percutaneous, rectal, subcutaneous, sublingual, topic, transdermal or
inhalative
application, containing, in addition to typical vehicles and extenders, a
compound of the
general formula (I), and/or a pharmaceutically acceptable salt thereof as
active
component.
The pharmaceutical compositions of the present invention contain one of the
compounds of the formula (I) disclosed herein as active component, typically
mixed with
suitable carrier materials, selected with respect to the intended form of
administration,
i.e. tablets to be administered orally, capsules (filled either with a solid,
a semi-solid or a
liquid), powders, orally administrable gels, elixirs, dispersible granulates,
syrups,
suspensions and the like in accordance with conventional pharmaceutical
practices. For
example, the compound of the formula (I) can as active agent component be
combined
with any oral, non-toxic, pharmaceutically acceptable, inert carrier, such as
lactose,
starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium
sulfate,
talc, mannitol, ethyl alcohol (liquid forms) and the like for the oral
administration in form
of tablets or capsules. Moreover, suitable binders, lubricants, disintegrants
and
Date Recue/Date Received 2024-03-07
89
colorants can be added to the mixture if required. Powders and tablets can
consist of
said inert carriers to an extent from about 5% per weight to about 95% per
weight of the
inventive composition.
Suitable binders include starch, gelatine, natural sugars, sweeteners made of
corn,
natural and synthetic gums, such as acacia gum, sodium alginate,
carboxymethylcellulose, polyethylene glycol and waxes. Possible lubricants for
the use
in said dosage forms include boric acid, sodium benzoate, sodium acetate,
sodium
chloride and the like. Disintegrants include starch, methylcellulose,
cyclodextrins, guar
gum and the like. If required, sweeteners and flavor additives and
preservatives can
also be included. Some of the terms used above, namely disintegrants,
extenders,
lubricants, binders and the like are discussed in greater detail below.
Additionally, the compositions of the present invention can be formulated in a
form with
sustained release to provide a controlled release rate of any one or more
components
or active components, in order to optimize the therapeutic effect, i.e. the
inhibitory
activity and the like. Suitable dosage forms for sustained release include
layered
tablets containing layers with varying degradation rates or controlled release
polymeric
matrices impregnated with the active components and in the form of a tablet or
capsule
containing such impregnated or encapsulated porous polymeric matrices.
Preparations in fluid form include solutions, suspensions and emulsions.
Exemplarily
mentioned are water or water propylene glycol solutions for parenteral
injections or the
addition of sweeteners and opacifiers for oral solutions, suspensions, and
emulsions.
Aerosol preparations suitable for inhalation may include solutions and solids
in the form
of powders which can be combined with a pharmaceutically acceptable carrier,
such as
a compressed inert gas, e.g. nitrogen.
For the preparation of suppositories a low melting wax, such as a mixture of
fatty acid
glycerides, e.g. cocoa butter, is melted firstly and the active component is
homogenously dispersed therein by stirring or similar mixing operations. The
melted
homogenous mixture is then poured in fitting forms, cooled and thus hardened.
Further preparations in solid form which are to be converted into preparations
in fluid
form for either oral or parenteral administration shortly before use are
included. Such
fluid forms include solutions, suspensions and emulsions.
Date Recue/Date Received 2024-03-07
90
Furthermore, the compounds of the present invention may be administered via
transdermal application. The transdermal compositions can have the form of
crèmes,
lotions, aerosols and/or emulsions.
The term capsule refers to a special container or casing composed of
methylcellulose,
polyvinyl alcohols or denatured gelatins or starches, in which the active
agents can be
enclosed. Typically, hard shell capsules are prepared from mixtures of bones
and
porcine skin gelatins having comparatively high gel strength. The capsule
itself can
contain small amounts of colorants, opacifiers, softening agents and
preservatives.
Tablet means a compressed or cast solid dosage form containing the active
components with suitable extenders. The tablet can be produced by compressing
mixtures or granulates obtained by wet granulation, dry granulation or
compaction,
which are known to the one skilled in the art.
.. Oral gels refer to the active components dispersed or solubilized in a
hydrophilic semi-
solid matrix.
Powders for compositions refer to powder mixtures containing the active
components
and suitable extenders which can be suspended in water or juices.
Suitable extenders are substances which usually form the largest part of the
composition or dosage form. Suitable extenders include sugars such as lactose,
sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and
potatoes;
and celluloses such as microcrystalline cellulose. The amount of extenders in
the
composition can range from about 5 to about 95% per weight of the total
composition,
preferably form about 25 to about 75% per weight and further preferred from
about 30 to
about 60% per weight.
The term disintegrants refers to materials added to the composition in order
to support
disintegration and release of the medicinal substance. Suitable disintegrants
include
starches, modified starches which are soluble in cold water, such as sodium
carboxymethyl starch; natural and synthetic gums such as locust bean gum,
caraya,
guar gum, tragacanth and agar; cellulose derivatives such as methylcellulose
and
sodium carboxymethylcellulose, microcrystalline celluloses and crosslinked
microcrystalline celluloses such as croscarmellose sodium; alginates such as
alginic
acid and sodium alginate; clays such as bentonites and foaming mixtures. The
amount
of disintegrants used in the composition can range from about 2 to 20% per
weight of
the composition and further preferred from about 5 to about 10% per weight.
Date Recue/Date Received 2024-03-07
91
Binders characterize substances binding or "gluing" powders to each other and
they
consequently serve as "glue" in the formulation. Binders add a cohesion starch
which is
already available in the extenders or the disintegrant. Suitable binders
include sugar,
such as sucrose; starches derived from wheat, corn, rice and potatoes; natural
gums
.. such as acacia gum, gelatine and tragacanth; derivatives of sea weed such
as alginic
acid, sodium alginate and ammonium calcium alginate, cellulose materials such
as
methyl cellulose and sodium carboxymethylcellu lose and
hydroxypropyl
methylcellulose, polyvinylpyrrolidone and inorganic compounds, such as
magnesium
aluminium silicate. The amount of binders in the composition can range from
about 2 to
.. about 20% per weight of the total composition, preferably form about 3 to
about 10%
per weight and further preferred from about 3 to about 6% per weight.
The term lubricant refers to a substance added to the dosage form in order to
allow for
the tablet, granulate, etc. to be released from the casting mold or pressing
mold, after
.. compression, by reducing the friction. Suitable lubricants include metallic
stearates such
as magnesium stearate, calcium stearate or potassium stearate; stearic acid;
waxes
with high melting points and water soluble lubricants such as sodium chloride,
sodium
benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine.
Due to
the fact that lubricants have to be present on the surface of the granulates
as well as
between the granulates and parts of the tablet press they are typically added
during the
last step prior to compression. The amount of lubricants in the composition
can range
from about 0.2 to about 5% per weight of the total composition, preferably
form about
0.5 to about 2% per weight and further preferred from about 0.3 to about 1.5 %
per
weight.
Lubricants are materials preventing caking and improving the flow
characteristics of
granulates so that the flow is smooth and uniform. Suitable lubricants include
silicon
dioxide and talc. The amount of lubricants in the composition can range from
about 0.1
to about 5 % per weight of the total composition, preferably form about 0.5 to
about 2 %
per weight.
Colorants are adjuvants coloring the composition or dosage form. Such
adjuvants can
include colorants having food quality which are adsorbed on a suitable
adsorption
means, such as clay or aluminium oxide. The amount of the colorant used can
vary
from about 0.1 to about 5% per weight of the composition and preferably from
about 0.1
to about 1% per weight.
As used herein, a "pharmaceutically effective amount" of a transglutaminase
inhibitor is
the amount or activity effective for achieving the desired physiological
result, either in
cells treated in vitro or in a patient treated in vivo. Specifically, a
pharmaceutical
effective amount is such an amount which is sufficient for inhibiting, for a
certain period
Date Recue/Date Received 2024-03-07
92
of time, one or more of the clinically defined pathological processes
associated with
transglutaminase 2. The effective amount can vary according to the specific
compound
of the formula (I) and additionally depends on a plurality of factors and
conditions
related to the subject to be treated and the severity of the disease. If, for
example, an
inhibitor is to be administered in vivo, factors such as age, weight and
health of the
patients as well as dose reaction curves and data regarding toxicity obtained
from
preclinical animal studies are amongst the data to be considered. If the
inhibitor in form
of the compound of the formula (I) described herein is to be brought in
contact with the
cells in vivo, a plurality of preclinical in vitro studies would be designed
in order to
determine parameters such as absorption, half-life, dose, toxicity, etc.
Determining a
pharmaceutically effective amount for a given pharmaceutically active
ingredient is part
of the ordinary skills of the one skilled in the art.
Examples
Following abbreviations used in the examples have the following meaning.
Boc (tert-butoxycarbonyl), Boc0Su
(N-tert-butoxycarbonyloxy-succinimide)
DCM (dichloromethane), DMAP (4-(Dimethylamino)-pyridine), TEA (triethylamine),
DMF (dimethylform am ide), DMP (Dess-Martin
periodiane), DI PEA
(N-Ethyldiisopropylamine), Glu (glutamic acid), EDC
(1-ethyl-3-(3'-
dimethylam inopropyl)carbodiimide), TFA (trifluoroacetic acid), THF
(tetrahydrofuran),
Et0Ac (ethyl acetate), HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-
triazolo[4,5-
b]pyridinium 3-oxid hexafluorophosphate), HOBt (hydroxybenzotriazole),
MTBE
(methyl tert-butyl ether), tBu (tert-butyl),
Chemical Examples
The following examples are intended to illustrate the invention with selected
compounds
without limiting the protecting scope of the present intellectual property
right on these
concrete examples. It is clear for a person skilled in the art that analogous
compounds
and compounds produced according to analogous synthetic ways fall under the
protecting scope of the present intellectual property right.
Example II. Synthetic method 11
Scheme 11-1
Date Recue/Date Received 2024-03-07
93
OH ChloroacetNvid 0
02N 1
Na3PO4
02 N AN OH >
ZED1657
1
2-Adamantylamine
EDC, DIPEA, DMF
10% Pd/C
0 0
H Me0H H
H2 N N < ________ 02 N N
N N
ZED3906 ZED3905
1 Preparation of compound ZED1657
o
02N -I0H
, N
2-(3-nitro-2-oxopyridin-1(2H)-yl)acetic acid
Chemical Formula: C7H6N205
Exact Mass: 198.03
Molecular Weight: 198.13
30.0 g (214 mmol) of 2-hydroxy-3-nitropyridine and 40.5 g (2 eq) of
chloroacetic acid
were suspended in 600 mL water. At 40 C, 245 g (3 eq) trisodium phosphate
dodecahydrate were added, and the reaction was stirred at room temperature
overnight.
250 mL HCI (32%) were added, and the suspension was stirred for another night
at 4 C.
The precipitate was filtered and dried. Yield: 41.2 g, 97% ESI-MS: 199.3 [M+H]
2 Preparation of compound ZED3905
0
H
02N
j\li N
N-(2-adamantyI)-2-(3-nitro-2-oxopyridin-1(2H)-yl)acetamide
Chemical Formula: C17H21N304
Exact Mass: 331.15
Molecular Weight: 331.37
17.0 g (85.8 mmol) of ZED1657, 16.1 g (1 eq) of 2-adamantanamine hydrochloride
and
11.6 g (1 eq) of HOBt were dissolved in 200 mL DMF and 17.9 mL (1.2 eq) DIPEA.
18.1
g (1.1 eq) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride
were added
and the reaction was stirred at room temperature overnight. The solvent was
evaporated, and the residue was dissolved in 500 mL DCM. The solution was
washed
with each 200 mL citric acid solution (10%), NaHCO3 solution (10%) and brine.
The
organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 24.1 g, 85% ESI-MS: 332.4 [M+H]
Date Recue/Date Received 2024-03-07
94
3 Preparation of compound ZED3906
0
H
H2N N N
2-(3-amino-2-oxopyridin-1(2H)-yI)-N-(2-adamantyhacetamide
Chemical Formula: C17H23N302
Exact Mass: 301.18
Molecular Weight: 30138
24.2 g (73.0 mmol) of ZED3905 were suspended in 600 mL Me0H before 2.42 g of
palladium (10%) on activated carbon (unreduced) were added. The suspension was
stirred overnight at room temperature under an atmosphere of hydrogen. The
catalyst
was filtered, and the solvent was evaporated. Yield: 15.7 g, 71% ESI-MS: 302.4
[M+H]
Scheme 11-2
o
0 OH 1. DMF, CH3I 0 H 1. Methyl Ac0 N
Cs2CO3 isocyanide
2. DMAP, ACN AcOH, DCM H
Boc20 2. TFA
Boc __________________________ Boc _______________ ..- Boc 'N OH
'N CO2tBu 'N CO2tBu
H 3. DIBAL-H Boc 3. Boc20 H
Et20, -78 C DIPEA, DMF
ZED721 ZED3632
0 H
H2N ti ,1 N a
HATU, DMF
I DIPEA
ZED3906
0 0
AcOJl..N Ac0 N
H H
0 0 0
H H 1) TFA, DCM H H
0
N N-AN N Bocl\I I\1AN-IN
I H H
2) 3-MethylbenzoN-
furan-2-carboxylic acid
ZED3264 ZED3907
HATU, DIPEA, DMF
1 K2CO3' Me0H
0 0
HO N
N
H
0 H H 0 Dess-Martin 0
H periodinane H
0 N N N 0 N N N
N
I H 1
DMF H
ZED3266 11-3
Preparation of compound ZED788
Date Recue/Date Received 2024-03-07
95
0 OM e
Boc'N OtBu
(S)-1-tert-butyl 5-methyl 2-(tert-butoxycarbonylamino)pentanedioate
Chemical Formula: C15H27N08
Exact Mass: 317,18
Molecular Weight: 317,38
12.0 g of Boc-L-Glu-OtBu (39.6 mmol) and 7.09 g of cesium carbonate (21.8
mmol, 0.55
eq) were suspended in 100 ml of DMF and stirred for 1 h at room temperature.
2.47 ml
iodomethane (39.6 mmol) we added, and the mixture was stirred at room
temperature
overnight. The solvent was evaporated, and the residue was dissolved in ethyl
acetate
and washed twice with each citric acid solution (10%), NaHCO3 solution (10%)
and
brine. The organic phase was dried over Na2SO4, filtered and the solvent was
evaporated. The raw product was used without further purification.
Yield: 13.4 g, >100%
ESI-MS: 318.3 [M+H]
Preparation of compound ZED720
0)0Me
Boc'Noil OtBu
e
(S)-1-tert-butyl 5-methyl 2-(bis(tert-butoxycarbonyl)amino)pentanedioate
Chemical Formula: C20H35N08
Exact Mass: 417,24
Molecular Weight: 417,49
13.4 g of ZED788 (-39,6 mmol) and 986 mg of N,N-dimethy1-4-aminopyridine
(DMAP)
were dissolved in 30 ml of acetonitrile. 17.6 g of di-tert-butyl bicarbonate
(77.1 mmol) in
100 ml of acetonitrile was added and the solution was stirred at room
temperature
overnight. The solvent was evaporated, and the residue was dissolved in ethyl
acetate
and washed twice with each citric acid solution (10%), NaHCO3 solution (10%)
and
brine. The organic phase was dried over Na2SO4, filtered and the solvent was
evaporated. The raw product was used without further purification.
Yield: 13.7 g, 83%
ESI-MS: 418.3 [M+H]
Preparation of compound ZED721
Date Recue/Date Received 2024-03-07
96
0).H
Boc'N15 OtBu
e0
(S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate
Chemical Formula: C19H33N07
Exact Mass: 387,23
Molecular Weight: 387,47
13.7 g of ZED720 (32.8 mmol) were dissolved in 200 ml of dry diethyl ether and
cooled
to -78 C under argon atmosphere. 36.1 ml of diisobutylaluminum hydride (1M in
hexane) were added dropwise and the solution was stirred for 30 min at -78 C
before
being quenched with potassium sodium tartrate (Rochelle salt) solution. The
organic
layer was separated, dried over Na2SO4, filtered, and concentrated to dryness.
The raw
product was used without further purification.
Yield: 13.3 g, >100%
ESI-MS: 388.3 [M+H]
4 Preparation of compound ZED3632
o
Ac0JIN
H
Boc'N OH
H
(2S)-5-acetoxy-2-(tert-butoxycarbonylamino)-6-(methylamino)-6-oxohexanoic acid
Chemical Formula: C14H24N207
Exact Mass: 332,16
Molecular Weight: 332,35
15.0 g (38.7 mmol) of the aldehyde (S)-tert-butyl 2-(bis(tert-
butoxycarbonyl)amino)-5-
oxopentanoate (ZED721) were dissolved in 60 mL DCM. At 0 C 2.42 mL (1.05 eq)
methyl isocyanide and 2.33 mL (1.05 eq) acetic acid were added, and the
reaction was
stirred at room temperature overnight. 75 mL TFA were added, and the reaction
was
stirred for another 3 h. The solvent was evaporated, and the residue was
dissolved in
40 mL DMF. 13.2 mL (2 eq) DIPEA and 10.4 g (46.6 mmol) di-tert-butyl
dicarbonate in
10 mL DMF were added and the reaction was stirred at room temperature
overnight.
The solvent was evaporated, and the residue was dissolved in DCM. After
extraction
with NaHCO3 solution (1.05 eq in water), 1.5 eq citric acid was added to the
aqueous
phase, followed by re-extraction with DCM. The organic phase was dried over
Na2SO4,
filtered and the solvent was evaporated. The residue was purified by flash
chromatography.
Yield: 12.5 g, 95%
ESI-MS: 333.5 [M+H]
Date Recue/Date Received 2024-03-07
97
Preparation of compound ZED3907
AVN
0
Boc'N
I\V1
(5S)-5-(tert-butoxycarbonylamino)-6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-
1,2-
dihydropyridin-3-ylamino)-1-(methylamino)-1,6-dioxohexan-2-ylacetate
Chemical Formula: C31H45N508
Exact Mass: 61533
Molecular Weight: 615/2
19.8 g (59.5 mmol) of ZED3632, 22.6 g (1 eq) HATU and 17.9 g (1 eq) ZED3906
were
5 dissolved in 400 mL DMF and 20.8 mL DIPEA (2 eq) and stirred at 45 C
overnight. The
solvent was evaporated; the residue was dissolved in 200 mL Et0Ac and washed
twice
with each 150 mL citric acid solution (10%), NaHCO3 solution (10%) and brine.
The
organic phase was dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 27.4 g, 75%
.. ESI-MS: 616.4 [M+H]
6 Preparation of compound ZED3264
AVN
0 0
0
I H 1\11
(5S)-6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-di hydropyridin-3-
ylamino)-1-
(methyla mino)-5-(3-methylbenzofuran-2-carboxamido)-1,6-d ioxohexan-2-y1
acetate
Chemical Formula: C36H43N508
Exact Mass: 673.31
Molecular Weight: 673/6
480 mg (0.78 mmol) of ZED3907 were dissolved in 4 ml DCM/TFA (1:1) and stirred
at
room temperature for 1 h. The solvent was evaporated, and the residue was
dissolved
in 4 ml DMF. 137 mg (1 eq) 3-methylbenzo[b]furan-2-carboxylic acid, 296 mg (1
eq)
HATU and 272 pl (2 eq) DIPEA were added, and the reaction was stirred at room
temperature overnight. The solvent was evaporated; the residue was dissolved
in 20 mL
Et0Ac and washed with each 10 mL citric acid solution (10%), NaHCO3 solution
(10%)
and brine. The organic phase was dried over Na2SO4, filtered and the solvent
was
evaporated.
Yield: 409 mg, 78%
ESI-MS: 674.4 [M+H]
Date Recue/Date Received 2024-03-07
98
7 Preparation of compound ZED3266
0
H OJI N
H
0 0
H H
0
I H 1 1
1-(1 -(2-(2-a da ma ntyla m ino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-y1)-5-
(2S)-N
hyd roxy-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)hexanediamide
Chemical Formula: C34H41 N507
Exact Mass: 63130
Molecular Weight: 63112
409 mg (0.61 mmol) of ZED3264 were dissolved in 5 ml Me0H. 126 mg (1.5 eq)
.. potassium carbonate were added, and the reaction was stirred at room
temperature for
1 h. The solution was diluted with DCM and washed with water. The organic
phase was
dried over Na2SO4, filtered and the solvent was evaporated.
Yield: 377 mg, 98%
ESI-MS: 632.4 [M+H]
8 Preparation of compound 11-3
0
N
0 -L H 0
H
0 N
N Fl \ II ) LN
I H
(31416\11-(1t-h(11--(r_manerylgelanmzionfou)r-a2n-o-rceatrhbta2m-oiy031_?_0-
dxiohKedxroapnyglaindd-yely
Chemical Formula: C34H39N507
Exact Mass: 629.28
Molecular Weight: 629.70
377 mg (0.60 mmol) of ZED3266 were dissolved in 2 ml DMF. 405 mg (1.6 eq) Dess-
Martin periodinane (DMP) were added and the reaction was stirred at room
temperature
over 2 h. The precipitate was filtered off and the filtrate was evaporated.
The residue
was purified by HPLC.
Yield: 314 mg, 67%
ESI-MS: 630.4 [M+H]
1H-NMR (DMSO-D6, 500 MHz, 8 [ppm]: 1.46 //1.98 (d // d, 2H // 2H, adamantyl-C4-
H2),
1.68 /11.78 (m, 4H, adamantyl-C4-H2), 1.71 (m, 2H, adamantyl-C1-H), 1.75 (m,
2H,
adamantyl-C6-H2), 1.78 (m, 2H, adamantyl-05-H), 2.05 // 2.16 (m // m, 1H //
1H, 3-
CH2), 2.53 (s, 3H, benzofuran-CH3), 2.64 (d, 3H, amide-N-CH3), 2.96 (t, 2H, y-
CH2),
Date Recue/Date Received 2024-03-07
99
3.82 (m, 1H, adamantyl-C2-H), 4.64 (s, 2H, N-CH2), 4.70 (ddd, 1H, a-CH2), 6.25
(t, 1H,
pyridinone-05-H), 7.33 (d, 1H, pyridinone-C6-H), 7.36 (t, 1H, benzofuran-CH),
7.51 (t,
1H, benzofuran-CH), 7.63 (d, 1H, benzofuran-CH), 7.76 (d, 1H, benzofuran-CH),
8.06
(d, 1H, adamantyl-NH), 8.21 (d, 1H, pyridinone-C4-H), 8.54 (q, 1H, methylamide-
NH),
8.87 (d, 1H, a-NH), 9.36 (s, 1H, pyridinone-NH).
13C-NMR (DMSO-D6, 500 MHz, 8 [ppm]: 8.62 (benzofuran-CH3), 24.50 (13-CH2),
25.37
(amide-N-CH3), 26.57 II 26.62 (adamantyl-05-H), 30.83 (adamantyl-C4-H2), 31.35
(adamantyl-C1-H), 33.61 (y-CH2), 36.66 (adamantyl-C4'-H2), 37.01 (adamantyl-C6-
H2),
51.64 (N-CH2), 52.80 (a-CH2), 53.24 (adamantyl-C2-H), 104.51 (pyridinone-05-
H),
111.55 (benzofuran-CH), 121.09 (benzofuran-CH), 121.72 (benzofuran-Cq), 122.53
(pyridinone-C4-H), 123.19 (benzofuran-CH), 127.28 (pyridinone-N-Cq), 127.89
(benzofuran-CH), 129.02 (benzofuran-Cq), 133.27 (pyridinone-C6-H), 142.31
(benzofuran-Cq), 152.68 (benzofuran-Cq), 156.55 (pyridinone-C=0), 159.59
(benzofuran-C=0), 161.32 (C=O-NH-CH3), 165.65 (C=0-adamantylamide), 170.42
(C=O-NH-pyridinone), 198.06 (C=0-methylamide).
9 Preparation of compound 11-2
o
OjANo
H
0
H H
0
IN NN-IN
H
(S)-2-(benzofura n-2-carboxamido)-N1-(1-(2-(2-ada mantyla mino)-2-oxoethyl )-2-
oxo-
1,2-di hydropyridin-3-yI)-N6-methyl-5-oxohexanediamide
Chemical Formula. C33H37N507
Exact Mass: 615.27
Molecular Weight: 615.68
To the a-hydroxyester precursor of compound 11-2 (242 mg, 0.39 mmol, prepared
by
.. using benzofuran-2-carboxylic acid in step 6 according to compound ZED3264)
in 8 mL
of acetonitrile, 1 mg of TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl, 1 mol%)
were
added. 56 mg of calcium hypochlorite (1 eq) were added at 0 C and the reaction
mixture was stirred at 25 C for 2 h. The suspension was filtered, diluted with
ethyl
acetate and washed with NaHCO3 solution (10%) and brine. The organic phase was
dried over Na2SO4, filtered and the solvent was evaporated. The residue was
purified by
HPLC.
Yield: 102 mg, 42%
ESI-MS: 616.3 [M+H]
Date Recue/Date Received 2024-03-07
100
Preparation of compound 11-4
0 c)(3 H 0
0
N N N
I H
CI
(SOXO-2-1-?t)1-19-rgiCg-n11-t-dirigg-Ocpjtrri?clina-311) - -1161-
14eitql2cTxdArrelralrtifedri
amide
Chemical Formula: C33H36CIN507
Exact Mass: 649.23
Molecular Weight: 650.12
To the a-hydroxyester precursor of compound 11-4 (124 mg, 0.19 mmol, prepared
by
using 3-chlorobenzofuran-2-carboxylic acid in step 6 according to compound
ZED3264)
5 in 4 ml DMSO, 106 mg of 2-iodoxybenzoic acid (IBX, 2 eq) were added and
the reaction
mixture was stirred at room temperature for 3 h. NaHCO3 solution (10%) was
added
and the suspension was extracted with Et0Ac. The organic phase was dried over
Na2SO4, filtered and the solvent was evaporated. The residue was purified by
HPLC.
Yield: 37 mg, 30% (last step)
10 ESI-MS: 650.3 / 652.3 [M+H]
11 Preparation of compound 11-5
H 0
0
N N N N
I H
(S)-2-(4-bromobenzofu ran-2-carboxamido)-N1 -(1 -(2-(2-adamantyla!-nino)-2-
oxoethyl)-
2-oxo-1 ,2-d ihyd ropyridin-3-yI)-N6-methyl-5-oxohexanediamide
Chemical Formula: C33H36BrN507
Exact Mass: 693.18
Molecular Weight: 694.57
The synthesis of compound 11-5 was performed according to compound 11-3, using
4-
.. bromo-1-benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 69 mg, 72% (last step)
ESI-MS: 694.3 / 696.3 [M+H]
Date Recue/Date Received 2024-03-07
101
12 Preparation of compound 11-6
N
c)-L H
0 0
N N N N
I H
(Wec1112-T-Mi!?1:11-8 ildrPArgPd-g-
Chemical Formula: C33H37N506S
Exact Mass: 631.25
Molecular Weight: 631/4
The synthesis of compound 11-6 was performed according to compound 11-3, using
benzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid
in step 6 (according to ZED3264).
Yield: 287 mg, 76% (last step)
ESI-MS: 632.3 [M+H]
13 Preparation of compound 11-7
il N
0 (211_1H 0
N
I H
Br
(S)-2-(5-bromobenzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C33H36BrN506S
Exact Mass: 709.16
Molecular Weight: 710.64
The synthesis of compound 11-7 was performed according to compound 11-3, using
5-
bromobenzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 145 mg, 59% (last step)
ESI-MS: 710.2 / 712.2 [M+H]
Date Recue/Date Received 2024-03-07
102
14 Preparation of compound 11-8
0
j)-L N
H
0 0
H H
N
H
(S)-2-(7-fluorobenzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C33H36FN506S
Exact Mass: 649.24
Molecular Weight: 649/3
The synthesis of compound 11-8 was performed according to compound 11-3, using
7-
fluorobenzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 78 mg, 71% (last step)
ESI-MS: 650.3 [M+H]
Preparation of compound 11-9
0
N
0 j) -L H 0
H H H
N N j-N N
N
I H
(S)-2-(1H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-
2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C33H38N606
Exact Mass: 614.29
10 Molecular Weight: 614.69
The synthesis of compound 11-9 was performed according to compound 11-3, using
1H-
indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in
step 6
(according to ZED3264).
Yield: 57 mg, 69% (last step)
15 ESI-MS: 615.4 [M+H]
Date Recue/Date Received 2024-03-07
103
16 Preparation of compound 11-10
0
oll N
H
0 0
H H H
N N N
N
I H il I\V/
F F
(S)-2-(4,5-difluoro-1H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C33H36F2N606
Exact Mass: 650.27
Molecular Weight: 650.67
The synthesis of compound 11-10 was performed according to compound 11-3,
using 4,5-
difluoro-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid
in step 6 (according to ZED3264).
Yield: 47 mg, 65% (last step)
ESI-MS: 651.3 [M+H]
17 Preparation of compound 11-1 1
0
0A N-
H
0 0
H H H
N N N I\ N
I H il V/
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
N6-methy1-2-(3-methy1-1 H-indole-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C34H40N606
Exact Mass: 62830
Molecular Weight: 628.72
The synthesis of compound 11-11 was performed according to compound 11-3,
using
3-methyl-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid
in step 6 (according to ZED3264).
Yield: 58 mg, 72% (last step)
ESI-MS: 629.4 [M+H]
Date Recue/Date Received 2024-03-07
104
18 Preparation of compound 11-12
0
N
0 j) -L H 0
H H H
i\j H
(S)-2-(1H-benzo[d]imidazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C32H37N706
Exact Mass: 615.28
Molecular Weight: 615.68
The synthesis of compound 11-12 was performed according to compound 11-3,
using
1H-benzo[d]imidazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 27 mg, 48% (last step)
ESI-MS: 616.4 [M+H]
19 Preparation of compound 11-13
0
0)11_\_11
N
H
0 0
H
N
N
H Ufic
(S)-2-(2,3-dihydro-1H-indene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C34H41N506
Exact Mass: 615.31
Molecular Weight: 615.72
The synthesis of compound 11-13 was performed according to compound 11-3,
using
2,3-dihydro-1H-indene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 38 mg, 61% (last step)
ESI-MS: 616.4 [M+H]
Date Recue/Date Received 2024-03-07
105
20 Preparation of compound 11-14
o
N
Br
0 j)(:) 0
H H
S
N N N N
(S)-2-(2-bromo-4-methylthiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide
Chemical Formula: C29H35BrN606S
Exact Mass: 674.15
Molecular Weight: 675.59
The synthesis of compound 11-14 was performed according to compound 11-3,
using
2-bromo-4-methylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 98 mg, 70% (last step)
ESI-MS: 675.2 / 677.2 [M+H]
21 Preparation of compound 11-15
0
(21)- N
0 cNN H 0
H H
F3C--INI 1 H
---...õ,.
matyY-1-14-ggh-l-I-5181=11012281A-2craglaVoTiorlicVn-agaigde
Chemical Formula: C30H35F3N606S
Exact Mass: 664.23
Molecular Weight: 664/0
The synthesis of compound 11-15 was performed according to compound 11-3,
using
4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-
methylbenzo[b]furan-
2-carboxylic acid in step 6 (according to ZED3264).
Yield: 67 mg, 51% (last step)
ESI-MS: 665.4 [M+H]
Date Recue/Date Received 2024-03-07
106
22 Preparation of compound 11-16
o1 N
0 H H 0
F3Ci\Sf N
Br
(S)-2-(4-bromo-2-(trifluoromethyl)thiazole-5-carboxamido)-N1-(1-(2-(2-
adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide
Chemical Formula: C29H32BrF3N606S
Exact Mass: 728.12
Molecular Weight: 729.57
The synthesis of compound 11-16 was performed according to compound 11-3,
using
4-bromo-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-
methylbenzo[b]furan-
2-carboxylic acid in step 6 (according to ZED3264).
Yield: 136 mg, 63% (last step)
ESI-MS: 729.3 / 731.3 [M+H]
23 Preparation of compound 11-17
0 H H 0
N
N
CI I H
CI
(SOXO-241-)d-2c-01Z-1th2a-RIO-Ocgrigia-Y-1/71) -k II-14412-goahre)I raltdri
igde2-
Chemical Formula: C28H32Cl2N606S
Exact Mass: 650.15
Molecular Weight: 651.56
The synthesis of compound 11-17 was performed according to compound 11-3,
using
2,4-dichlorothiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 102 mg, 71% (last step)
ESI-MS: 651.2 / 653.2 [M+H]
Date Recue/Date Received 2024-03-07
107
24 Preparation of compound 11-18
o
N
0 H 0
H H
S N
Me01\j_kAHN N
(S )r--Zitficliji2-ernaalbalZigen-ig-W1;carrtiihdici3--fie-(ncl-elli20-Pg
rordAdnielgad2e (2 -
Chemical Formula: C30H38N607S
Exact Mass: 626.25
Molecular Weight: 626/2
The synthesis of compound 11-18 was performed according to compound 11-3,
using
2-methoxy-4-methylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-
2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 56 mg, 63% (last step)
ESI-MS: 627.3 [M+H]
25 Preparation of compound 11-19
o
oil
N
H
0 0
H H
S N N N
N
(97riNegill42-r--geigla-2-VerrOggilxe -gt-CYair)1;OgriVdi OilgtdoraPxYgdergati
6-
Chemical Formula: C35H40N606S
Exact Mass: 672.27
Molecular Weight: 672/9
The synthesis of compound 11-19 was performed according to compound 11-3,
using
4-methyl-2-phenylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 46 mg, 67% (last step)
ESI-MS: 673.4 [M+H]
Date Recue/Date Received 2024-03-07
108
26 Preparation of compound 11-20
oll N
0 H 0
N N N
I HN
(Scii2o214d-i2m-gnt-acgIciPcgrrgi-a3m-P-146\1-1414-g--oaxdohreTZYgraZe2-
Chemical Formula: C30H38N606S
Exact Mass: 610.26
Molecular Weight: 610/2
The synthesis of compound 11-20 was performed according to compound 11-3,
using
2,4-dimethylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 216 mg, 77% (last step)
ESI-MS: 611.4 [M+H]
27 Preparation of compound 11-21
N
0 j)-L H 0
N
Br
\ I H
(S)-2-(5
-obegjagixeot-h1q-hgederrOP-0-b3 -N
-R161- 4111-yY CO-Zgflaecxlaarrilailitgrdnen )-2-
Chemical Formula: C30H36BrN506S
Exact Mass: 673.16
Molecular Weight: 674.61
The synthesis of compound 11-21 was performed according to compound 11-3,
using
5-bromo-3-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 178 mg, 79% (last step)
ESI-MS: 674.2 / 676.2.4 [M+H]
Date Recue/Date Received 2024-03-07
109
28 Preparation of compound 11-22
0 c)
H
C:1 0
Br
\ I H
Br
(S)gafkli-b2r-Orrx10-t[11ird[1171gplgirgx-g-Tili)d-a-Nnlec42-eo-
ghaerraitgarnrVe-2-
Chemical Formula: C29H33Br2N506S
Exact Mass: 737.05
Molecular Weight: 73948
The synthesis of compound 11-22 was performed according to compound 11-3,
using
3,5-dibromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 89 mg, 67% (last step)
ESI-MS: 738.2 / 740.2 / 742.2 [M+H]
29 Preparation of compound 11-23
0 j)N
- H 0
Br
\ I H
(ggegy-1?)r-Tig-1132h-neigr-ganini-VIVIT61-r--gill2y-lCi--gOITArgi:cgigd--
Chemical Formula: C29H34BrN506S
Exact Mass: 659.14
Molecular Weight: 660.58
The synthesis of compound 11-23 was performed according to compound 11-3,
using
5-bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid
in step 6 (according to ZED3264).
Yield: 141 mg, 72% (last step)
ESI-MS: 660.2 / 662.2 [M+H]
Date Recue/Date Received 2024-03-07
110
30 Preparation of compound 11-24
0
N
0 c)- H 0
N N N
CI _______________________ \ I H
gdegyl- 2 - ratOl-i P2h-gheA:g 1N6 Vegy-1(-25--aocx1O1-Tang:cg
Chemical Formula: C29H34CIN506S
Exact Mass: 615.19
Molecular Weight: 616.13
The synthesis of compound 11-24 was performed according to compound 11-3,
using
5-chlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid
in step 6 (according to ZED3264).
Yield: 117 mg, 78% (last step)
ESI-MS: 616.3 / 618.3 [M+H]
31 Preparation of compound 11-25
il N
0 oH 0
0
N
Br N
\ H
(S)aO5e-tbhrycl)m-Y-ant9Ydfiltiryadr:-O2prlid?r?-x3a-celtiggy-F6g)al
raanneYdliTrInVIV-2-
Chemical Formula: C30H36BrN507
Exact Mass: 657.18
Molecular Weight: 658.54
The synthesis of compound 11-25 was performed according to compound 11-3,
using
5-bromo-3-methylfuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 173 mg, 72% (last step)
ESI-MS: 658.2 / 660.2 [M+H]
Date Recue/Date Received 2024-03-07
Ill
32 Preparation of compound 11-26
oll N
0 H 0
0
N N N N
CI \ I H
(S)-2-(5-chgo-flurT_A-Milrirnii-da-M1r-aigAd_roahnly(lxnrrelicrilWaxoethyl)-2-
Chemical Formula: C29H34CIN507
Exact Mass: 599.21
Molecular Weight: 600.06
The synthesis of compound 11-26 was performed according to compound 11-3,
using
5-chlorofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic
acid in
step 6 (according to ZED3264).
Yield: 127 mg, 56% (last step)
ESI-MS: 600.3 / 602.3 [M+H]
33 Preparation of compound 11-27
0
N
0 H 0
N
CI / Nr1
(gdegy1-2 -rg-i7P2h-gheigt:grAfr31-iNf\IN61-gici20-25--aocx1O1-Tangi:cgrgg-
Chemical Formula: C29H34CIN506S
Exact Mass: 615.19
Molecular Weight: 616.13
The synthesis of compound 11-27 was performed according to compound 11-3,
using
5-chlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid
in step 6 (according to ZED3264).
Yield: 112 mg, 65% (last step)
ESI-MS: 616.3 / 618.3 [M+H]
Date Recue/Date Received 2024-03-07
112
34 Preparation of compound 11-28
o
0 )N
-L H 0
H H
N N
CI /1 H 1 Ific
CI
(S)(;)Oggy-fii-c2h-larg-t111irdhilliA-g-pcyl[gx-gli):1-1W-nlet412-
eggraitgarnrnirle-2-
Chemical Formula: C29H33Cl2N506S
Exact Mass: 649.15
Molecular Weight: 650.57
The synthesis of compound 11-28 was performed according to compound 11-3,
using
2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 319 mg, 77% (last step)
ESI-MS: 650.3 / 652.3 [M+H]
35 Preparation of compound 11-29
o
N
0 j)r -L H 0
H H
N
Br /1 H 1 I\VIN
Br
(S)-2-(2,5-dibromothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C29H33Br2N506S
Exact Mass: 737.05
Molecular Weight: 73948
The synthesis of compound 11-29 was performed according to compound 11-3,
using
2,5-dibromothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 98 mg, 52% (last step)
ESI-MS: 738.2 / 740.2 / 742.2 [M+H]
Date Recue/Date Received 2024-03-07
113
36 Preparation of compound 11-30
0llN
0 H H 0
Br
(ggegy-1?)r-Tig-1132h-tlEhedr-ganini-VIVIT61-r--ggilq--gOlTgril:cgigd--
Chemical Formula: C29H34BrN506S
Exact Mass: 659.14
Molecular Weight: 660.58
The synthesis of compound 11-30 was performed according to compound 11-3,
using
5-bromothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid
in step 6 (according to ZED3264).
Yield: 171 mg, 73% (last step)
ESI-MS: 660.2 / 662.2 [M+H]
37 Preparation of compound 11-31
il N
0 (::1 H 0
N
(S)-2OggIVIT-5-Zoe-t1hV-tPliiagitir9ig- 3x-
;15VIIMieltii;liggAdefanrWlirmnildne )-2-
Chemical Formula: C29H35CIN606S
Exact Mass: 630.20
Molecular Weight: 631.14
The synthesis of compound 11-31 was performed according to compound 11-3,
using
2-chloro-5-methylthiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 32 mg, 41% (last step)
ESI-MS: 631.3 / 633.3 [M+H]
Date Recue/Date Received 2024-03-07
114
38 Preparation of compound 11-32
0 0
N
CI
(S)-2-(2,5-dichlorothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C28H32Cl2N606S
Exact Mass: 650.15
Molecular Weight: 651.56
The synthesis of compound 11-32 was performed according to compound 11-3,
using
2,5-dichlorothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 41 mg, 35% (last step)
ESI-MS: 651.2 / 653.2 [M+H]
39 Preparation of compound 11-33
0 0
N
Br [1
Br
(S)-2-(2,5-dibromothiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C28H32Br2N606S
Exact Mass: 738.05
Molecular Weight: 740.46
The synthesis of compound 11-33 was performed according to compound 11-3,
using
2,5-dibromothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 21 mg, 32% (last step)
ESI-MS: 739.2 / 741.2 / 743.2 [M+H]
Date Recue/Date Received 2024-03-07
115
40 Preparation of compound 11-34
0 0
NcN
Br--___(/s H
(S)-2-(2-bromo-5-methylthiazole-4-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C29H35BrN606S
Exact Mass: 674.15
Molecular Weight: 675.59
The synthesis of compound 11-34 was performed according to compound 11-3,
using
2-bromo-5-methylthiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 42 mg, 57% (last step)
ESI-MS: 675.2 / 677.2 [M+H]
41 Preparation of compound 11-35
H 0
N13)- N
Br HN
=Tdot-I-ijtf)b-12 -cracli-h1ia2z-diry4cir9c2r9iNnm-Ad-g-N6li:ri-ec42-?-
g3IcinhaerPallaerrdil raTrele
Chemical Formula: C28H33BrN606S
Exact Mass: 660.14
Molecular Weight: 661.57
The synthesis of compound 11-35 was performed according to compound 11-3,
using
2-bromothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in
step 6 (according to ZED3264).
Yield: 66 mg, 46% (last step)
ESI-MS: 661.2 / 663.2 [M+H]
Date Recue/Date Received 2024-03-07
116
42 Preparation of compound 11-36
0
N
H 0
O)O-gtql-)c-21-1cOrg-h1I-calgYiges Pljn9arn- 3d-jiI3--IN 6=i-1424:5a-col
naeranagralglicie
Chemical Formula: C28H33CIN606S
Exact Mass: 616.19
Molecular Weight: 617.12
The synthesis of compound 11-36 was performed according to compound 11-3,
using
2-chlorothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in
step 6 (according to ZED3264).
Yield: 74 mg, 58% (last step)
ESI-MS: 617.3 / 619.3 [M+H]
43 Preparation of compound 11-37
0
N
0 j)-() H 0
N
I 11
(S)
-a-21-ircrg-hnu- lariAgiaDragraicy119-4161-gegataorliara2ctnrilide
Chemical Formula: C31H39N507
Exact Mass: 593.28
Molecular Weight: 593.67
The synthesis of compound 11-37 was performed according to compound 11-3,
using
2,5-dimethylfuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid
in step 6 (according to ZED3264).
Yield: 152 mg, 73% (last step)
ESI-MS: 594.4 [M+H]
Date Recue/Date Received 2024-03-07
117
44 Preparation of compound 11-38
0 c)-(:) H 0
NHNNH
H
9-x2Odlijt-IV-i2m-gitYjlth2a-cfilVd-i?o=a-3m-A -1416\1-1m-
(eitagadoahnelVeraVde-2-
Chemical Formula: C301-138N606S
Exact Mass: 610.26
Molecular Weight: 610.72
The synthesis of compound 11-38 was performed according to compound 11-3,
using
4,5-dimethylthiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 46 mg, 38% (last step)
ESI-MS: 611.4 [M+H]
45 Preparation of compound 11-39
0 c) -L
H
0
SAN NN
H
(Sik2o-glijii)d-2m-gUilt-acgliNcgrridctii-a3m-P-146\1-UtIllg--
oaxdohrreElVIrralgiV-
Chemical Formula: C28H33BrN606S
Exact Mass: 660.14
Molecular Weight: 661.57
The synthesis of compound 11-39 was performed according to compound 11-3,
using
4-bromothiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in
step 6 (according to ZED3264).
Yield: 84 mg, 68% (last step)
ESI-MS: 661.2 / 663.2 [M+H]
Date Recue/Date Received 2024-03-07
118
46 Preparation of compound 11-40
0
0j)-
N
H
0
H H
S
\ 1 H
B
(S)-2-(4-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-
2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C29H34BrN506S
Exact Mass: 659.14
Molecular Weight: 660.58
The synthesis of compound 11-40 was performed according to compound 11-3,
using
4-bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid
in step 6 (according to ZED3264).
Yield: 163 mg, 73% (last step)
ESI-MS: 660.2 / 662.2 [M+H]
47 Preparation of compound 11-41
0
oil N
H
0 0
H H
S N N
, N
\ 1 H il I\V1
B
(S)-2-(4-bromo-3-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C30H36BrN506S
Exact Mass: 673.16
Molecular Weight: 674.61
The synthesis of compound 11-41 was performed according to compound 11-3,
using
4-bromo-3-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 114 mg, 68% (last step)
ESI-MS: 674.2 / 676.2 [M+H]
Date Recue/Date Received 2024-03-07
119
48 Preparation of compound 11-42
N
0 j):() H 0
NA N
\ H
Br
T)Z-1:2)e-fgy-1?)r-2r-nocginh-igEheyt-ciOicd)faiVIVIT61-r--gi1120-i--
gOlTeaxilii:cgri-Vd-
Chemical Formula: C29H34BrN506S
Exact Mass: 659.14
Molecular Weight: 660.58
The synthesis of compound 11-42 was performed according to compound 11-3,
using
3-bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid
in step 6 (according to ZED3264).
Yield: 149 mg, 76% (last step)
ESI-MS: 660.2 / 662.2 [M+H]
49 Preparation of compound 11-43
0 jcAo H 0
FiltN
\ I H
CI
(S)-2-(3-chloro-4-methylthiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C30H36CIN506S
Exact Mass: 629.21
Molecular Weight: 630.15
The synthesis of compound 11-43 was performed according to compound 11-3,
using
3-chloro-4-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-
2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 110 mg, 64% (last step)
ESI-MS: 630.3 / 632.3 [M+H]
Date Recue/Date Received 2024-03-07
120
50 Preparation of compound 11-44
oil N
N
CI
\ H
(S)-2-(4-bromo-5-chlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C29H33BrCIN506S
Exact Mass: 693.10
Molecular Weight: 695.02
The synthesis of compound 11-44 was performed according to compound 11-3,
using
4-bromo-5-chlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 126 mg, 59% (last step)
ESI-MS: 694.2 / 696.2 / 698.2 [M+H]
51 Preparation of compound 11-45
ojA
N
0 0
N N N N
Br _______________________ \ H
(S)-2-(4,5-dibromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C29H33Br2N506S
Exact Mass: 737.05
Molecular Weight: 73948
The synthesis of compound 11-45 was performed according to compound 11-3,
using
4,5-dibromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 89 mg, 51% (last step)
ESI-MS: 738.2 / 740.2 / 742.2 [M+H]
Date Recue/Date Received 2024-03-07
121
52 Preparation of compound 11-46
0
oll N
0
N
Br , N
H
OMe
Br
(S)-2-(4,5-dibromo-3-methoxythiophene-2-carboxamido)-N1-(1-(2-(2-
adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide
Chemical Formula: C30H35Br2N507S
Exact Mass: 767.06
Molecular Weight: 769.50
The synthesis of compound 11-46 was performed according to compound 11-3,
using
4,5-dibromo-3-methoxythiophene-2-carboxylic acid instead of 3-
methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 59 mg, 40% (last step)
ESI-MS: 768.2 / 770.2 / 772.2 [M+H]
53 Preparation of compound 11-47
0
N
0 0
0
N N
\ I H
(S)-2-(4-bromofuran-2-carboxamido)-N1-11-(2-(2-adamantylamino)-2-
oxoethyl)-2-oxo-1,2-dihydropyndin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C29H34BrN507
Exact Mass: 643.16
Molecular Weight: 644.51
The synthesis of compound 11-47 was performed according to compound 11-3,
using
4-bromofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic
acid in
step 6 (according to ZED3264).
Yield: 90 mg, 69% (last step)
ESI-MS: 644.3 / 646.3 [M+H]
Date Recue/Date Received 2024-03-07
122
54 Preparation of compound 11-48
0 )C:N
1 11-1 0
0
Br
\ H
aeti144:21-i lOrxre2u-rdllillytrcoaprybrg gr-T3i-cM-41--rciegy-c-26-
taorlig=iargia2e-
Chemical Formula: C29H33Br2N507
Exact Mass: 721.07
Molecular Weight: 72341
The synthesis of compound 11-48 was performed according to compound 11-3,
using
4,5-dibromofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid
in step 6 (according to ZED3264).
Yield: 72 mg, 56% (last step)
ESI-MS: 722.2 / 724.2 / 726.2 [M+H]
55 Preparation of compound 11-49
oil N
0 H 0
NA
CI , N
H
CI
(S)-2-(4,5-dichlorothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C29H33Cl2N506S
Exact Mass: 649.15
Molecular Weight: 650.57
The synthesis of compound 11-49 was performed according to compound 11-3,
using
4,5-dichlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 55 mg, 48% (last step)
ESI-MS: 650.3 / 652.3 [M+H]
Date Recue/Date Received 2024-03-07
123
56 Preparation of compound 11-50
o
o .
N
H
N
0 ci__, 0
H
N N N
(S)-2-((S)-1-acetylpyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C31H42N607
Exact Mass: 610.31
Molecular Weight: 610/0
The synthesis of compound 11-50 was performed according to compound 11-3,
using
(S)-1-acetylpyrrolidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 190 mg, 78% (last step)
ESI-MS: 611.4 [M+H]
57 Preparation of compound 11-51
o
oil
N
H
0d o
H
N
NIF\I
Uir
(S)r-nNe411:4i2-Zithrjila-1nl!IV-IMiY-ViLgint-CYalgo3=162)--1:51
ildorliggerCariPcile16-
Chemical Formula: C28H36N806
Exact Mass: 580.28
Molecular Weight: 580.64
The synthesis of compound 11-51 was performed according to compound 11-3,
using
1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-
2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 28 mg, 35% (last step)
ESI-MS: 581.4 [M+H]
Date Recue/Date Received 2024-03-07
124
58 Preparation of compound 11-52
0
N
H
0 cA() 0
N,7AN N
1-11\1' H
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
N6-methy1-5-oxo-2-(2H-tetrazole-5-carboxamido)hexanediamide
Chemical Formula: C26H33N906
Exact Mass: 567.26
Molecular Weight: 567.60
The synthesis of compound 11-52 was performed according to compound 11-3,
using
2H-tetrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic
acid in
step 6 (according to ZED3264).
Yield: 23 mg, 31% (last step)
ESI-MS: 568.4 [M+H]
59 Preparation of compound 11-53
0
oil
N
0 0
NAN N
f H
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-methy1-5-oxo-2-(pyrazine-2-carboxamido)hexanediamide
Chemical Formula: C29H35N706
Exact Mass: 577.26
Molecular Weight: 577.63
The synthesis of compound 11-53 was performed according to compound 11-3,
using
pyrazine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid
in step 6
(according to ZED3264).
Yield: 79 mg, 74% (last step)
ESI-MS: 578.3 [M+H]
Date Recue/Date Received 2024-03-07
125
60 Preparation of compound 11-54
0 JA N
H 0
H
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
N6-methyl-24(S)-1-methylpyrrolidine-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C30H42N606
Exact Mass: 58232
Molecular Weight: 582.69
The synthesis of compound 11-54 was performed according to compound 11-3,
using
(S)-1-methylpyrrolidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 68 mg, 82% (last step)
ESI-MS: 583.4 [M+H]
61 Preparation of compound 11-55
N
0 JA H 0
N
Hc?ri jnc N
¨
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
N6-methyl-5-oxo-24(S)-pyrrolidine-3-carboxamido)hexanediamide
Chemical Formula: C29H40N606
Exact Mass: 56830
Molecular Weight: 568.66
The synthesis of compound 11-55 was performed according to compound 11-3,
using
(S)-1-Boc-pyrrolidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264). The final product was obtained by
deprotection
(DCM/TFA) as described above and purified by HPLC.
Yield: 43 mg, 79% (last step)
ESI-MS: 569.4 [M+H]
Date Recue/Date Received 2024-03-07
126
62 Preparation of compound 11-56
0 jA(N
) H 0
NcN
H
Br:
(S)-2-((2S,4S)-4-bromopyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide
Chemical Formula: C29H39BrN606
Exact Mass: 646.21
Molecular Weight: 647.56
The synthesis of compound 11-56 was performed according to compound 11-3,
using
(2S,4S)-1-Boc-4-bromopyrrolidine-2-carboxylic acid instead of 3-
methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264). The final product was
obtained by
deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 45 mg, 73% (last step)
ESI-MS: 647.3 / 649.3 [M+H]
63 Preparation of compound 11-58
0 )-L() N
H 0
NJ I NU N
H
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-methyl-5-oxo-24(S)-piperidine-2-carboxamido)hexanediamide
Chemical Formula: C30H42N606
Exact Mass: 58232
Molecular Weight: 582.69
The synthesis of compound 11-58 was performed according to compound 11-3,
using (S)-
1-Boc-piperidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in
step 6 (according to ZED3264). The final product was obtained by deprotection
(DCM/TFA) as described above and purified by HPLC.
Yield: 53 mg, 86% (last step)
ESI-MS: 583.4 [M+H]
Date Recue/Date Received 2024-03-07
127
64 Preparation of compound 11-59
ojAN121
HNAN N
H
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-methyl-5-oxo-24(R)-piperidine-3-carboxamido)hexanediamide
Chemical Formula: C30H42N606
Exact Mass: 58232
Molecular Weight: 582.69
The synthesis of compound 11-59 was performed according to compound 11-3,
using (R)-
1-Boc-piperidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in
step 6 (according to ZED3264). The final product was obtained by deprotection
(DCM/TFA) as described above and purified by HPLC.
Yield: 43 mg, 77% (last step)
ESI-MS: 583.4 [M+H]
65 Preparation of compound 11-60
oA
N
0 0
NN N
I\V1
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
N6-methyl-24(R)-morpholine-3-carboxamido)-5-oxohexanediamide
Chemical Formula: C29H40N607
Exact Mass: 58430
Molecular Weight: 584.66
The synthesis of compound 11-60 was performed according to compound 11-3,
using (R)-
4-Boc-morpholine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid
in step 6 (according to ZED3264). The final product was obtained by
deprotection
(DCM/TFA) as described above and purified by HPLC.
Yield: 67 mg, 85% (last step)
ESI-MS: 585.4 [M+H]
Date Recue/Date Received 2024-03-07
128
66 Preparation of compound 11-61
0
N
N
0 H 0
N N)-NcN
H
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-methy1-5-oxo-2-(quinuclidine-3-carboxamido)hexanediamide
Chemical Formula: C32H44N606
Exact Mass: 60833
Molecular Weight: 608/3
The synthesis of compound 11-61 was performed according to compound 11-3,
using
quinudidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic
acid in step
6 (according to ZED3264).
Yield: 24 mg, 54% (last step)
ESI-MS: 609.4 [M+H]
67 Preparation of compound 11-62
0
C:1A N
0 c H 0
H H
02N
N NANIN
H
02Me
(S)-methyl 3-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate
Chemical Formula: C33H38N6010
Exact Mass: 678.26
Molecular Weight: 678.69
The synthesis of compound 11-62 was performed according to compound 11-3,
using
mono-methyl 5-nitroisophthalate instead of 3-methylbenzo[b]furan-2-carboxylic
acid in
step 6 (according to ZED3264).
Yield: 57 mg, 66% (last step)
ESI-MS: 679.3 [M+H]
Date Recue/Date Received 2024-03-07
129
68 Preparation of compound 11-63
0
0 )-L() .. N
H 0
H H
0,1\1 N N
1 H
N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-methy1-2-(5-nitronicotinamido)-5-oxohexanediamide
Chemical Formula: C30H35N708
Exact Mass: 621.25
Molecular Weight: 621.64
The synthesis of compound 11-63 was performed according to compound 11-3,
using 5-
nitronicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step
6
(according to ZED3264).
Yield: 76 mg, 65% (last step)
ESI-MS: 622.3 [M+H]
69 Preparation of compound 11-64
0
-L(:)
N
0 c) H 0
H H
H02C-N N N N
1 H
N
(S)-5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-
ylamino)-
6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid
Chemical Formula: C31H36N608
Exact Mass: 620.26
Molecular Weight: 620.65
The synthesis of compound 11-64 was performed according to compound 11-3,
using 3,5-
pyridinedicarboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid
in step 6
(according to ZED3264).
Yield: 16 mg, 52% (last step)
.. ESI-MS: 621.3 [M+H]
Date Recue/Date Received 2024-03-07
130
70 Preparation of compound 11-65
oll N
0 H 0
Me0 C
2 N
H
(S)-methyl 5-(1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinate
Chemical Formula: C32H38N608
Exact Mass: 634.28
Molecular Weight: 634.68
The synthesis of compound 11-65 was performed according to compound 11-3,
using 5-
(methoxycarbonyl)nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic
acid in
step 6 (according to ZED3264).
Yield: 34 mg, 62% (last step)
ESI-MS: 635.3 [M+H]
71 Preparation of compound 11-66
0 o
il N
I H
PAY' l--9-g-gegyfrrnTdral IcT2114112-Zgrel-1511-1C-a-gxVii02i-sci))-h5Y-dorx
oPhYgliZe3d-ialge-
Chemical Formula: C31 H37N706S
Exact Mass: 635.25
Molecular Weight: 635.73
The synthesis of compound 11-66 was performed according to compound 11-3,
using 6-
methylimidazo[2,1-b]thiazole-5-carboxylic acid instead of 3-
methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 45 mg, 37% (last step)
ESI-MS: 636.4 [M+H]
Date Recue/Date Received 2024-03-07
131
72 Preparation of compound 11-67
0
)L NIH
04H01
I
0 N
N
I H il I\V/
(S)-N1-(1-(2-(2-adamantyl(methyl)amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C35H41 N507
Exact Mass: 64330
Molecular Weight: 643.73
The synthesis of compound 11-67 was performed according to compound 11-3,
using
N-methyl-2-adamantanamine instead of 2-adamantanamine in step 2 (according to
ZED3905).
Yield: 66 mg, 45% (last step)
ESI-MS: 644.4 [M+H]
73 Preparation of compound 11-68
0
AN
H
0 0
H H
0
I H OH
(S)-N1-(1-(2-(5-hydroxyadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C34H39N508
Exact Mass: 645.28
Molecular Weight: 645.70
The synthesis of compound 11-68 was performed according to compound 11-3,
using 5-
hydroxy-2-adamantanamine instead of 2-adamantanamine in step 2 (according to
ZED3905).
Yield: 21 mg, 34% (last step)
ESI-MS: 646.4 [M+H]
Date Recue/Date Received 2024-03-07
132
74 Preparation of compound 11-69
0
c)-N
H
0
H H
0
I H F
(S)-N 1 -(1 -(2-(5-fluoroadamantane-2-amino)-2-oxoethyl)-2-oxo-1 ,2-
dihydropyridin-
3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C34H38FN507
Exact Mass: 647.28
Molecular Weight: 647.69
The synthesis of compound 11-69 was performed according to compound 11-3,
using 5-
fluoro-2-adamantanamine instead of 2-adamantanamine in step 2 (according to
ZED3905).
Yield: 48 mg, 57% (last step)
ESI-MS: 648.4 [M+H]
75 Preparation of compound 11-70
0
AN
H
0 0
H H
0 N N
N
I H il I\V/
CI
(S)-N 1 -(1 -(2-(5-chloroadamantane-2-amino)-2-oxoethyl)-2-oxo-1 ,2-
dihydropyrid in-
3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C34H38CIN507
Exact Mass: 663.25
Molecular Weight: 664.15
The synthesis of compound 11-70 was performed according to compound 11-3,
using 5-
chloro-2-adamantanamine instead of 2-adamantanamine in step 2 (according to
ZED3905).
Yield: 45 mg, 35% (last step)
ESI-MS: 664.3 / 666.3 [M+H]
Date Recue/Date Received 2024-03-07
133
76 Preparation of compound 11-71
0
oil N0
H
0j
H H
0
N NIN
I H Br
(S)-N1-(1-(2-(5-bromoadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C34H38BrN507
Exact Mass: 707.20
Molecular Weight: 708.60
The synthesis of compound 11-71 was performed according to compound 11-3,
using 5-
bromo-2-adamantanamine instead of 2-adamantanamine in step 2 (according to
ZED3905).
Yield: 31 mg, 34% (last step)
ESI-MS: 708.3 / 710.3 [M+H]
77 Preparation of compound 11-72
0
AN
H
0 0
H H
0 NA N
N
I H il I\V/
(S)-N1-(1-(2-(5-methyladamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C35H41 N507
Exact Mass: 64330
Molecular Weight: 643.73
The synthesis of compound 11-72 was performed according to compound 11-3,
using
5-methyl-2-adamantanamine instead of 2-adamantanamine in step 2 (according to
ZED3905).
Yield: 68 mg, 54% (last step)
ESI-MS: 644.4 [M+H]
Date Recue/Date Received 2024-03-07
134
78 Preparation of compound 11-73
0
:cAN
H
0
H H CN
0 N N
N
I H il I\V/
(S)-N1-(1-(2-(2-carbonitrileadamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C35H38N607
Exact Mass: 654.28
Molecular Weight: 654.71
The synthesis of compound 11-73 was performed according to compound 11-3,
using
2-aminoadamantane-2-carbonitrile instead of 2-adamantanamine in step 2
(according to
ZED3905).
Yield: 26 mg, 46% (last step)
ESI-MS: 655.4 [M+H]
79 Preparation of compound 11-74
0
oil N
H
0d 0
H H CO2Me
0 N N
N
I H il N
(S)-N1-(1-(2-(2-methyl adamantane-2-carboxylate-2-amino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C36H41 N509
Exact Mass: 687.29
Molecular Weight: 687.74
The synthesis of compound 11-74 was performed according to compound 11-3,
using 2-
methyl 2-aminoadamantane-2-carboxylate instead of 2-adamantanamine in step 2
(according to ZED3905).
Yield: 38 mg, 61% (last step)
ESI-MS: 688.4 [M+H]
Date Recue/Date Received 2024-03-07
135
80 Preparation of compound 11-87
0
A N 11
H
0
H H
0 N N
N
I H il I\V/
(S)-N1-(1-(2-(1-adamantylmethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C35H41 N507
Exact Mass: 64330
Molecular Weight: 643/3
The synthesis of compound 11-87 was performed according to compound 11-3,
using 1-
adamantanemethylamine instead of 2-adamantanamine in step 2 (according to
ZED3905).
Yield: 43 mg, 53% (last step)
ESI-MS: 644.4 [M+H]
81 Preparation of compound 11-88
o
0)-L N-
H
0 0
H H
0 N N
N
I H J1 1\11
(S)-N1-(1-(2-(1-(1-adamantypethanamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C35H41 N507
Exact Mass: 643.30
Molecular Weight: 643.73
The synthesis of compound 11-88 was performed according to compound 11-2,
using 1-
rimantadine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 31 mg, 41% (last step)
ESI-MS: 644.4 [M+H]
Date Recue/Date Received 2024-03-07
136
82 Preparation of compound 11-90
0
JA N 1)
H
0
H
0 N N )-LN NH
I H
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C31 H35N 507
Exact Mass: 589.25
Molecular Weight: 589.64
The synthesis of compound 11-90 was performed according to compound 11-3,
using ( )-
endo-2-norbornylamine instead of 2-adamantanamine in step 2 (according to
ZED3905).
Yield: 67 mg, 65% (last step)
ESI-MS: 590.4 [M+H]
83 Preparation of compound 11-92
o
:c)-N
H
0 0
H
0 N NANINH
I H
(S)-N1-methyl-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-
((1R,2S,4R)-
1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
Chemical Formula: C34 H41 N507
Exact Mass: 63130
Molecular Weight: 631/2
The synthesis of compound 11-92 was performed according to compound 11-3,
using (R)-
(+)-bornylamine instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 52 mg, 66% (last step)
ESI-MS: 632.5 [M+H]
Date Recue/Date Received 2024-03-07
137
84 Preparation of compound 11-94
0
cA N
H
0 0
H H.1/43....
0
N N-)-LNIN
I H
(S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C31H35N507
Exact Mass: 589.25
Molecular Weight: 589.64
The synthesis of compound 11-94 was performed according to compound 11-3,
using exo-
2-aminonorbornane instead of 2-adamantanamine in step 2 (according to
ZED3905).
Yield: 62 mg, 68% (last step)
ESI-MS: 590.4 [M+H]
85 Preparation of compound 11-95
0
N
0 H
N Ell tN
I H
(S)-N1-(1-(2-(bicyclo[2.2.1]heptan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C31H35N507
Exact Mass: 589.25
Molecular Weight: 589.64
The synthesis of compound 11-95 was performed according to compound 11-3,
using
bicyclo[2.2.1]heptan-1-ylamine instead of 2-adamantanamine in step 2
(according to
ZED3905).
Yield: 14 mg, 32% (last step)
ESI-MS: 590.4 [M+H]
Date Recue/Date Received 2024-03-07
138
86 Preparation of compound 11-96
o
H
0
H
0 N NH
N
I H il N
(S)-N1 -(1 -(2-(bicyclo[2.2.1]heptan-7-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C31 H35N507
Exact Mass: 589.25
Molecular Weight: 589.64
The synthesis of compound 11-96 was performed according to compound 11-3,
using
bicyclo[2.2.1]heptan-7-ylamine instead of 2-adamantanamine in step 2
(according to
ZED3905).
Yield: 36 mg, 53% (last step)
ESI-MS: 590.4 [M+H]
87 Preparation of compound 11-97
o
:c)-N
H
0 0
H
0 N NH
N
I H il Inc
(S)-N1 -(1 -(2-(bicyclo[2.2.1 ]hept-5-en-2-ylamino)-2-oxoethyl)-2-oxo-1 ,2-d
ihydropyrid in-
3-yI)-N6-methyl-2-(3-methylbenzofuran-2-carboxa mido)-5-oxohexaned iamide
Chemical Formula: C31 H 33 N 507
Exact Mass: 587.24
Molecular Weight: 587.62
The synthesis of compound 11-97 was performed according to compound 11-3,
using
bicyclo[2.2.1]hept-5-en-2-amine instead of 2-adamantanamine in step 2
(according to
ZED3905).
Yield: 21 mg, 44% (last step)
ESI-MS: 588.4 [M+H]
Date Recue/Date Received 2024-03-07
139
88 Preparation of compound 11-98
0
N
j)-L H 0 0
0
N N
I H
(2S)-N1-(1-(2-(bicyclo[2.2.2]octan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C32H37N507
Exact Mass: 603.27
Molecular Weight: 603.67
The synthesis of compound 11-98 was performed according to compound 11-3,
using
bicyclo[2.2.2]oct-2-ylamine instead of 2-adamantanamine in step 2 (according
to
ZED3905).
Yield: 25 mg, 41% (last step)
ESI-MS: 604.4 [M+H]
89 Preparation of compound 11-99
0
N
0 (::1 .. il H 0
0
N
I H
(S)-N1-methyl-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-
((1R,2R,4R)-
1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
Chemical Formula: C34H41 N507
Exact Mass: 63130
Molecular Weight: 63112
The synthesis of compound 11-99 was performed according to compound 11-3,
using (R)-
(-)-isobornylamine instead of 2-adamantanamine in step 2 (according to
ZED3905).
Yield: 27 mg, 48% (last step)
ESI-MS: 632.5 [M+H]
Date Recue/Date Received 2024-03-07
140
90 Preparation of compound 11-100
0
o1 N
0 N N,
I 1\1 ,
H
1
(S)-N1-methyl-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-
((1R,2R,3R,5S)-
2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
Chemical Formula: C34H41N507
Exact Mass: 63130
Molecular Weight: 631/2
The synthesis of compound 11-100 was performed according to compound 11-3,
using
(1R,2R,3R,5S)-(-)-isopinocampheylamine instead of 2-adamantanamine in step 2
(according to ZED3905).
Yield: 17 mg, 39% (last step)
ESI-MS: 632.5 [M+H]
91 Preparation of compound 11-101
0
0j)-LN
0d 0
/NJ0 N
I H I\V1
(S)-N1-methyl-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-
((1S,2S,3S,5R)-
2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
Chemical Formula: C34 H4iN507
Exact Mass: 631.30
Molecular Weight: 631/2
The synthesis of compound 11-101 was performed according to compound 11-3,
using
(1S,2S,3S,5R)-(+)-isopinocampheylamine instead of 2-adamantanamine in step 2
(according to ZED3905).
Yield: 25 mg, 41% (last step)
ESI-MS: 632.5 [M+H]
Date Recue/Date Received 2024-03-07
141
92 Preparation of compound 11-103
0
N
H
0 j)-(21 0
HQ
N
I H
(S)-N1-(1-(2-(4-homoisotwistane-3-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C35H41 N507
Exact Mass: 64330
Molecular Weight: 643/3
The synthesis of compound 11-103 was performed according to compound 11-3,
using 3-
amino-4-homoisotwistane instead of 2-adamantanamine in step 2 (according to
ZED3905).
Yield: 12 mg, 28% (last step)
ESI-MS: 644.5 [M+H]
93 Preparation of compound 11-104
0 o
N ,LNcNH
I H
(S)-N1-(1-(2-(diamantane-1-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C38H43N507
Exact Mass: 68132
Molecular Weight: 68118
The synthesis of compound 11-104 was performed according to compound 11-3,
using 1-
aminodiamantane instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 17 mg, 35% (last step)
ESI-MS: 682.5 [M+H]
Date Recue/Date Received 2024-03-07
142
94 Preparation of compound 11-105
0
0)-
N
H
0
H o H
0
I H 1 1
(S)-N1-(1-(2-(diamantane-4-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C38H43N507
Exact Mass: 68132
Molecular Weight: 68118
The synthesis of compound 11-105 was performed according to compound 11-3,
using 4-
aminodiamantane instead of 2-adamantanamine in step 2 (according to ZED3905).
Yield: 8 mg, 26% (last step)
ESI-MS: 682.5 [M+H]
Scheme 11-3 New Building Block
OH 1-(Bromomethyl)- 0
adamantane
N N
0, 02N
' ____________________________________ ,..-
J1 N
DMF, DIPEA
ZED4893
i10% Pd/C
Me0H
0
H2N
J1 N
ZED4894
95 Preparation of compound ZED4893
o
o2N
i N
1-(1-adamantylmethyl)-3-nitropyridin-2(1H)-one
Chemical Formula: C16H20N203
Exact Mass: 288.15
Molecular Weight: 288.34
500 mg (3.57 mmol) of 2-hydroxy-3-nitropyridine and 818 mg (1 eq) of 1-
(bromomethyl)adamantane were dissolved in 10 mL DMF and 1.24 mL DIPEA (2 eq)
Date Recue/Date Received 2024-03-07
143
and stirred at room temperature overnight. The solvent was evaporated; the
residue
was dissolved in 30 mL Et0Ac and washed twice with each 10 mL citric acid
solution
(10%), NaHCO3 solution (10%) and brine. The organic phase was dried over
Na2SO4,
filtered and the solvent was evaporated. The residue was purified by HPLC.
Yield: 484 mg, 47% ESI-MS: 289.3 [M+H]
96 Preparation of compound ZED4894
Fi2NN
3-amino-1-(1-adamantylmethyl)pyridin-2(1H)-one
Chemical Formula: C16H22N20
Exact Mass: 258.17
Molecular Weight: 25836
484 mg (1.68 mmol) of ZED4893 were suspended in 30 mL Me0H before 50 mg of
palladium (10%) on activated carbon (unreduced) were added. The suspension was
stirred for 3 h at room temperature under an atmosphere of hydrogen. The
catalyst was
filtered, and the solvent was evaporated.
Yield: 339 mg, 78%
ESI-MS: 259.4 [M+H]
97 Preparation of compound11-107
0
N
H
0 j)(::1 0
0
N N
I H I I
m(g0-21((131i-nairaritzYcirfrultti-9t%VaM-g-rcoTOfiraVeYcliAe
Chemical Formula: C33H38N406
Exact Mass: 586.28
Molecular Weight: 586.68
The synthesis of compound 11-107 was performed according to compound 11-3,
using
ZED4894 instead of ZED3906 in step 5 (according to ZED3907).
Yield: 41 mg, 49% (last step)
ESI-MS: 587.4 [M+H]
Date Recue/Date Received 2024-03-07
144
98 Preparation of compound 11-108
0
o11
N
H
04H0
0 N
, N
1 H J1 N
H
(2S)-N1-(14(3-hydroxy-1-adamantypmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C33H38N407
Exact Mass: 602.27
Molecular Weight: 602.68
The synthesis of compound 11-108 was performed according to compound 11-107,
using
3-(bromomethyl)-1-adamantanol instead of 1-(bromomethyl)adamantane (according
to
ZED4893).
Yield: 16 mg, 36% (last step)
ESI-MS: 603.4 [M+H]
99 Preparation of compound 11-109
0
N1
H
04H0A
0 N
N1 N
I H
nY
(2S)-N1-(14(3-bromo-1-adamantypmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C33H37EirN406
Exact Mass: 664.19
Molecular Weight: 665.57
The synthesis of compound 11-109 was performed according to compound 11-107,
using
1-bromo-3-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane
(according to ZED4893).
Yield: 24 mg, 41% (last step)
ESI-MS: 665.3 / 667.3 [M+H]
Date Recue/Date Received 2024-03-07
145
100 Preparation of compound 11-110
0
N
0 )-F1 0
0 1E1 N
N
I H 1 I
(S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-
2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C33H38N406
Exact Mass: 586.28
Molecular Weight: 586.68
The synthesis of compound 11-110 was performed according to compound 11-107,
using
2-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to
ZED4893).
Yield: 46 mg, 62% (last step)
ESI-MS: 587.4 [M+H]
101 Preparation of compound 11-111
0
0 )-L() N
H 0
H H
N N N N
I H
N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-N6-methy1-2-(nicotinamido)-5-oxohexanediamide
Chemical Formula: C30H36N606
Exact Mass: 576.27
Molecular Weight: 576.64
The synthesis of compound 11-111 was performed according to compound 11-3,
using
nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6
(according to
ZED3264).
Yield: 65 mg, 46% (last step)
ESI-MS: 577.4 [M+H]
Date Recue/Date Received 2024-03-07
146
102 Preparation of compound 11-112
0
N
jA(:) H 0 H H
0
N
(S)-2-(isonicotinamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-
1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C30H36N606
Exact Mass: 576.27
Molecular Weight: 576.64
The synthesis of compound 11-112 was performed according to compound 11-3,
using
isonicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6
(according
to ZED3264).
Yield: 47 mg, 52% (last step)
ESI-MS: 577.4 [M+H]
103 Preparation of compound 11-113
0
oil
N
0 0
N N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
N6-methy1-5-oxo-2-(pyridazine-4-carboxamido)hexanediamide
Chemical Formula: C29H36N706
Exact Mass: 577.26
Molecular Weight: 577.63
The synthesis of compound 11-113 was performed according to compound 11-3,
using
pyridazine-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic
acid in step
6 (according to ZED3264).
Yield: 34 mg, 46% (last step)
ESI-MS: 578.4 [M+H]
Date Recue/Date Received 2024-03-07
147
104 Preparation of compound 11-114
0
ll N
0 (::1 H 0
*1 N N N
I
1\1-
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
N6-methyl-5-oxo-2-(pyridazine-3-carboxamido)hexanediamide
Chemical Formula: C29H35N706
Exact Mass: 577.26
Molecular Weight: 577.63
The synthesis of compound 11-114 was performed according to compound 11-3,
using
pyridazine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic
acid in step
6 (according to ZED3264).
Yield: 43 mg, 56% (last step)
ESI-MS: 578.4 [M+H]
105 Preparation of compound 11-115
0
N
0 0
0 N
I H
(S)-N1-cyclopropyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide
Chemical Formula: C36H41 N507
Exact Mass: 65530
Molecular Weight: 655.74
The synthesis of compound 11-115 was performed according to compound 11-3,
using
cyclopropyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632).
Yield: 47 mg, 64% (last step)
ESI-MS: 656.5 [M+H]
Date Recue/Date Received 2024-03-07
148
106 Preparation of compound 11-116
0
0)- N H
0
H 0 H
0
N
I H
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
2-(3-methylbenzofuran-2-carboxamido)-5-oxo-N6-pentylhexanediamide
Chemical Formula: C38H47N507
Exact Mass: 68535
Molecular Weight: 685.81
The synthesis of compound 11-116 was performed according to compound 11-3,
using
pentyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632).
Yield: 87 mg, 71% (last step)
ESI-MS: 686.5 [M+H]
107 Preparation of compound 11-117
o
0 N
H
0d 0
H H
0 N N
N
I H il I\V1
(S)-N1-allyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide
Chemical Formula: C36H41 N507
Exact Mass: 65530
Molecular Weight: 655.74
The synthesis of compound 11-117 was performed according to compound 11-3,
using
allyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632).
Yield: 42 mg, 63% (last step)
ESI-MS: 656.5 [M+H]
Scheme 11-4
Date Recue/Date Received 2024-03-07
149
o
0 H HO CN HO CN HOANH2
)c H202, LiOH
_______________________________ ..- ___________________ ..-
Boc 'N OtBu Et3N, CH2C Boc 'N Me0H
OtBu Boc 'N OtBu
I2
eoco eoca oc 11
1) Ac20, NEt3 2) TFA/DCM
DMAP, DCM 3) Boc20
DI PEA, DMF
0 0 H 0
AV NH2 H2N,a,N,c1 AV
NH2
HATUDMF
I 8
0
H H . _____
Boc 1\1 N N N Boc 'N OtBu
, H H DIPEA
1
1) TFA/DCM 16
2) 3-MethylbenzoN-
furan-2-carboxylic acid
HATU, DIPEA, DMF
0 0
AV NH2 NH2
1) K2CO3' Me0H ()
H II H H
0 0 N f\jANIN N NI\VIN 2)
Dess-Martin
I H periodinane I H i i
DMF a
11-118
Preparation of compound 10
HO CN
Boc'6N0tBu
:c
(2S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-cyano-5-hydroxypentanoate
Chemical Formula: C20H34N207
Exact Mass: 414,24
Molecular Weight: 414,49
5 15.0 g (38.7 mmol) of the aldehyde (S)-tert-butyl 2-(bis(tert-
butoxycarbonyl)amino)-5-
oxopentanoate (ZED721) were dissolved in 150 ml DCM. 6.42 ml (46.3 mmol)
trimethylamine and 7.37 ml (79.9 mmol) acetone cyanohydrin were added, and the
reaction was stirred at room temperature overnight. The solution was washed
twice with
each citric acid solution (10%) and brine. The organic phase was dried over
Na2SO4,
10 filtered and the solvent was evaporated. The residue was purified by flash
chromatography.
Yield: 16.2 g, >100%
ESI-MS: 437.6 [M+Na]
Date Recue/Date Received 2024-03-07
150
Preparation of compound 11
o
H:cA N H2
Boc ' N OtBu
60c
(2 S)-tert-butyl 6-ami no-2-(bis(tert-butoxycarbonyl)amino)-5-hyd roxy-6-
oxohexanoate
Chemical Formula: C20H36N208
Exact Mass: 432,25
Molecular Weight: 432,51
16.2 g (-38.6 mmol) of cyanohydrin 10 were dissolved in 95 ml Me0H at 4 C and
1.91
g (45.5 mmol) lithium hydroxide monohydrate were added. 18.6 ml hydrogen
peroxide
(35%) were added dropwise, and the reaction was stirred at room temperature
for 1.5 h
before quenching with sodium thiosulfate solution (5%). The aqueous phase was
extracted with DCM. The combined organic phases were dried over Na2SO4,
filtered
and the solvent was evaporated. The residue was purified by flash
chromatography.
Yield: 8.61 g, 52%
ESI-MS: 455.2 [M+Na]
Preparation of compound 15
o
Ac0j)-L NH2
Boc 'N OtBu
Boc
(2 S)-tert-butyl 5-acetoxy-6-amino-2-(bis(tert-butoxycarbonyl)amino)-6-
oxohexanoate
Chemical Formula: C22H38N209
Exact Mass: 474,26
Molecular Weight: 474,55
8.61 g (19.9 mmol) of hydroxyamide 10 were dissolved in 55 ml DCM. 3.45 ml
(24.9
mmol) 1.91 g (45.5 mmol) trimethylamine, 2.12 ml acetic anhydride and 62 mg
(0.50
mmol) DMAP were added, and the reaction was stirred at room temperature for 3
h.
After washing with water and brine, the organic phase was dried over Na2SO4,
filtered
and the solvent was evaporated. The product precipitates from MTBE solution by
addition of hexane.
Yield: 8.08 g, 86%
ESI-MS: 475.5 [M+H]
Date Recue/Date Received 2024-03-07
151
Preparation of compound 16
o
AV NH2
Boc'N OH
H
(2S)-5-acetoxy-6-amino-2-(tert-butoxycarborylamino)-6-oxohexanoic acid
Chemical Formula: C13r-122N207
Exact Mass: 318,14
Molecular Weight: 318,32
8.08 g (17.0 mmol) of 15 were dissolved in 140 ml DCM/TFA (1:1) and stirred at
room
temperature for 3 h. The solvent was evaporated, and the residue was dissolved
in
.. 40 ml DMF. 5.80 ml (2 eq) DIPEA and 4.55 g (20.4 mmol) di-tert-butyl
dicarbonate in 20
ml DMF were added and the reaction was stirred at room temperature overnight.
The
solvent was evaporated, and the residue was dissolved in 80 ml Et0Ac. After
extraction
with NaHCO3 solution (1.05 eq in water), the product precipitates from the
aqueous
phase by addition of 1.5 eq citric acid.
Yield: 1.64 g, 30%
ESI-MS: 319.4 [M+H]
108 Preparation of compound 11-118
0
0 )NH2
- 0
H H
0 N N
N
(3)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C33H37N507
Exact Mass: 615.27
Molecular Weight: 615.68
The synthesis of compound 11-118 was performed according to compound 11-3,
using
compound 16 instead of ZED3632 in step 5 (according to ZED3907).
Yield: 158 mg, 56% (last step)
ESI-MS: 616.4 [M+H]
Date Recue/Date Received 2024-03-07
152
109 Preparation of compound 11-119
o
)-
N
H
0
:cH 0 H
0
N N-)-LNIN
I H
Chemical Formula: C35H39N507
Exact Mass: 641.28
Molecular Weight: 641/1
(S)-N1-ally1-5-(benzofuran-2-carboxamido)-N6-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide
The synthesis of compound 11-119 was performed according to compound 11-2,
using
allyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632).
Yield: 56 mg, 71% (last step)
ESI-MS: 642.4 [M+H]
110 Preparation of compound 11-120
0
0)-N
H
INjN
0 0
H H
0 ) H il I\ NV/
Chemical Formula: C351-141N507
Exact Mass: 643.30
Molecular Weight: 643.73
(S)-2-(benzofuran-2-carboxamido)-N6-isopropyl-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide
The synthesis of compound 11-120 was performed according to compound 11-2,
using
isopropyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632).
Yield: 62 mg, 65% (last step)
ESI-MS: 644.5 [M+H]
Date Recue/Date Received 2024-03-07
153
111 Preparation of compound 11-121
o
o N.A=
H
0 0
H H
0 N N
N
I H il Inc
Chemical Formula: C35H39N507
Exact Mass: 641.28
Molecular Weight: 641.71
(S)-2-(benzofuran-2-carboxamido)-N6-cyclopropyl-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide
The synthesis of compound 11-121 was performed according to compound 11-2,
using
cyclopropyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632).
Yield: 44 mg, 51% (last step)
ESI-MS: 642.4 [M+H]
112 Preparation of compound 11-122
0 0
0j)r -N
H
0
H 0 H
0 N N
N
I H il I\V1
Chemical Formula: C38H39N507
Exact Mass: 677.28
Molecular Weight: 677.75
(S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-
2-oxo-1,2-dihydropyridin-3-y1)-5-oxo-N6-phenylhexanediamide
The synthesis of compound 11-122 was performed according to compound 11-2,
using
phenyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632).
Yield: 37 mg, 56% (last step)
ESI-MS: 678.4 [M+H]
Date Recue/Date Received 2024-03-07
154
113 Preparation of compound 11-123
0
:c)-N
H
0
H 0 H
0 N N
N
I H il I\V/
Chemical Formula: C39H41 N507
Exact Mass: 691,30
Molecular Weight: 691,77
(S)-2-(benzofuran-2-carboxamido)-N6-benzyl-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide
The synthesis of compound 11-123 was performed according to compound 11-2,
using
benzyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632).
.. Yield: 46 mg, 52% (last step)
ESI-MS: 692.5 [M+H]
114 Preparation of compound 11-124
0
0)-L N H2
0 0
H H
0
I H
Chemical Formula: C32H35N507
Exact Mass: 601.25
Molecular Weight: 601.65
(S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-
2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide
The synthesis of compound 11-124 was performed according to compound 11-118,
using
benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic
acid in step
6 (according to ZED3264).
Yield: 96 mg, 81% (last step)
ESI-MS: 602.4 [M+H]
Date Recue/Date Received 2024-03-07
155
115 Preparation of compound 11-125
0
NH2
0 -_i() 0
H
N N
CI N / N
I H
CI
Chemical Formula: C28H31C12N606S
Exact Mass: 635.14
Molecular Weight: 636.55
(S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide
The synthesis of compound 11-125 was performed according to compound 11-124,
using
2,5-dichlorothiophene-3-carboxylic acid instead of benzofuran-2-carboxylic
acid in step
6 (according to ZED3264).
Yield: 78 mg, 71% (last step)
ESI-MS: 636.3 / 638.3 [M+H]
116 Preparation of compound 11-126
0
() - NH2
0 i_1 0
H
F3C N
--....,,I
Chemical Formula: C29H33F3N6063
Exact Mass: 650.21
Molecular Weight: 650.67
(3)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-
(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide
The synthesis of compound 11-126 was performed according to compound 11-124,
using
4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of benzofuran-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 53 mg, 67% (last step)
ESI-MS: 651.3 [M+H]
Date Recue/Date Received 2024-03-07
156
117 Preparation of compound 11-127
0
NH2
0 () -0
H
N N N
1\l/AH
Is\I_N
\
Chemical Formula: C27H34N806
Exact Mass: 566.26
Molecular Weight: 566.61
(3)-N1-(1-(2-(2-adamantylai-nino)-2-oxoethyl)-2-oxo-1,2-dihydropyridip-3-y1)-
2-(1-methyl-1H-1,2,3-triazole-5-carboxamiclo)-5-oxohexanediamide
The synthesis of compound 11-127 was performed according to compound 11-124,
using
1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of benzofuran-2-
carboxylic acid in
step 6 (according to ZED3264).
Yield: 26 mg, 49% (last step)
ESI-MS: 567.3 [M+H]
118 Preparation of compound 11-128
o
o
N
0 H H 0 H
N N N
Cl _______________________ / N
I H
CI
(2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-
1,2-
dihydropyridin-3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methyl-5-
oxohexanediamide
Chemical Formula: C26H29Cl2N606S
Exact Mass: 609.12
Molecular Weight: 610.51
The synthesis of compound 11-128 was performed according to compound 11-97,
using
2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 53 mg, 73% (last step)
ESI-MS: 610.3 / 612.3 [M+H]
Date Recue/Date Received 2024-03-07
157
119 Preparation of compound 11-129
o
oll
o H HN 0
s__AN NN
F3C1\1
(2S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-
1,2-dihydropyridin-
3-yI)-N6-methyl-2-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-5-
oxohexanediamide
Chemical Formula: C27F131F3N606S
Exact Mass: 624.20
Molecular Weight: 624.63
The synthesis of compound 11-129 was performed according to compound 11-97,
using
4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-
methylbenzo[b]furan-
2-carboxylic acid in step 6 (according to ZED3264).
Yield: 42 mg, 60% (last step)
ESI-MS: 625.3 [M+H]
120 Preparation of compound 11-130
0
Ni0
N
H
0 0
H 4....
N
N/A H
j'
\
(23)-N 1 -(1 -(2-((1 R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-
oxo-1 ,2-d ihydropyrid in-
3-yI)-N6-methyl-2-(1 -methyl-1 H-1 ,2,3-triazole-5-carboxa mid o)-5-oxohexaned
ia mid e
Chemical Formula: C25H32N806
Exact Mass: 540.24
Molecular Weight: 540.57
The synthesis of compound 11-130 was performed according to compound 11-97,
using
1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-
2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 15 mg, 39% (last step)
ESI-MS: 541.3 [M+H]
Date Recue/Date Received 2024-03-07
158
121 Preparation of compound 11-131
0
N
H
0 0
AH H
\N -
H
Chemical Formula: C271-134N806
Exact Mass: 566.26
Molecular Weight: 566.61(3)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-N6-methyl-5-oxo-2-(2H-1,2,3-triazole-4-
carboxamido)hexanediamide
The synthesis of compound 11-131 was performed according to compound 11-3,
using
2H-1,2,3-triazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in
step 6 (according to ZED3264).
Yield: 28 mg, 56% (last step)
ESI-MS: 567.4 [M+H]
122 Preparation of compound 11-132
0
0j-LN
H
0 0
H H
N N
HI\17Y-H N
\N, N
Chemical Formula: C271-134N806
Exact Mass: 566.26
Molecular Weight: 566.61
(3)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
N6-methyl-5-oxo-2-(1 H-1 ,2,3-triazole-4-carboxamido)hexanediamide
The synthesis of compound 11-132 was performed according to compound 11-3,
using
1H-1,2,3-triazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in
step 6 (according to ZED3264).
Yield: 14 mg, 45% (last step)
ESI-MS: 567.4 [M+H]
Date Recue/Date Received 2024-03-07
159
123 Preparation of compound 11-133
0
0
N
H
0 H 0
H
N -LN N
¨NH
Chemical Formula: C28H36N806
Exact Mass: 580.28
Molecular Weight: 580.64
(3)-TiNeilITCF- i2- Zitgr1n141-1P 21iY-ViLcot.e4t-hcYair)1;2oZrni di b2)--c51
i-hadorager21-11Pd-le16-
The synthesis of compound 11-133 was performed according to compound 11-3,
using 1-
methyl-1H-1,2,3-triazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 36 mg, 61% (last step)
ESI-MS: 581.4 [M+H]
124 Preparation of compound 11-134
o
(21)- N
0 H 0
NjH H
N)-Nr N
H
Chemical Formula: C27H34N806
Exact Mass: 566.26
Molecular Weight: 566.61
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-122-dihydropyridih-3-y1)-
N6-methyl-5-oxo-2-(1H-1,2,4-triazole-3-carboxamiclo)hexanediamide
The synthesis of compound 11-134 was performed according to compound 11-3,
using
1H-1,2,4-triazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in
step 6 (according to ZED3264).
Yield: 21 mg, 43% (last step)
ESI-MS: 567.4 [M+H]
Date Recue/Date Received 2024-03-07
160
125 Preparation of compound 11-135
0
0 H 0
NNNN
(NI N H
Chemical Formula: C28H36N806
Exact Mass: 580.28
Molecular Weight: 580.64
(3)-TiNeltrIcl:?4i2-4:11.71nIt-IV-Inli.1411gactICYair)1;2oZrnidi b2)--c5ii-
hadoragenZniPcile16-
The synthesis of compound 11-135 was performed according to compound 11-3,
using 1-
methyl-1H-1,2,4-triazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 39 mg, 67% (last step)
ESI-MS: 581.4 [M+H]
126 Preparation of compound 11-136
0
N
0 0H 0
N
I H
Chemical Formula: C33H37N507
Exact Mass: 615.27
Molecular Weight: 615.68
oxalli-e-roTof-111rMagrIgInd-Y-A-1461:geiktd5TixaoralcaanniendQda-rnide
The synthesis of compound 11-136 was performed according to compound 11-3,
using
benzofuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic
acid in step
6 (according to ZED3264).
Yield: 56 mg, 71% (last step)
ESI-MS: 616.4 [M+H]
Date Recue/Date Received 2024-03-07
161
127 Preparation of compound 11-137
0
N
0 jA H 0
H H
N 1\1-ANIN
I H
Chemical Formula: C33H37N6063
Exact Mass: 631.25
Molecular Weight: 631.74
(Odeilbig2D-Mir2h-t1g-d3alina-rii-VIY-IC11\61-ggag)d(glileaxiglarlig)d--
The synthesis of compound 11-137 was performed according to compound 11-3,
using
benzo[b]thiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid
in step 6 (according to ZED3264).
Yield: 49 mg, 64% (last step)
ESI-MS: 632.4 [M+H]
128 Preparation of compound 11-138
0
N
H 0
H H
NA N
/
(3)-1\irn-S1443AaeThay7-WITDOZ3V-x3TIVO-x2042i:ahotMeigilacie-N6-
Chemical Formula: C29H37N706
Exact Mass: 579.28
Molecular Weight: 579.65
The synthesis of compound 11-138 was performed according to compound 11-3,
using 1-
methyl-1H-pyrazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 43 mg, 59% (last step)
ESI-MS: 580.4 [M+H]
Date Recue/Date Received 2024-03-07
162
129 Preparation of compound 11-139
0
0
N
0 H H 0 H
N )-LI\IN
NOAH
N 8
/
(3)-Nrn-S1443AaeThay7-VITDOZ3V-x4TIVO-x2MIOlilhotMeigiiVi-cie-N6-
Chemical Formula: C29H37N706
Exact Mass: 579.28
Molecular Weight: 579.65
The synthesis of compound 11-139 was performed according to compound 11-3,
using 1-
methyl-1H-pyrazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 53 mg, 62% (last step)
ESI-MS: 580.4 [M+H]
130 Preparation of compound 11-140
0
N
H 0
H H
N ANN
(3)-Nrn-ec1443AaeThay7-WITDOZ3V-Vg-ax20112i:ahotMeigiiVi-cie-N6-
Chemical Formula: C29H37N706
Exact Mass: 579.28
Molecular Weight: 579.65
The synthesis of compound 11-140 was performed according to compound 11-3,
using 1-
methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 39 mg, 48% (last step)
ESI-MS: 580.4 [M+H]
Date Recue/Date Received 2024-03-07
163
131 Preparation of compound 11-141
0 )N
-() H 0
NA
N'S_kA
\\1
(S)r-riNeliWill:ff-r--rTeithjnila-1nT3-TliPgitgr-gt-tPair=d1
tadoragrilergediel
Chemical Formula: C28H35N706S
Exact Mass: 597.24
Molecular Weight: 597.69
The synthesis of compound 11-141 was performed according to compound 11-3,
using 4-
methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
.. acid in step 6 (according to ZED3264).
Yield: 54 mg, 58% (last step)
ESI-MS: 598.4 [M+H]
132 Preparation of compound 11-142
0
N
H 0
N
"\s_ki H
(3)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1õ2-dihydropyridih-3-y1)-
N6-methyl-5-oxo-2-(1,2,5-thiadiazole-3-carboxamido)hexanediamide
Chemical Formula: C271-133N7063
Exact Mass: 583.22
Molecular Weight: 583.66
The synthesis of compound 11-142 was performed according to compound 11-3,
using
1,2,5-thiadiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in
step 6 (according to ZED3264).
Yield: 36 mg, 43% (last step)
.. ESI-MS: 584.4 [M+H]
Date Recue/Date Received 2024-03-07
164
133 Preparation of compound 11-143
0
0
N
i 0 H 0
H H
N N
---,. N
L " N
(S)-2-(4-iodo-1-methy1-1H-pyrazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide
Chemical Formula: C29H36IN706
Exact Mass: 705.18
Molecular Weight: 705.54
The synthesis of compound 11-143 was performed according to compound 11-3,
using 4-
iodo-1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 24 mg, 49% (last step)
ESI-MS: 706.3 [M+H]
134 Preparation of compound 11-144
0
NH2
H H
N N
---,. N
_NAI-1 N
(3)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide
Chemical Formula: C28H35N706
Exact Mass: 565.26
Molecular Weight: 565.62
The synthesis of compound 11-144 was performed according to compound 11-118,
using
1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 26 mg, 68% (last step)
ESI-MS: 566.4 [M+H]
Date Recue/Date Received 2024-03-07
165
135 Preparation of compound 11-145
o
).,1\ jo N H2
0 14 0
H
N'SN NN
I H 1 1
N
(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-
244-methyl-I ,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide
Chemical Formula: C27H33N706S
Exact Mass: 583.22
Molecular Weight: 583.66
The synthesis of compound 11-145 was performed according to compound 11-118,
using
4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-
2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 35 mg, 62% (last step)
ESI-MS: 584.4 [M+H]
136 Preparation of compound 11-146
o
NH2
0 -L()) 0
0
N N-ANIN
I H
(S)-2-(benzofuran-2-carboxamido)-N1-(1-(24(1R,2R,4S)-bicyclo[2.2.11heptan-
2-ylarnino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide
Chemical Formula: C29 H 3 1 N507
Exact Mass: 561.22
Molecular Weight: 561.59
The synthesis of compound 11-146 was performed according to compound 11-118,
using
benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic
acid in step
6 (according to ZED3264) and using exo-2-aminonorbornane instead of 2-
adamantan-
amine in step 2 (according to ZED3905).
Yield: 43 mg, 60% (last step)
ESI-MS: 562.4 [M+H]
Date Recue/Date Received 2024-03-07
166
137 Preparation of compound 11-147
o
2
cA NH
0 0
H H.,..iizzi_
0
N NANIN
I H
(S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1 2-
dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediarnIcle
Chemical Formula: C30H33N507
Exact Mass: 575.24
Molecular Weight: 575.61
The synthesis of compound 11-147 was performed according to compound 11-118,
using
using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according
to
ZED3905).
Yield: 56 mg, 67% (last step)
ESI-MS: 576.4 [M+H]
138 Preparation of compound 11-148
o
NH2
0 0
H
0 N N N NH
I H
(S)-2-(benzofuran-2-carboxamido)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.11hebtan-
2-ylarnino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide
Chemical Formula: C29H31 N507
Exact Mass: 561.22
Molecular Weight: 561.59
The synthesis of compound 11-148 was performed according to compound 11-118,
using
benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic
acid in step
6 (according to ZED3264) and using ( )-endo-2-aminonorbornane instead of 2-
adamantanamine in step 2 (according to ZED3905).
Yield: 49 mg, 66% (last step)
ESI-MS: 562.4 [M+H]
Date Recue/Date Received 2024-03-07
167
139 Preparation of compound 11-149
o
OA NH02
0
H
0 N NNINH
I H
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C30H33N507
Exact Mass: 575.24
Molecular Weight: 575.61
The synthesis of compound 11-149 was performed according to compound 11-118,
using
using ( )-endo-2-aminonorbornane instead of 2-adamantanamine in step 2
(according
to ZED3905).
Yield: 64 mg, 75% (last step)
ESI-MS: 576.4 [M+H]
140 Preparation of compound 11-150
o
oA NH2
o o
H
0 N NANINH
I H
(S)-2-(benzofuran-2-carboxamido)-5-oxo-N1-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
Chemical Formula: C32H37N507
Exact Mass: 603.27
Molecular Weight: 603.67
The synthesis of compound 11-150 was performed according to compound 11-118,
using
benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic
acid in step
6 (according to ZED3264) and using (R)-(+)-bornylamine instead of 2-
adamantanamine
in step 2 (according to ZED3905).
Yield: 38 mg, 53% (last step)
ESI-MS: 604.4 [M+H]
Date Recue/Date Received 2024-03-07
168
141 Preparation of compound 11-151
o
:cANHO2
0
H
0 N N N cNH
I H
(S)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo-N1-(2-oxo-1-(2-oxo-2-
((1R,2S,4R)-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
Chemical Formula: C33H39N507
Exact Mass: 617.28
Molecular Weight: 617.69
The synthesis of compound 11-151 was performed according to compound 11-118,
using
using (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (according to
ZED3905).
Yield: 31 mg, 59% (last step)
ESI-MS: 618.5 [M+H]
142 Preparation of compound 11-152
0
OA
N
H
0 0
H H,....a
N' 1 hi 1 N
N
(S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methyl-2-(4-methyl-1,2,3-thiadiazole-5-carboxamido)-5-
oxohexanediamide
Chemical Formula: C25H31 N706S
Exact Mass: 557.21
Molecular Weight: 557.62
The synthesis of compound 11-152 was performed according to compound 11-94,
using
4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-
2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 53 mg, 68% (last step)
ESI-MS: 558.4 [M+H]
Date Recue/Date Received 2024-03-07
169
143 Preparation of compound 11-153
0
0 )N
.'CI H 0
H H,....:3....
N N
---,. N
\ H
U N
_N
\
(S)-N1 -(1 -(2-((1 R,2 R,4S)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-
1 ,2-dihydropyridin-
3-y1)-N6-methyl-2-(1-methyl-1 H-pyrazole-5-carboxamido)-5-oxohexanediamide
Chemical Formula: C26H33N706
Exact Mass: 539.25
Molecular Weight: 539.58
The synthesis of compound 11-153 was performed according to compound 11-94,
using
1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 60 mg, 67% (last step)
ESI-MS: 540.4 [M+H]
144 Preparation of compound 11-154
0
N
0 JA H 0
H
N,,, NH
F3C ________________________ \ii IF1 1 I;Ic
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-yI)-N6-methyl-2-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-5-
oxohexanediamide
Chemical Formula: C27H31 F3N606S
Exact Mass: 624.20
Molecular Weight: 624.63
The synthesis of compound 11-154 was performed according to compound 11-90,
using
4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-
methylbenzo[b]furan-
2-carboxylic acid in step 6 (according to ZED3264).
Yield: 68 mg, 74% (last step)
ESI-MS: 625.3 [M+H]
Date Recue/Date Received 2024-03-07
170
145 Preparation of compound 11-155
o
N
0 '3H 0
H
N
CI / 1 IF1 1 IncNH
CI
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methyl-5-oxohexanediamide
Chemical Formula: C26H29Cl2N506S
Exact Mass: 609.12
Molecular Weight: 610.51
The synthesis of compound 11-155 was performed according to compound 11-90,
using
2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 74 mg, 68% (last step)
ESI-MS: 610.3 / 612.3 [M+H]
146 Preparation of compound 11-156
o
0
N
0 H H 0
N N NH
1\l',S___Al FiN
IV
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methyl-2-(4-methyl-1,2,3-thiadiazole-5-carboxamido)-5-
oxohexanediamide
Chemical Formula: C25H31 N706S
Exact Mass: 557.21
Molecular Weight: 557.62
The synthesis of compound 11-156 was performed according to compound 11-90,
using
4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-
2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 56 mg, 61% (last step)
ESI-MS: 558.4 [M+H]
Date Recue/Date Received 2024-03-07
171
147 Preparation of compound 11-157
o
N
0 c)(3 ti H 0
N N-A NH
H N
sis\i_N
N
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methyl-2-(1-methyl-1H-1,2,3-triazole-5-carboxamido)-5-
oxohexanediamide
Chemical Formula: C25H32N806
Exact Mass: 540.24
Molecular Weight: 540.57
The synthesis of compound 11-157 was performed according to compound 11-90,
using
1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-
2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 34 mg, 52% (last step)
ESI-MS: 541.4 [M+H]
148 Preparation of compound 11-158
0
N
.73.---
---,. N
\ H N
_N
\
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methyl-2-(1-methyl-1H-pyrazole-5-carboxamido)-5-oxohexanediamide
Chemical Formula: C26H33N706
Exact Mass: 539.25
Molecular Weight: 539.58
The synthesis of compound 11-158 was performed according to compound 11-90,
using
1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 55 mg, 64% (last step)
ESI-MS: 540.4 [M+H]
Date Recue/Date Received 2024-03-07
172
149 Preparation of compound 11-159
o
o H HNO
F3C-1\il H 1 i --I-NH
(3)-N1-methyl-5-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-2-oxo-N6-
(2-oxo-1-(2-oxo-2-
((1R,23,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylaminp)ethyl)-1,2-
dihydropyridin-3-yphexanediamide
Chemical Formula: C30ri37F3N6063
Exact Mass: 666.24
Molecular Weight: 666.71
The synthesis of compound 11-159 was performed according to compound 11-92,
using
4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-
methylbenzo[b]furan-
2-carboxylic acid in step 6 (according to ZED3264).
Yield: 52 mg, 57% (last step)
ESI-MS: 667.4 [M+H]
150 Preparation of compound 11-160
o
o
N
0 H H 0
N N)-Nc NH
CI
(S)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methyl-5-oxo-N1-(2-oxo-1-(2-oxo-
2-((1R,2S,4R)-
1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-
yl)hexanediamide
Chemical Formula: C29H35Cl2N506S
Exact Mass: 651.17
Molecular Weight: 652.59
The synthesis of compound 11-160 was performed according to compound 11-92,
using
2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 66 mg, 61% (last step)
ESI-MS: 652.3 / 654.3 [M+H]
Date Recue/Date Received 2024-03-07
173
151 Preparation of compound 11-161
0
0)-L
N 1
H
0
H
N'
NNH
1 H
(3)-N1 -methyl-5-(4-methyl-1 ,2,3-thiadiazole-5-carboxamido)-2-oxo-N6-(2-oxo-1-
(2-oxo-2-((1 R,23,4R)-
1 ,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1 ,2-dihydropyridin-3-
yl)hexanediamide
Chemical Formula: C28H37N7063
Exact Mass: 599.25
Molecular Weight: 599.70
The synthesis of compound 11-161 was performed according to compound 11-92,
using
4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-
2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 41 mg, 51% (last step)
ESI-MS: 600.4 [M+H]
152 Preparation of compound 11-162
0
0)-
N
H
0 0
H
N NH
NH N
(3)-N1 -methyl-5-(1-methyl-1 H-1,2,3-triazole-5-carboxamido)-2-oxo-N6-(2-oxo-1-
(2-oxo-2-((1 R,23,4R)-
1 ,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1 ,2-dihydropyridin-3-
yl)hexanediamide
Chemical Formula: C28H38N806
Exact Mass: 582.29
Molecular Weight: 582.65
The synthesis of compound 11-162 was performed according to compound 11-92,
using
1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-
2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 28 mg, 46% (last step)
ESI-MS: 583.5 [M+H]
Date Recue/Date Received 2024-03-07
174
153 Preparation of compound 11-163
0
N
N NH
H
_N
(3)-N1 -methyl-5-(1 -methyl-1 H-pyrazole-5-carboxamido)-2-oxo-N6-(2-oxo-1 -(2-
oxo-2-((1 R,23,4R)-
1 ,7,7-trimethylbicyclo[2.2.1 ]heptan-2-ylamino)ethyl)-1 ,2-dihydropyridin-3-
yl)hexanediamide
Chemical Formula: C29H39N706
Exact Mass: 581.30
Molecular Weight: 581.66
The synthesis of compound 11-163 was performed according to compound 11-92,
using
1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 44 mg, 58% (last step)
ESI-MS: 582.5 [M+H]
154 Preparation of compound 11-164
0
0
0 0
m
HN N
a d(a2nSikri-Atritbigly-11)1-12--Porci- 13-igla94:TyrPi giVrnid e
Chemical Formula: C33H45N505
Exact Mass: 59134
Molecular Weight: 59114
The synthesis of compound 11-164 was performed according to compound 11-107,
using
1-(2-bromoethyl)adamantane instead of 1-(bromomethyl)adamantane (according to
ZED4893) and 5-tert-butyl-1H-pyrrole-3-carboxylic acid instead of 3-methyl-
benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 32 mg, 56% (last step)
ESI-MS: 592.5 [M+H]
Date Recue/Date Received 2024-03-07
175
155 Preparation of compound 11-165
0 c)- H 0
N N
NC
N
(2S)- rn.riV2-1-1.;Ix-g-Yillgy-cdT-ZsiadrAl-d3 -)acTxectliVe- C11 ale
Chemical Formula: C32H40N605
Exact Mass: 588.31
Molecular Weight: 588/0
The synthesis of compound 11-165 was performed according to compound 11-107,
using
1-(3-bromopropyl)adamantane instead of 1-(bromomethyl)adamantane (according to
ZED4893) and 4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid instead of 3-methyl-
benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 27 mg, 48% (last step)
ESI-MS: 589.5 [M+H]
156 Preparation of compound 11-166
-L
N
0 c)H 0
0?N
Me N
(S)-N1-(1-(3-(2-adamantylamino)-3-oxopropy1)-2-oxo-1,2-dihydropyridih-3-y1)-
2-(5-methoxyoxazole-2-carboxamido)-N6-methyl-5-oxohexanediamide
Chemical Formula: C30H38N608
Exact Mass: 610.28
Molecular Weight: 610.66
The synthesis of compound 11-166 was performed according to compound 11-3,
using 3-
chloropropionic acid instead of chloroacetic acid (according to ZED1657) and 5-
methoxyoxazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic
acid in
step 6 (according to ZED3264).
Yield: 31 mg, 59% (last step)
ESI-MS: 611.4 [M+H]
Date Recue/Date Received 2024-03-07
176
157 Preparation of compound 11-167
0
N
0 JA H 0
H
0
I H
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C29H31 N507
Exact Mass: 561.22
Molecular Weight: 561.59
The synthesis of compound 11-167 was performed according to compound 11-3,
using 1-
bicyclo[1.1.1]pentylamine instead of 2-adamantanamine in step 2 (according to
ZED3905).
Yield: 45 mg, 67% (last step)
ESI-MS: 562.4 [M+H]
158 Preparation of compound 11-168
0
.A N
H
0 0
0 NDA r r NH"n H
nc 1 c
(S)-2-(2-acetyloxazole-4-carboxamido)-N1-(1-(2-(bicyclo[1A .1]pentan-
1Tylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide
Chemical Formula: C25H28N608
Exact Mass: 540.20
Molecular Weight: 540.53
The synthesis of compound 11-168 was performed according to compound 11-167,
using
2-acetyloxazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in
step 6 (according to ZED3264).
Yield: 26 mg, 48% (last step)
ESI-MS: 541.4 [M+H]
Date Recue/Date Received 2024-03-07
177
159 Preparation of compound 11-169
0
N
0 c)- H 0
H H
0
N N-)-LNIN
I H
(S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C30H33N507
Exact Mass: 575.24
Molecular Weight: 575.61
The synthesis of compound 11-169 was performed according to compound 11-3,
using
bicyclo[2.1.1]hexan-1-amine instead of 2-adamantanamine in step 2 (according
to
ZED3905).
Yield: 33 mg, 61% (last step)
ESI-MS: 576.4 [M+H]
160 Preparation of compound 11-170
0
N
0 cA H 0
H H
03)-N NAN
)rNT9'
(S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-2-(2-isopropyloxazole-5-carboxamido)-N6-methy1-5-oxohexanediamide
Chemical Formula: C27H34N607
Exact Mass: 554.25
Molecular Weight: 554.59
The synthesis of compound 11-170 was performed according to compound 11-169,
using
2-isopropyloxazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid
in step 6 (according to ZED3264).
Yield: 32 mg, 54% (last step)
ESI-MS: 555.4 [M+H]
Date Recue/Date Received 2024-03-07
178
161 Preparation of compound 11-171
o
cA N
H
0 0
H
0 N
N El \II
I H
(2S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide
Chemical Formula: C31 H35 N507
Exact Mass: 589.25
Molecular Weight: 589.64
The synthesis of compound 11-171 was performed according to compound 11-2,
using
bicyclo[3.2.1]octan-8-amine instead of 2-adamantanamine in step 2 (according
to
ZED3905).
Yield: 42 mg, 60% (last step)
ESI-MS: 590.4 [M+H]
162 Preparation of compound 11-172
0
il N
0 oH 0
)A H
N H
0 H 1 NiviN
1\1= N
(2S)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-2-(3,5-dimethylisoxazole-4-carboxamido)-N6-methyl-5-oxohexanediamide
Chemical Formula: C28H36N607
Exact Mass: 568.26
Molecular Weight: 568.62
The synthesis of compound 11-172 was performed according to compound 11-171,
using
3,5-dimethylisoxazole-4-carboxylic acid instead of benzofuran-2-carboxylic
acid in step
6 (according to ZED3264).
Yield: 35 mg, 58% (last step)
ESI-MS: 569.4 [M+H]
Date Recue/Date Received 2024-03-07
179
163 Preparation of compound 11-173
oll N
N
N
1\11
CO2H
(S)-N1-(1-(2-(5-carboxy-2-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methy1-2-(4-methylpyrimidine-5-carboxamido)-5-oxohexanediamide
Chemical Formula: C31 H37N708
Exact Mass: 635.27
Molecular Weight: 635.67
The synthesis of compound 11-173 was performed according to compound 11-3,
using 4-
aminoadamantane-1-carboxylic acid instead of 2-adamantanamine in step 2
(according
to ZED3905) and 4-methylpyrimidine-5-carboxylic acid instead of 3-methyl-
benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 25 mg, 49% (last step)
ESI-MS: 636.4 [M+H]
164 Preparation of compound 11-174
0
N
N
(23)-N1-(1-(2-(4-aminoadamantane-N,N-dimethy1-1-carboxamide)-2-oxoethyl)-2-oxo-
1,2-dihydropyridin-
3-y1)-N6-methyl-5-oxo-2-(1,2,3,4-tetrahydronaphthalene-2-
carboxamido)hexanediamide
Chemical Formula: C38H48N607
Exact Mass: 700.36
Molecular Weight: 700.82
The synthesis of compound 11-174 was performed according to compound 11-3,
using 4-
aminoadamantane-N,N-dimethy1-1-carboxamide instead of 2-adamantanamine in step
2
(according to ZED3905) and 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid
instead of
3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 33 mg, 56% (last step)
ESI-MS: 701.5 [M+H]
Date Recue/Date Received 2024-03-07
180
165 Preparation of compound 11-175
0
0 0
N)-LN
(aScVngt)y-Ildtinligsg-bOVocetql.)2-22-}acMilijidi?-23arTgirMtrot-
xbouhtgra\irieicIligiC12e-
Chemical Formula: C34H49N706
Exact Mass: 651.37
Molecular Weight: 651.80
The synthesis of compound 11-175 was performed according to compound 11-3,
using
tert-butyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632) and
1,4-diazabicyclo[2.2.2]octane-2-carboxylic acid instead of 3-
methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 39 mg, 53% (last step)
ESI-MS: 652.5 [M+H]
166 Preparation of compound 11-176
0 cA H 0
N
I H
(S)-N1-tert-butyl-5-(1H-indole-3-carboxamido)-N6-(1-(2-(2-adarbantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide
Chemical Formula: C36H44N606
Exact Mass: 65633
Molecular Weight: 656/7
The synthesis of compound 11-176 was performed according to compound 11-3,
using
tert-butyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632) and
1H-indole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid
in step 6
(according to ZED3264).
Yield: 52 mg, 62% (last step)
ESI-MS: 657.5 [M+H]
Date Recue/Date Received 2024-03-07
181
167 Preparation of compound 11-177
o
N (17
0
NDAN
I H
(3)-N1-tert-butyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-5-(6-methylimidazo[2,1-b]thiazole-3-carboxamido)-2-oxohexanediamide
Chemical Formula: C34H43N7063
Exact Mass: 677.30
Molecular Weight: 677.81
The synthesis of compound 11-177 was performed according to compound 11-3,
using
tert-butyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632) and
6-methylimidazo[2,1-b][1,3]thiazole-3-carboxylic acid instead of 3-
methylbenzo[b]furan-
2-carboxylic acid in step 6 (according to ZED3264).
Yield: 42 mg, 53% (last step)
ESI-MS: 678.5 [M+H]
168 Preparation of compound 11-178
0 L).
0 JA H 0
SN NHANINH
N H
(S)-2-(benzo[d]thiazole-2-carboxamido)-N1-(1-(2-((1S,2R,4R)-
bicyclo[2.2.1]heptan-2-ylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopenty1-5-oxohexanediamide
Chemical Formula: C33H38N6065
Exact Mass: 646.26
Molecular Weight: 646.76
The synthesis of compound 11-178 was performed according to compound 11-90,
using
cyclopentyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632)
and 1,3-benzothiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 54 mg, 61% (last step)
ESI-MS: 647.4 [M+H]
Date Recue/Date Received 2024-03-07
182
169 Preparation of compound 11-179
o JD.
H H
N )cNH
¨
S/
(S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-cyclopenty1-2-(imidazo[2,1-13]thiazole-6-carboxamido)-5-
oxohexanediamide
Chemical Formula: C31 H37N1706S
Exact Mass: 635.25
Molecular Weight: 635/3
The synthesis of compound 11-179 was performed according to compound 11-90,
using
cyclopentyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632)
and imidazo[2,1-b][1,3]thiazole-6-carboxylic acid instead of 3-
methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 36 mg, 51% (last step)
ESI-MS: 636.4 [M+H]
170 Preparation of compound 11-180
o
OH 0 h H 0
F3C N
-
N NH
H
1\1
(3)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyriclin-3-y1)-
N6-cyclopenty1-2-(4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxamido)-5-
oxohexanediarrucle
Chemical Formula: C36H39F3N608
Exact Mass: 740.28
Molecular Weight: 740.73
The synthesis of compound 11-180 was performed according to compound 11-90,
using
cyclopentyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632)
and 4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxylic acid instead of 3-
methyl-
benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 19 mg, 41% (last step)
ESI-MS: 741.5 [M+H]
Date Recue/Date Received 2024-03-07
183
171 Preparation of compound 11-181
o
o 1 IN IP
I A H
N'
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-2-(cinnoline-3-carboxamido)-N6-cyclohexy1-5-oxohexanediamide
Chemical Formula: C33H37N706
Exact Mass: 627.28
Molecular Weight: 627.69
The synthesis of compound 11-181 was performed according to compound 11-167,
using
cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632)
and 3-cinnolinecarboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic
acid in
step 6 (according to ZED3264).
Yield: 37 mg, 56% (last step)
ESI-MS: 628.5 [M+H]
172 Preparation of compound 11-182
o
N
0 c)L() H H 0
0
N H
N
I H N
(S)-N1-(1-(2-(bicyclo[1 A .1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-cyclohexy1-2-(3-ethylbenzofuran-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C35H41 N507
Exact Mass: 64330
Molecular Weight: 643.73
The synthesis of compound 11-182 was performed according to compound 11-167,
using
cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632)
and 3-ethylbenzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 53 mg, 68% (last step)
ESI-MS: 644.5 [M+H]
Date Recue/Date Received 2024-03-07
184
173 Preparation of compound 11-183
OAoH
N
H
--------\ 0 0
N
N NN H
I H
(S)-N 1 -(1 -(2-(bicyclo[1 A .1 ]pentan-1 -yla min o)-2-oxoethyl)-2-oxo-1 ,2-d
ihyd ropyrid in-
3-y1)-N6-cyclohexy1-2-(1 -ethyl-1H-indole-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C35H42N606
Exact Mass: 64232
Molecular Weight: 642.74
The synthesis of compound 11-183 was performed according to compound 11-167,
using
cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632)
and 1-ethyl-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 41 mg, 57% (last step)
ESI-MS: 643.5 [M+H]
174 Preparation of compound 11-184
o
OjA N
H
0 0
H
H
1 H
N N
(S)-N 1 -(1 -(2-(bicyclo[1 .1 .1 ]pentan-1 -yla mino)-2-oxoethyl)-2-oxo-1 ,2-
dihydropyridin-3-y1)-
N6-cyclohexy1-2-(2-methy1-1 ,8-naphthyridine-3-carboxamido)-5-oxohexanediamide
Chemical Formula: C34H39N706
Exact Mass: 64120
Molecular Weight: 64112
The synthesis of compound 11-184 was performed according to compound 11-167,
using
cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to
ZED3632)
and 2-methyl-1,8-naphthyridine-3-carboxylic acid instead of 3-
methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 26 mg, 54% (last step)
ESI-MS: 642.5 [M+H]
Date Recue/Date Received 2024-03-07
185
175 Preparation of compound 11-185
oll
N-
H
0 H 0
N
1\1/
(S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-
N6-methyl-5-oxo-2-(1,2,3,4-tetrahydroquinoline-6-carboxamido)hexanediamide
Chemical Formula: C30H36N606
Exact Mass: 576.27
Molecular Weight: 576.64
The synthesis of compound 11-185 was performed according to compound 11-169,
using
N-Boc-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of 3-
methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264). The final product was
obtained by
deprotection (DCM/TFA) as described above and purified by HPLC.
Yield: 39 mg, 61% (last step)
ESI-MS: 577.4 [M+H]
176 Preparation of compound 11-186
oil N
0 0
H CO2H
0 N
1\1/
HN CF3
(S)-N1-(1-(2-(2-carboxy-2-amino-5-(trifluoromethypadamantane)-2-oxoethyl)-2-
oxo-1,2-dihydropyridin-
3-y1)-N6-methyl-5-oxo-2-(3-oxo-1,2,3,4-tetrahydroisoquinoline-6-
carboxamido)hexanediamide
Chemical Formula: C36H39F3N609
Exact Mass: 756.27
Molecular Weight: 756.72
The synthesis of compound 11-186 was performed according to compound 11-3,
using 2-
amino-5-(trifluoromethyl)adamantane-2-carboxylic acid instead of 2-
adamantanamine in
step 2 (according to ZED3905) and 3-oxo-1,2,3,4-tetrahydroisoquinoline-6-
carboxylic
acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according
to
ZED3264).
Yield: 12 mg, 36% (last step)
ESI-MS: 757.4 [M+H]
Date Recue/Date Received 2024-03-07
186
177 Preparation of compound 11-187
0
N
0 j)-LCI H 0
N
N
(3)-N1-(1-(2-(5-ethyladamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-
3-y1)-
N6-methyl-2-(1,6-naphthyridine-2-carboxamido)-5-oxohexanediamide
Chemical Formula: C35H41N706
Exact Mass: 655.31
Molecular Weight: 655.74
The synthesis of compound 11-187 was performed according to compound 11-3,
using 5-
ethyladamantane-2-amine instead of 2-adamantanamine in step 2 (according to
ZED3905) and 1,6-naphthyridine-2-carboxylic acid instead of 3-
methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 26 mg, 51% (last step)
ESI-MS: 656.5 [M+H]
178 Preparation of compound 11-188
0ilN
N 0 H 0
NAN
N
N H
(S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methyl-2-(2,6-naphthyridine-1-carboxamido)-5-oxohexanediamide
Chemical Formula: C29H31 N706
Exact Mass: 573.23
Molecular Weight: 573.60
The synthesis of compound 11-188 was performed according to compound 11-169,
using
2,6-naphthyridine-1-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid
in step 6 (according to ZED3264).
Yield: 33 mg, 56% (last step)
ESI-MS: 574.4 [M+H]
Date Recue/Date Received 2024-03-07
187
179 Preparation of compound 11-189
o
N
H2N 0 H 0
H
H
b-
(S)-2-(4-amino-1,2,5-oxadiazole-3-carboxamido)-N1-(1-(2-(bicyclo[1.1.1]pentan-
1-
ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-
oxohexanediamide
Chemical Formula: C22H26N807
Exact Mass: 514.19
Molecular Weight: 514A9
The synthesis of compound 11-189 was performed according to compound 11-167,
using
4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid instead of 3-
methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264). The amine was deprotected by
TFA in
the final step.
Yield: 16 mg, 69% (last step)
ESI-MS: 515.3 [M+H]
180 Preparation of compound 11-190
o
N
0 j H 0
H
0
\N I H
/
(S)-N1-(1-(2-(bicyclo11.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyndin-3-y1)-
2-(6-(dimethylamino)benzofuran-2-carboxamido)-N6-methyl-5-oxohexanediamide
Chemical Formula: C30H34N607
Exact Mass: 590.25
Molecular Weight: 590.63
The synthesis of compound 11-190 was performed according to compound 11-167,
using
6-(dimethylamino)benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-
2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 38 mg, 55% (last step)
ESI-MS: 591.4 [M+H]
Date Recue/Date Received 2024-03-07
188
181 Preparation of compound 11-191
o
o
N
0 H H 0
SDAN N H
HN
\b
(S)-2-(2-acetamidothiazole-5-carboxamido)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-
ylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide
Chemical Formula: C25H29N7073
Exact Mass: 571.18
Molecular Weight: 571.61
The synthesis of compound 11-191 was performed according to compound 11-167,
using
2-acetylamino-5-thiazolecarboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 21 mg, 46% (last step)
ESI-MS: 572.3 [M+H]
182 Preparation of compound 11-192
o
N
0 ki H
/ N N
I 1 1
H2N H H
(S)-N4-(1-(1-(2-(bicyclo[1A .1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-y1)-1H-pyrrole-2,4-
dicarboxamide
Chemical Formula: C25H29N707
Exact Mass: 539.21
Molecular Weight: 539.54
The synthesis of compound 11-192 was performed according to compound 11-167,
using
5-carbamoy1-1H-pyrrole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 13 mg, 38% (last step)
ESI-MS: 540.4 [M+H]
Date Recue/Date Received 2024-03-07
189
183 Preparation of compound 11-193
o
OJA
N
H
0
0 H H
N 0
I H 1 N
H2N/ 0 N Jj"---
H
(S)-N 1 -(1-(2-(1-acetylamino-4-aminoadamantane)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methy1-5-oxo-2-(5-sulfamoylfuran-3-carboxamido)hexanediamide
Chemical Formula: C31H39N7010S
Exact Mass: 701.25
Molecular Weight: 701/5
The synthesis of compound 11-193 was performed according to compound 11-3,
using 1-
acetylamino-4-aminoadamantane instead of 2-adamantanamine in step 2 (according
to
ZED3905) and 5-sulfamoylfuran-3-carboxylic acid instead of 3-
methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 10 mg, 27% (last step)
ESI-MS: 702.4 [M+H]
184 Preparation of compound 11-194
o
0j)r N
H
0 0
H H
N N
/ N
H _ J1 I\V1 0
N-ji"-----
H
(S)-2-(benzofuran-5-carboxamido)-N1-(1-(2-(1-acetylamino-4-aminoadamantane)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C35H40N608
Exact Mass: 672.29
Molecular Weight: 672/3
The synthesis of compound 11-194 was performed according to compound 11-3,
using 1-
acetylamino-4-aminoadamantane instead of 2-adamantanamine in step 2 (according
to
ZED3905) and benzofuran-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 23 mg, 52% (last step)
ESI-MS: 673.5 [M+H]
Date Recue/Date Received 2024-03-07
190
185 Preparation of compound 11-195
0
N
H
0 ) 0
0 NjH H
NA N
\ H 1 NcNH2
(S)-2-(benzofuran-6-carboxamido)-N1-(1-(2-(4-aminoadamantane-1-carboxamide)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C34H38N608
Exact Mass: 658.28
Molecular Weight: 658.70
The synthesis of compound 11-195 was performed according to compound 11-3,
using 4-
aminoadamantane-1-carboxamide instead of 2-adamantanamine in step 2 (according
to
ZED3905) and benzofuran-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 26 mg, 57% (last step)
ESI-MS: 659.4 [M+H]
186 Preparation of compound 11-196
0
OAN
H
0 0
H H
N
N N
A N
\ H 1 cNH2
(3)-N1-(1-(2-(4-aminoadamantane-1-carboxamide)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-
N6-methy1-2-(3-(1-methylcyclopropy1)-1,2,4-oxadiazole-5-carboxamido)-5-
oxohexanediamide
Chemical Formula: C32H40N808
Exact Mass: 664.30
Molecular Weight: 664.71
The synthesis of compound 11-196 was performed according to compound 11-3,
using 4-
aminoadamantane-1-carboxamide instead of 2-adamantanamine in step 2 (according
to
ZED3905) and 3-(1-methylcyclopropyI)-1,2,4-oxadiazole-5-carboxylic acid
instead of 3-
methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 15 mg, 38% (last step)
ESI-MS: 665.5 [M+H]
Date Recue/Date Received 2024-03-07
191
187 Preparation of compound 11-197
o
N
0 H 0
/NI yN NH N H
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-
N6-methyl-2-(5-methyl-1,2,4-oxadiazole-3-carboxamiclo)-5-oxohexanediamide
Chemical Formula: C23H27N707
Exact Mass: 513.20
Molecular Weight: 513.50
The synthesis of compound 11-197 was performed according to compound 11-167,
using
5-methyl-1,2,4-oxadiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 36 mg, 58% (last step)
ESI-MS: 514.4 [M+H]
188 Preparation of compound 11-198
o
)i_N_IO
N
H
0 0
H
SAIF\I N
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-yI)-N6-methyl-5-oxo-2-(1,2,3-thiad iazole-4-ca rboxa mid o)hexa ned ia mide
Chemical Formula: C22H25N706S
Exact Mass: 515.16
Molecular Weight: 515.54
The synthesis of compound 11-198 was performed according to compound 11-167,
using
1,2,3-thiadiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in
step 6 (according to ZED3264).
Yield: 29 mg, 48% (last step)
ESI-MS: 516.3 [M+H]
Date Recue/Date Received 2024-03-07
192
189 Preparation of compound 11-199
0
oll
N
0 H H 0
S
H
N' eH
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methyl-5-oxo-2-(1,2,4-thiadiazole-5-carboxamido)hexanediamide
Chemical Formula: C22H25N706S
Exact Mass: 515.16
Molecular Weight: 515.54
The synthesis of compound 11-199 was performed according to compound 11-167,
using
1,2,4-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in
step 6 (according to ZED3264).
Yield: 35 mg, 56% (last step)
ESI-MS: 516.3 [M+H]
190 Preparation of compound 11-200
0
N
0 c)0 H 0
syLN NHAN H
i\j H
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methyl-5-oxo-2-(1,3,4-thiadiazole-2-carboxamido)hexanediamide
Chemical Formula: C22H25N706S
Exact Mass: 515.16
Molecular Weight: 515.54
The synthesis of compound 11-200 was performed according to compound 11-167,
using
1,3,4-thiadiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in
step 6 (according to ZED3264).
Yield: 24 mg, 41% (last step)
ESI-MS: 516.3 [M+H]
Date Recue/Date Received 2024-03-07
193
191 Preparation of compound 11-201
0
oil
N 1
H
0
H
S N H
N' 1 r,
I'vl
Is\I
(S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-
2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N6-methyl-5-oxohexanediamide
Chemical Formula: C25H29N706S
Exact Mass: 555.19
Molecular Weight: 555.61
The synthesis of compound 11-201 was performed according to compound 11-167,
using
4-cyclopropyl-[1,2,3]thiadiazole-5-carboxylic acid instead of 3-
methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 43 mg, 67% (last step)
ESI-MS: 556.4 [M+H]
192 Preparation of compound 11-202
o
OAN
H
0 0
H H
S N N
N' H
il Inc
(S)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-
adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide
Chemical Formula: C30H37N706S
Exact Mass: 623.25
Molecular Weight: 623/2
The synthesis of compound 11-202 was performed according to compound 11-3,
using 4-
cyclopropyl-[1,2,3]thiadiazole-5-carboxylic acid instead of 3-
methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 42 mg, 56% (last step)
ESI-MS: 624.4 [M+H]
Date Recue/Date Received 2024-03-07
194
193 Preparation of compound 11-203
0
:c)-No
H
0
H H
S N
N' 1 hi N N
IV
(S)-2-(4-isopropy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-
adamantylamino)-
2-oxoetiy1)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide
Chemical Formula: C30H39N706S
Exact Mass: 625.27
Molecular Weight: 625.74
The synthesis of compound 11-203 was performed according to compound 11-3,
using 4-
(propan-2-yI)-1,2,3-thiadiazole-5-carboxylic acid instead of 3-
methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 36 mg, 52% (last step)
ESI-MS: 626.4 [M+H]
194 Preparation of compound 11-204
0
oil
N
H
0 0
H H
S N NN
N' 1 hi
1\\I
(S)-2-(4-ethy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide
Chemical Formula: C29H37N706S
Exact Mass: 611.25
Molecular Weight: 611/1
The synthesis of compound 11-204 was performed according to compound 11-3,
using 4-
ethyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 33 mg, 47% (last step)
ESI-MS: 612.4 [M+H]
Date Recue/Date Received 2024-03-07
195
195 Preparation of compound 11-205
ojAN
NN
N
\\1
(S)-2-(4-formy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide
Chemical Formula: C28H33N707S
Exact Mass: 611.22
Molecular Weight: 611.67
The synthesis of compound 11-205 was performed according to compound 11-3,
using 4-
(hydroxymethyl)-1,2,3-thiadiazole-5-carboxylic acid instead of 3-
methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 13 mg, 32% (last step)
ESI-MS: 612.4 [M+H]
196 Preparation of compound 11-206
oN
0 0
N
fic\I\\I
(S)-2-(4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-
adamantylamino)-
2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide
Chemical Formula: C28H35N707S
Exact Mass: 613.23
Molecular Weight: 613.69
The synthesis of compound 11-206 was performed according to compound 11-3,
using 4-
((tetrahydro-2H-pyran-2-yloxy)methyl)-1,2,3-thiadiazole-5-carboxylic acid
instead of 3-
methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The
tetrahydropyranyl (Thp) protecting group was cleaved by TFA in the final step.
Yield: 9 mg, 46% (last step)
ESI-MS: 614.4 [M+H]
Date Recue/Date Received 2024-03-07
196
197 Preparation of compound 11-207
0
0 0
NH
N/Y.H
(3)-Nr;i1fily-c2-AlmizratiViagArildo120-1ceng_ectWdzi2i-j),-25-_gal-mnrcdliina-
n3X-N6-
Chemical Formula: C29H37N706
Exact Mass: 579.28
Molecular Weight: 579.65
The synthesis of compound 11-207 was performed according to compound 11-3,
using 1-
adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905)
and
1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic
acid in step 6 (according to ZED3264).
Yield: 64 mg, 71% (last step)
ESI-MS: 580.4 [M+H]
198 Preparation of compound 11-208
0
0 0H 0
N-LN
(3)-N1-(1-(2-(((1S,2R,53)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methylamino)-2-
oxoethyl)-2-oxo-1,2-
dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-imidazole-2-carboxamido)-5-
oxohexanediamide
Chemical Formula: C29H39N706
Exact Mass: 581.30
Molecular Weight: 581.66
The synthesis of compound 11-208 was performed according to compound 11-3,
using
(-)-cis-myrtanylamine instead of 2-adamantanamine in step 2 (according to
ZED3905)
and 1-methyl-1H-imidazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 43 mg, 59% (last step)
ESI-MS: 582.5 [M+H]
Date Recue/Date Received 2024-03-07
197
199 Preparation of compound 11-209
oA
N
0
N N
HN/Y-
N
(S)-N1-(1-(2-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1 A ]heptan-2-yl)methylamino)-
2-oxoethyl)-2-oxo-
1,2-dihydropyridin-3-y1)-2-(1H-imidazole-4-carboxamido)-N6-methyl-5-
oxohexanediamide
Chemical Formula: C28H37N706
Exact Mass: 567.28
Molecular Weight: 567.64
The synthesis of compound 11-209 was performed according to compound 11-3,
using
(-)-cis-myrtanylamine instead of 2-adamantanamine in step 2 (according to
ZED3905)
and 1-methyl-1H-imidazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-
carboxylic acid in step 6 (according to ZED3264).
Yield: 31 mg, 55% (last step)
ESI-MS: 568.4 [M+H]
200 Preparation of compound 11-210
oAN
0 0
N NH
NN
(S)-N 141 -(2-(3,5-dimethyladamantane-1 -amino)-2-oxoethyl)-2-oxo-1 ,2-
dihydropyridin-
3-y1)-N6-methy1-2-(1 -methyl-1 H-imidazole-5-carboxamido)-5-oxohexanediamide
Chemical Formula: C31 F141 N706
Exact Mass: 607.31
Molecular Weight: 607/0
The synthesis of compound 11-210 was performed according to compound 11-3,
using
3,5-dimethy1-1-adamantanamine instead of 2-adamantanamine in step 2 (according
to
ZED3905) and 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methyl-
benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 46 mg, 66% (last step)
ESI-MS: 608.5 [M+H]
Date Recue/Date Received 2024-03-07
198
201 Preparation of compound 11-211
0
N
0 JAC:1 H 0
N NH
(S)-N1-(1-(2-(3,5,7-trimethy1-1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-
dihydropyridin-
3-y1)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide
Chemical Formula: C32H43N706
Exact Mass: 62t33
Molecular Weight: 621/3
The synthesis of compound 11-211 was performed according to compound 11-3,
using
3,5,7-trimethy1-1-adamantanamine instead of 2-adamantanamine in step 2
(according to
ZED3905) and 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methyl-
benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).
Yield: 53 mg, 70% (last step)
ESI-MS: 622.5 [M+H]
202 Preparation of Reference Compound 6
0
N
j)L H
0 0
N N
(S)-N1-methyl-5-(nicotinamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-
(phenethylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide
Chemical Formula: C28H30N606
Exact Mass: 546.22
Molecular Weight: 546.57
The synthesis of reference compound 6 was performed according to compound 11-
3,
using 2-phenylethylamine instead of 2-adamantanamine in step 2 (according to
ZED3905) and nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid
in step
6 (according to ZED3264).
Yield: 89 mg, 79% (last step)
ESI-MS: 547.4 [M+H]
Biological Examples
Example B-1. Inhibitory effect of the compounds according to the invention
Transglutaminase assay
Date Recue/Date Received 2024-03-07
199
For the determination of potency of inhibitors against tissue
transglutaminase, the
incorporation of dansylcadaverine into dimethylcasein (Zedira product T036,
Lorand et
a/., Anal Biochem, 1971, 44:221-31) was measured using recombinant human
transglutaminase 2 (Zedira Product T022).
The tissue transglutaminase is diluted in buffer (50 mM Tris-HCI, 7.5 mM
CaCl2, 150
mM NaCI, pH = 7.4). The final concentration of TG2 in the assay is 10 nM.
A 10 mM inhibitor stock solution is prepared in DMSO, and from this a serial
1:2-fold
dilution series is prepared also in DMSO. Each of the initial dilutions is
subsequently
diluted 1:50-fold with buffer (50 mM Tris-HCI, 7.5 mM CaCl2, 150 mM NaCI, pH =
7.4) to
yield the final working dilutions containing 2% (v/v) DMSO.
pl of inhibitor working dilution are added per well of a 96 well microtiter
plate. As
control, 15 pl of a 2% (v/v) DMSO solution prepared using the buffer mentioned
above
15 .. are added per well.
Immediately before starting the assay, 600 pl transglutaminase working
solution are
added to 11.4 ml assay buffer (50 mM Tris-HCI, 10 mM CaCl2, 10 mM glutathione,
2.5%
glycerol, 16.7 pM dansylcadaverine, 4 pM N,N-dimethylcasein, 200 mM NaCI, pH =
8.0). 285 pl of this reaction mix are added per well containing the inhibitor.
Increase in fluorescence is measured using Aex = 330 nm and Aem = 500 nm at 37
C for
min. A slope of the increase in fluorescence between 20 and 30 min is
calculated for
determination of the ICso value (inhibitor concentration at which 50% of the
initial activity
is blocked).
Analysis of enzymatic activity is performed by calculation of the slope of an
increase in
25 fluorescence intensity. ICso values are calculated by plotting the
enzymatic activity (as
percentage from control containing 2% DMSO instead of inhibitor) against the
inhibitor
concentration. ICso is defined as the inhibitor concentration blocking 50 % of
initial
enzyme activity.
30 The inhibitory activity of the inventive compounds in regard to tissue
transglutaminase
(TG2) is shown in the following table 1 using ICso-values.
Table 1. efficacy of reversible TG2 inhibitors
A: ICso < 40 nM, B: 40 nM ICso < 400 nM, C: 400 nM ICso <2,500 nM,
D: 2,500 nM ICso < 10,000 nM
IC50 I C50
Compound Compound
TG2 [nM] TG2 [nM]
11-2 A 11-117 B
Date Recue/Date Received 2024-03-07
200
11-3 A 11-118 A
11-4 A 11-119 B
11-5 A 11-120 B
11-6 A 11-121 B
11-7 A 11-122 C
11-8 A 11-123 C
11-9 A 11-124 B
11-10 A 11-125 B
11-11 A 11-126 B
11-12 B 11-127 B
11-13 A 11-128 B
11-14 A 11-129 B
11-15 A 11-130 B
11-16 A 11-131 B
11-17 B 11-132 C
11-18 B 11-133 C
11-19 B 11-134 C
11-20 C 11-135 B
11-21 A 11-136 B
11-22 A 11-137 B
11-23 B 11-138 C
11-24 B 11-139 C
11-25 B 11-140 B
11-26 B 11-141 B
11-27 B 11-142 B
11-28 A 11-143 C
11-29 A 11-144 C
11-30 A 11-145 B
11-31 B 11-146 A
11-32 B 11-147 A
11-33 B 11-148 A
11-34 B 11-149 A
11-35 B 11-150 B
11-36 B 11-151 B
11-37 B 11-152 B
11-38 C 11-153 C
11-39 B 11-154 B
11-40 A 11-155 A
Date Recue/Date Received 2024-03-07
201
11-41 B 11-156 B
11-42 B 11-157 B
11-43 C 11-158 B
11-44 A 11-159 B
11-45 A 11-160 B
11-46 B 11-161 B
11-47 A 11-162 B
11-48 A 11-163 B
11-49 A 11-164 C
11-50 A 11-165 C
11-51 B 11-166 C
11-52 C 11-167 A
11-53 B 11-168 B
11-54 B 11-169 A
11-55 B 11-170 B
11-56 B 11-171 A
11-58 B 11-172 B
11-59 B 11-173 B
11-60 B 11-174 B
11-61 B 11-175 C
11-62 A 11-176 C
11-63 A 11-177 C
11-64 B 11-178 B
11-65 B 11-179 C
11-66 C 11-180 C
11-67 C 11-181 C
11-68 B 11-182 B
11-69 A 11-183 B
11-70 A 11-184 C
11-71 A 11-185 C
11-72 A 11-186 C
11-73 B 11-187 C
11-74 C 11-188 C
11-87 B 11-189 C
11-88 B 11-190 C
11-90 B 11-191 C
11-92 B 11-192 C
11-94 A 11-193 C
Date Recue/Date Received 2024-03-07
202
11-95 B 11-194 B
11-96 B 11-195 B
11-97 B 11-196 C
11-98 B 11-197 C
11-99 B 11-198 B
11-100 B 11-199 B
11-101 B 11-200 B
11-103 B 11-201 B
11-104 B 11-202 B
11-105 B 11-203 B
11-107 B 11-204 B
11-108 B 11-205 B
11-109 B 11-206 B
11-110 B 11-207 B
11-111 A 11-208 C
11-112 A 11-209 C
11-113 B 11-210 B
11-114 B 11-211 B
11-115 B Ref. 1 C
11-116 B Ref. 2 B
Ref. 6 D Ref. 3 D
Ref. 1 (ZED3641) Ref. 2 (ZED1227)
0 OMe
0
: H
%
0 H 0 0 /
H
NN N 8 NENi
A
N
\
Ref. 3 (A8, ZED1047) Ref. 6
o o o
c)F-N
?,
/
H
0
H H 0
H
N f\jAN<N N N N
i H
8 I H jnc
1\1 1\1
Date Recue/Date Received 2024-03-07
203
Example B-2. logD values of the inventive compounds
In order to classify the inventive compounds according to their lipophilicity,
LogD values
(distribution coefficient) were determined by means of the well-established
shake flask
method, measuring the partition of a compound between an octanol and phosphate-
buffered saline (PBS, pH 7.4) by HPLC.
The LogD is pH dependent and is a "predictor" for in-vivo properties. LogD
combines
lipophilicity (intrinsic structural property of the molecule, logP) and
ionizability (pKa).
Compounds with a moderate lipophilicity (LogD values from 0 to 3) are usually
advantaged for oral absorption, being in balance between solubility and
permeability.
However, sophisticated formulation of a compound might improve oral
bioavailability for
highly lipophilic compounds.
Table 2. logD values of reversible TG2 inhibitors
A: logD < 1, B: 1 logD < 3, C: 3 logD < 5
Compound logD Compound logD
11-2 B 11-117 C
11-3 B 11-118 B
11-4 B 11-119 C
11-5 C 11-120 C
11-6 C 11-121 C
11-7 C 11-122 C
11-8 C 11-123 C
11-9 B 11-124 B
11-10 C 11-125 B
11-11 B 11-126 A
11-12 C 11-127 A
11-13 B 11-128 B
11-14 B 11-129 B
11-15 B 11-130 A
11-16 B 11-131 A
11-17 B 11-132 A
11-18 B 11-133 A
11-19 C 11-134 A
11-20 B 11-135 A
11-21 C 11-136 B
11-22 C 11-137 C
Date Recue/Date Received 2024-03-07
204
11-23 C 11-138 A
11-24 B 11-139 A
11-25 B 11-140 A
11-26 B 11-141 A
11-27 B 11-142 B
11-28 B 11-143 A
11-29 C 11-144 A
11-30 C 11-145 A
11-31 B 11-146 A
11-32 B 11-147 A
11-33 B 11-148 A
11-34 B 11-149 A
11-35 B 11-150 B
11-36 B 11-151 B
11-37 B 11-152 A
11-38 C 11-153 A
11-39 B 11-154 B
11-40 C 11-155 B
11-41 C 11-156 A
11-42 B 11-157 A
11-43 B 11-158 A
11-44 C 11-159 B
11-45 C 11-160 B
11-46 C 11-161 A
11-47 B 11-162 A
11-48 C 11-163 A
11-49 C 11-164 C
11-50 A 11-165 C
11-51 A 11-166 B
11-52 A 11-167 A
11-53 B 11-168 A
11-54 B 11-169 A
11-55 A 11-170 A
11-56 B 11-171 A
11-58 B 11-172 A
11-59 B 11-173 A
11-60 A 11-174 A
11-61 B 11-175 B
Date Recue/Date Received 2024-03-07
205
11-62 B 11-176 C
11-63 B 11-177 C
11-64 B 11-178 C
11-65 B 11-179 B
11-66 B 11-180 C
11-67 C 11-181 B
11-68 A 11-182 B
11-69 B 11-183 B
11-70 B 11-184 B
11-71 B 11-185 A
11-72 C 11-186 A
11-73 B 11-187 C
11-74 B 11-188 A
11-87 C 11-189 A
11-88 C 11-190 A
11-90 B 11-191 A
11-92 C 11-192 A
11-94 B 11-193 A
11-95 B 11-194 A
11-96 B 11-195 A
11-97 B 11-196 A
11-98 B 11-197 A
11-99 C 11-198 A
11-100 C 11-199 A
11-101 C 11-200 A
11-103 B 11-201 A
11-104 B 11-202 A
11-105 C 11-203 B
11-107 C 11-204 B
11-108 B 11-205 A
11-109 C 11-206 A
11-110 C 11-207 A
11-111 B 11-208 B
11-112 B 11-209 B
11-113 A 11-210 B
11-114 A 11-211 B
11-115 C Ref. 1 A
11-116 C Ref. 2 B
Date Recue/Date Received 2024-03-07
206
Ref. 6 A Ref. 3 B
Example B-3. Caco-2 permeability assay of the inventive compounds
Permeability coefficients (Papp values) were obtained from Caco-2 barrier
studies
predicting oral/intestinal bioavailability of the tested compounds. The assays
were
performed by using CacoReadyTM ready-to-use kits from ReadyCell according to
the
manufacturers protocol.
It is considered that compounds bearing Papp values above 1x10-6 cm/s are
classified as
permeable whereas compounds bearing Papp values below 1x10-6 cm/s are
classified as
not permeable.
Table 3. Caco2 permeability assay of reversible TG2 inhibitors
A: Papp < 1x106 CM/S, B: Papp 1X10-6 CM/S Papp < 10x106 CM/S
C: Papp 10X10-6 CM/S
Papp [cm/s] Papp [cm/s]
Compound Compound
x10-6 X10-6
11-2 B 11-117 B
11-3 B 11-118 B
11-4 B 11-119 B
11-5 B 11-120 B
11-6 B 11-121 B
11-7 B 11-122 B
11-8 B 11-123 B
11-9 B 11-124 B
11-10 A 11-125 B
11-11 B 11-126 B
11-12 A 11-127 A
11-13 B 11-128 B
11-14 B 11-129 A
11-15 B 11-130 A
11-16 B 11-131 A
11-17 B 11-132 A
11-18 A 11-133 B
11-19 A 11-134 A
11-20 B 11-135 B
Date Recue/Date Received 2024-03-07
207
11-21 B 11-136 B
11-22 B 11-137 B
11-23 B 11-138 A
11-24 B 11-139 A
11-25 B 11-140 A
11-26 B 11-141 A
11-27 B 11-142 A
11-28 B 11-143 A
11-29 B 11-144 A
11-30 B 11-145 A
11-31 B 11-146 B
11-32 B 11-147 B
11-33 C 11-148 B
11-34 C 11-149 B
11-35 B 11-150 B
11-36 B 11-151 B
11-37 B 11-152 A
11-38 B 11-153 A
11-39 B 11-154 B
11-40 A 11-155 B
11-41 B 11-156 A
11-42 B 11-157 A
11-43 B 11-158 A
11-44 B 11-159 B
11-45 B 11-160 B
11-46 A 11-161 A
11-47 B 11-162 A
11-48 B 11-163 A
11-49 B 11-164 B
11-50 A 11-165 B
11-51 B 11-166 B
11-52 A 11-167 B
11-53 A 11-168 A
11-54 A 11-169 B
11-55 A 11-170 B
11-56 A 11-171 B
11-58 A 11-172 B
11-59 A 11-173 A
Date Recue/Date Received 2024-03-07
208
11-60 A 11-174 A
11-61 A 11-175 A
11-62 B 11-176 B
11-63 A 11-177 B
11-64 A 11-178 B
11-65 A 11-179 B
11-66 A 11-180 A
11-67 B 11-181 A
11-68 A 11-182 B
11-69 B 11-183 B
11-70 B 11-184 A
11-71 B 11-185 A
11-72 A 11-186 A
11-73 A 11-187 B
11-74 A 11-188 A
11-87 B 11-189 A
11-88 A 11-190 A
11-90 A 11-191 A
11-92 B 11-192 A
11-94 B 11-193 A
11-95 B 11-194 A
11-96 B 11-195 A
11-97 B 11-196 A
11-98 B 11-197 A
11-99 B 11-198 A
11-100 B 11-199 A
11-101 B 11-200 A
11-103 B 11-201 A
11-104 B 11-202 A
11-105 B 11-203 A
11-107 B 11-204 A
11-108 A 11-205 A
11-109 B 11-206 A
11-110 B 11-207 A
11-111 A 11-208 A
11-112 A 11-209 A
11-113 A 11-210 A
11-114 A 11-211 A
Date Recue/Date Received 2024-03-07
209
11-115 B Ref. 1 A
11-116 B Ref. 2 A
Ref. 6 A Ref. 3 A
Bioavailability studies
Presumed from promising Papp values (permeability coefficients, see below),
the
inventors had proven the oral bioavailability of the inhibitors of the present
application
by the representative compounds 11-3, 11-15, and 11-28.
For this selected set of
representative compounds, pharmacokinetic profiles were determined in male
C57BL/6
mice (N=3, each). Briefly, the compounds were administered as single-dose
soluble,
oral formulation [20 mg/ml in PBS / (2-HydroxypropyI)-R-cyclodextrin
formulation] at 200
mg/kg. Plasma samples were taken at (0, 0.25, 0.5, 1, 2, 4, and 6 hours) and
analyzed
by LC-MS to determine the concentration of the representative compounds.
The calculated pharmacokinetic parameters are summarized in the table.
cmax cmax AUCt Kej MRT t112 CL/F Vd/F
R2
[ng/mL] [nM] [ng/mL*h] [1/h] [h] [h] [L/h/kg] [L/h/kg]
11-3 13,594 21,588 12,023 1.0 1.0 0.7 16.6
16.3 0.87
11-28 15,143 23,277 14,468 0.6 1.6 1.1 14.8
23.8 0.98
11-15 32,322 48,626 36,878 0.9 1.1 0.9 6.1
7.5 0.93
Cmax: maximum plasma concentration.
AUCt: area under the plasma concentration time curve from administration to
last observed
concentration at time t measured by trapezoidal rules.
Kel: is estimated by the linear regression of the logarithm of the terminal
concentration as a
function of time. Point used to calculate the Kel are selected the 'Best Fit'
option of Winnonlin.
MRT: mean residence time.
t112: is calculated by application of the equation In2 / K.
CL/F: apparent plasma clearance calculated as follow: Dose/AUCinf.
Vd/F (L/kg): apparent volume of distribution following administration. The
parameter are
calculated as Vd/F = (CL/F) / Kei
R2: correlation coefficient.
Papp [CM/S]
IC50 [nM] ICso [nM]
*10-6
11-3 23 180 8.4
11-28 24 240 7.4
11-15 35 375 5.9
Date Recue/Date Received 2024-03-07
210
The corresponding PK profiles reveal that the plasma levels for all
representative
compounds exceed the ICoo for 3.5 hours and the ICso during the whole study (6
hours).
In summary, the high cmax values observed in the PK-studies exceed the ICoo
levels
>100-times. We therefore expect to occupy all active TG2 accessible.
Additionally, in a multiple-dosing PK study, 11-3 was orally administered to 3
mice with
200 mg/kg doses (dose volume 10 mlikg) twice daily (12 h intervals).
After the
animals were sacrificed, the liver and lung were removed. The homogenates of
the
respective tissues were analyzed by LC-MS to determine the concentration of
the
compound. The tissue concentration in lung and liver after the eighth dose
(four days)
was 6,800 and 10,400 ng/g, respectively, showing that the compound reaches the
tissue at pharmacological active concentration.
Date Recue/Date Received 2024-03-07
