CA3231322A1

CA3231322A1 - Inhibitors of transglutaminases

Info

Publication number: CA3231322A1
Application number: CA3231322A
Authority: CA
Inventors: Ralf Pasternack; Christian Buchold; Martin Hils; Martin Stieler; Uwe Gerlach
Original assignee: Zedira GmbH
Current assignee: Zedira GmbH
Priority date: 2021-06-30
Filing date: 2022-06-30
Publication date: 2022-12-30
Also published as: CA3166252A1; CA3231327A1

Abstract

The invention relates to the compound of general formula (l) as novel inhibitors of transglutaminases, to methods for producing the inventive compounds, to pharmaceutical compositions containing said inventive compounds and to their use for the prophylaxis and treatment of diseases associated with transglutaminases, in particular transglutaminase 2.

Description

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 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):

H
NJNI- R3 (I) R2,1 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 R1 represents o =
, R2 represents RN RN
0 Ra R11 0 R8 __ _ S R8 R11 S R8 _ _ N
Ra R11 N Ra _ N _ ' R9 R10 rµD9 9 R10 9 9 RN RN RN RN RN
R11 N R11 N,N _ _ N Ri 1 N RN

I __ t - _ II R8 r R10 µs / R9 R10 9 R10 R10 ; , ' R10 R10 , 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 i R _ .õ ,N,N
1 t N RiN 1 ----- N N'--- R10 p10 N pN
" --- N -¨
\_ N
Rio Rio , , R13 17-(:1 R13 r __ /':1 R13 N

_ 1!...õ. \ N LJ
-ni N=N ------ R14 NIRia N - - R14 N- Ria RN

oo12 N R12 N rµ 0 ./ ... S ./ ,... 13 Ri6 - - - ¨R
\ ,i)R --\R14 R14 14 N 14 -----\R
N'14 10 10 10 , \
R13 s N 71õ,,,N,õ:7._ R14 co \7R ( iRio D14 -'---'-'¨'--%. 14 10--lc-) S ____ - -\ /-------_ ' s " , "
RN

1\1 R9 D__119 R9 S , -, _ NY \ I - -)''''''r/
-,---, Ri.. <õ,-, N-, ---, R ..
, - .. ---------' R8 , S,- ' R8 NI NIL s , N , - N , - 0 R8N 1\1 N6'. - R8--<1 R8--(/0 I
- -H' i , , Date Recue/Date Received 2024-03-07

6 N N
---NNH ---NNH
---( 1 ----N3 V V ( 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
, 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 , 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 _____ , ' , ' 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 _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 ' 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:

1\1 R12 0 R12 S R12 Rio \ ___________ Rio \I ( Rio \
\

ii Ria , R R14 Ria , - -( - - -- _________ - - -N __ \I.NrLRi i R137 7 R12 S\\I

R12 , , R12 ;
, N-RN
' -eS
i\l3, 1 , R 2 _ R13 j:' 6l, R12 ,,õ-4, Ri2 R "' N , R13 R12 ---( r ---( N ----e0 ----- -e0 N N
R130 6 7 R12 \\I v __ ( 1\13_ R12 R13 R13/Ni.. \)-- 12 N R
R12 , R13 iv Ri2 o Ri2 s R12 iv R12 o Ri2 s R12 -- \ - - \ -- \

1-I.

R14 R14 R i ;
N s R1 1 ;

, 1\1 s R13 R12 __ ___T- R12 -- / \ __ R13 , 11 RN 13 RN
' SN

-_N¨-- - - _T- R12 ------11 %N12 N

13 )s13 ;
;
Date Recue/Date Received 2024-03-07

14 R13 RN\ R13 S N

- _-\__R12 . 1\

, , 0____NI
---?14¨R13 N
--f-- ___R12 N-N R12 - - R13 _ N

RN 13 RN' , 13 _______ N 0 _-___N-----1R13 N 12 ____ - -__Tir R12 - - /

11 12 0- -N _N /
, 13 11 'N
, , ., N R13 . R12 õ R13 . , 1 ====. --., --., / R12 R9 N- R13 ---"" R12 , , =

N R9 R10., ., -.
N
/ Rlo Rlo R1c, -, , N R13 ., N R12 --., 1 If R13 N R9 Rio N Ri2 ---- Ri i Ria Ri i Rio , --, ., -.., .
y -Nr R13 R12 ...,.. R9 N R9 ., ---:-.--- N N
NI
N----",Rio R10 . N N R13 R9 ., --., 1 ., ,NN

R14 , R10 R11 Date Recue/Date Received 2024-03-07

15 , N R12 . N R12 N R11 1 , N 1 __, R9rR9---y---- N-:"-", R11 R9-----N-----,-r" R12 ' .
..., ..., , R9---- N-----..,,H" R12 R9 N( N 1 R9- N1\1 R13 R13 R13 , Nr1\1 R11 . R12 õ , ''--(N -.., -.., NI
-..(\i--------- ---- R12 . . . . , r --- - . . . õ ri ---- - - R1.2 1\1N

. N N R12 . N N R12 12 õ 'Tr <--.-.---'" --'--.-----ifr-rN
-,...õ. -.., NI R N

, . N N R12 f õ N N . N N R12 ' ----; -=:-.---- --.1----1 I , i\j/\1 R11 wol\I-N
N R11 R10v R10 , , , , N N . N N R12 . N N R12 '--! N ' ---; --.--.-.--- ==1---I,õ .y. 1 , R9 R9 r N - ----" R12 R9 ------õr N---- R11 , , N N R13 õ N N R13 .,,NN
w o' NI" w 2 N
...,--r%\i--------- R12 1 NI
R9..

, .,,NN ,NN ,,,NN
R9 1 Nr.... R1.. Ri o' I\1 R12 R10-'-'' N-.--m-,:"

. N R11 õ N R12 . T--, N. -,....

,1 ,N r\ir.r N
R9 N-- N Rio wo N R10 R11 , Date Recue/Date Received 2024-03-07

16 ., N R12 . N R13 .
1 NJ N'l -.õ-r---N-:;---wi 'Nr R12 R1cN-N--2-----R11 i ..., NN . , NN ., NI, N

N R10 , ,N R11 -, 1\,1 R11 N R11 N r-rN ' -- ----k---, ---.-:-..---I õ NI
-,..(------" N-2--- R12 R9"-- N------- N-:%---- RI 2 R9 R12 , R9 N R11 ., ., N '' ---, N
-N w-.2-y-----" R12 2 1\i ''N
R12---N NI -----y--., N r-rN N--- R ._ 1, -y-----R9---- N------- N-.)--- w 2 R9 R12 , R9 ., -ri N .
NJ -N-:2----,r1---" R12 1 N'r'e R13.1\1N--N
R13 , R9 , , wo R11 -, -....õ --.., R12 , ., ,N,N
N 'NN
NI 1 õ
' N N R13 w o---- N------ N"--J--- R12 , I N R9 , . .
RN- R11 Rii -RN R1 Rlo RN
R13 Rlo Date Recue/Date Received 2024-03-07

17 -, R9 R11 Ri 1 R9 N R9 R13 N
'RN

RN/

N __ ( __ N i4 _ 1\,\-- 0 R NN
-- \ / R9 N=1 __ \ z Rto Ri 1_,\I lik (1\1 Ri 1 R14 R11 \

R11 R13 \ /
-(R12 .13 R12 R12 , R12 13 R12 13 , N N N N
\ R10 __ R10 R10 N?_Rio \ R11 R11 R11 R11 \ / ' s /

R10 R9 R10 R10 R9 R10 Ro H\1 \__N/ R9 __ \ / R10 R9 R11 D13 R11 R13 / R13 R11 R114 1¨R13 \ 1\/' s ¨

12 R9 /(IR10 R11 12 \R10 R9 ' c N _ N __ c / - - -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 Date Recue/Date Received 2024-03-07

18 N_c _ N_c N_ Rio /

\ / '' \ / __ '' N
Ri2 ii R12 12 R13 12 R11 NI_ N__R10 _ 10 N_ R N__ N R10 _ R10 - ___________________ --R
___\I /R1C) - - - \ /

-N
-\1_/ /c R12 R11 's \ / 's )R11 R12 11 , R.,,, . 12 , , 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 _NJ _NI _NI _NI
N R10 -- _______________________________________ R10 _ R10 _ i __ \ i_ / - \ /
1\,:R11 R11 R12 N)_R11 ¨/c11 /(R Is\I /
R12 11 , R12 12 , (N 2¨c c Rs R10 __\1_, - (N
R12 c R1-2-- /c - ___________________ / R12 \ / R11 R11 ¨c11 R12 (R 11 ; R12 _ - - \ / R13 R13 \ ./, ___ Ki i\i4 >_R10 12 ¨N ; Rlo kio or N- .
One embodiment is directed to compounds of the general formula (I):
R'l H
N L (i) R2 hi 1 NY R3 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

R10 R9 , R9 R10 R9 9 R10 9 9 R11 NR11 1\1 R11 0 -- R11 0 R8 - _ ),--0 R10 R8 - - " 0) 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 )\ N N sN--- 0 R. R10 Rio R10 , __ , , Rio N RN
----- 'N-- N N N -------------------------- r'1/21 R13 ) ) ..,. R13 'ND -' ' NA LI NI
\,:j ---------\R14 R13 - Ria N. R14 RN

R12 N R12 0 ./ 13 S ./ N

R13 --'3_R -- \ 1 R13 R14 \R14 -\R14 N Ria N. R14 Ib0 10 , /') R13 R13 N\--N R14 4 j \¨,j -----\I ,õ,\--J
(.11 R9 N
R14 R14 --"--------"--;-"- \R14 _____________ R10 N'; -\__,-----.R10 RN RN

il R9 _ r -/_, Rio R10 ,1\1. -/-Ri o -/--, D 10 )''''--/- - -N ¨., ) o \\IR8 --N/ N - N
- -- -S)- ---- R8 R8 1\I 74 N'p\; R8 --_< '''' R8---(/0 N , H

S
\ \ \
N
i , , N N
- --eNNH -- cNH
----\"- J

/ _______________________________________________________________ \\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
, -cNr1-- N-N-0 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

N NI
N NI N
, Date Recue/Date Received 2024-03-07

21 , N N . N N
.--rNN
N
--!
I
N Nr ---- --<.--- ---.1 I\IN
, N N . N N , N N
'-! N T ' 1 N
N
, N N ., N N . N
'-! N

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:

- ---? , , . . 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 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 , _ _ R11 S
R8 R8 -- _ S R8 R11 N
R
0)r (3)\IZ --1 i." ---Q---- --$' _________________________________________________________________________ Ni \N---- , Rs R10 R10 R10 , RN

NI' KI Rio R10 N RN
N N R13 i-r-'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 _ _ _ N14 1\1\11114.\-) N14\-) N14 10 \R14.
\R14 5 , RN

iv I \

R14 iv ___ :/.., ' - I 13 - - 1\ ,TR
----\iR14 R12 '/'\T) R13 L j 7 R

` R9 N R
N 7 ii R9 . 1õ,,..._ R14.

r--- - i R1c, N . , I __ s ( r--- -71 Rio ,...õ ---,--, R
in ..
Rio------4N--- - - ------ R10 ) 0 , ;
R8 R8 S , - R8 R9 S ,-Na / II

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
, , , , , ' 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

H H
, --Nr--/ - 0 -N t , , 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

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
, 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 , 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

_ --1 jt1 I I l( Rio µs // R9 R10 9 R10 R10 ' , " R10 R10 ' R11 0 0 p8 - ' R1 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 , , N N N-R x ri -1 1k) R13 1.1.: R13 f R13 N/.) --,kN
Lt, j \-) N-N N=N1 ----- R 1 4 , N Ri4 N Ri4 N' 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 RN

.
-,7"-------- K 13 \ NykrR14 II

I I R13 L i R r--- "ii Rio - id s (KI R9 R14 R.. RioN-') - \___,-----...R10 RN

il R9 _ r Yr Rio p 1 0 o N/¨

--/--. 10 )'''''-r- S)-\õ ¨,. N ¨1-= ?\1 c R8 S,- ' R8 N'.___Nil S- . N - N ,-R8 , 1\ d'Il- R8 , --__< R8-__c) II

' ' ' ' H

\ \ \ N \( , N
, , , , , Date Recue/Date Received 2024-03-07

31 ---NH - - -CO S N s - - -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

II1N7LR3 (I) R2 hi 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 R19 .
--101_1R8 ,o)--i Rto R11 S ii S 8 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

S i A p13 1\1 1 'Al p 13 /' s 1, - 7------../
p12 - - \ 1 \T- -- \ 1 - R''-' i R13 r/1 R13 _......_ -\ in 10 ' RN 14 , \R N ----\\;14 \-----) R4., ,, id /\\-' pp . .
, RN

\......:R:
7/Rio N'\

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 __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):

zrIJ N-R6 (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 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 R11 N R11 k N
N - ---- 'N
R1,1 .,0 _ _ R11 0 R8 - _ )c(:).__ R8 3\ d i __ ,---R10 µs / __ R9 R10 \R9 R10 ; ; ;
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' 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 , R13 N/.) R13 r R13 -- \ 1 TR -- \ 1 R
N\11114 \-) N. Ru N. Ru 10 -\.i-R14 -\;j14 RN

1\1 A 13 RN R12 - - ._ S
---3C,\TR II R9 R1-.3 N----- 14\'R
, 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

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
- -Rio Rio Rio / \ N
, = , , , , ' , RN
RN Ri2 Ri2 N
, NI Rio o IAio N,NIA

NI N D N ir..1 R13 R13 \---- NI
- - -L 'N.1 - - 'N-' ' N -=NI 44 z' , ri.....:1 R13 N/.) R13 IR) ,) R
N N N \11S14 \') . R14 \-) . R14. io - 14 \R14 RN
Ri2 RN

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 N
. R9 % µ
14 R ii R9 Ni r 1 r /I
Rio--)c R
-) ___________ s (II,R9 Rio -,- Rio 7 R9 1\1 Ri.n Rio , _/_, N'\ 1 N - S).- - .. / m \N

,-- 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), H 1- (I) 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)-;

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

...

I ¨R 1 R13 Rh' __ \ ,\ 9II R - -4 1 I

1\\\-) R14 r_ N----14 10 10 10 ----\___/-------R10 S H , ________ N
vN___Ri4 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

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), H L (I) R2N N Nv R3 wherein L represents ¨L1¨ or L1 represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, ¨CH2CH2C0¨;
L2 is a bond, ¨NR'¨, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRN1CH(CH3)¨;

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

--- 'N Rii N
N --------N i ---- 'N
NA
Rio Rio Rio N RN /-1 R13 R13 R13 N r 4) - - -N--.%\-414 \-) R13 \-) N=N N Rizt 'N Rizt N Rizt N Rizt , , , Date Recue/Date Received 2024-03-07

41 RN

0 A _ i.<13 ___ \R14 S ./) _ i.<13 --10 \R14 N
-- I }R13 \
io i.g14 R12 --I\L----/') 13 N------\\-R14 , U13 r-.7- 13 Ri4 K1 R9 TR L i R3 N r,\! (riR9 r -/i - sR14 R14 R10---N) - \ -R _ Rio RN

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 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

iv _......, L( % R13 - - \ 1 gR13 R - - \ 1 --/'\ R13 - - 4 1 ,JR13 10 R14 N -----\\fR14 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)-\\NI 11 " R8 \S-N `N,-_- N 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 N 0 Nii__f 0 c)-(:"H 0 0 c 0 RC
R2 N L Ra JNH

N L NI-1N,L--L Rb ) N 2 Rb Fe"
H

Ra (IV-a) (IV-b) o o (: N-R6 0 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 0 711' 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 -0 oil NH

o H Rb Ra H H R

c o 1\1AN L2 N

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 Rd H
(IV-i) (IVA) N-R6 (7t) N-R6 H H

R2Am N N

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 (IV-m) (IV-n) o o ol Ni4R6 o H
0 C 0 0 il 0 2&NH NH 1 0 N N N 1-2"- R

-r-N-----L2 I \ 1 H 8 o o R9 Rio (IV-o) (V-a) o o )-LC) N - R (:)6 0 j H H 0 0 H H 0 S R8 N R3 R8 NI N- le L2l 'AV
-1'4 I H

(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), ()-L

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

Date Recue/Date Received 2024-03-07

46 Me ____//N õ - .----o'N) -<
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

N"N ',N 'N N' N' N, ----, N / 1,1=1 , CO2Me N-, NO2 ,-0O2H .,CO2Me . N

'A N
, ' , N H ' N7--- i N
N_--r- _-N ---- HN -'- N ---- --...--Nv- G-- L Br - . HN__.'=
' 0 \ \ , __ -- \
---- N.--- N-----1--S _______ S.----N -- \
, \ 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"

---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-methy1-5-1 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-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

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-s N 1\1NN H dihydropyridin-3-y1)-N6-methyl-5-oxohexanediamide 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

11-8: 1\1 (S)-2-(5-bromobenzo[b]thiophene-2-carboxamido)-N1-(1-(2-(2-H dihydropyridin-3-y1)-N6-methyl-5-H adamantylamino)-2-oxoethyl)-2-oxo-1,2-N r\jANIN
H
oxohexanediamide 11-9: 0 N (S)-2-(1H-indole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-H H H H 1,2-dihydropyridin-3-y1)-N6-methyl-5-N N Ncr\iNa H oxohexanediamide o 11-10: A(3N (S)-2-(4,5-difluoro-1H-indole-2-H H II H adamantylamino)-2-oxoethyl)-2-oxo-1,2-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-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)-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-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 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)-H H H
SJiNJN,>-CNN,a, N6-methyl-2-(4-methyl-2-phenylthiazole-5-H
carboxamido)-5-oxohexanediamide \ I 8 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-)-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-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-H II H adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-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)-le (i -(2-(2-ada mantylami no)-2-oxoethyl)-2-H II H
0 N oxo-1,2-dihydropyridin-3-y1)-N6-methy1-oxohexanediamide o 11-27: (S)-2-(5-chlorothiophene-3-carboxamido)-le Ni -(1 -(2-(2-adamantyl amino)-2-oxoethyl)-H H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-Nyjr N
5-oxohexanediamide 11-28: o 0 (S)-2-(2,5-dichlorothiophene-3-re H carboxamido)-N1 -(1 -(2-(2-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-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)-le N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-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-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-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)-H H 2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-p s N f\JAN{N H 8 5-oxohexanediamide B

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

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

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 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-H II H oxo-1,2-dihydropyridin-3-y1)-N6-methy1-N NI\VIN
\ I H oxohexanediamide B

11-48: (S)-2-(4,5-dibromofuran-2-carboxamido)-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

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------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-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

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

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

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 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

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-N NncN
H trioxohexan-2-ylcarbamoy1)-5-nitrobenzoate 02Me 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

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

f\V 8 trioxohexan-2-ylcarbamoyl)nicotinic acid H

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 g trioxohexan-2-ylcarbamoyl)nicotinate 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-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-H H H dihydropyridin-3-y1)-N6-methyl-2-(3-g I
0 N 1\12-cNiN H methylbenzofuran-2-carboxamido)-5-OH
oxohexanediamide 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-N Nj-7.nfN
I H methylbenzofuran-2-carboxamido)-5-F
oxohexanediamide 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 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-H 1µ1 II N H dihydropyridin-3-y1)-N6-methyl-2-(3-N -rN
I H methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-73: :c re (S)-N1-(1-(2-(2-carbonitrileadamantane-A
H amino)-2-oxoethyl)-2-oxo-1,2-H II H CN dihydropyridin-3-y1)-N6-methyl-2-(3-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 11-87: (S)-N1-(1-(2-(1-adamantylmethylamino)-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-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-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-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-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-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-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 11-105: 0 N (S)-N1-(1-(2-(diamantane-4-amino)-2-V
oxoethyl)-2-oxo-1 ,2-d ihydropyrid in-3-y1)-H H H N6-methyl-2-(3-methylbenzofura n-2-0 N Ncr\JN

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

N NN oxohexanediamide I H

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 N NN methylbenzofuran-2-carboxamido)-5-1 H oxohexanediamide H

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 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 N NN oxohexanediamide I H

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 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\1-11-115: (S)-N1-cyclopropyl-N6-(1-(2-(2-oFr,i/--adamantylamino)-2-oxoethyl)-2-oxo-1,2-o 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-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-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-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-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)-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 o 11-123: (S)-2-(benzofuran-2-carboxamido)-N6-H =C))11 N 1::11 benzyl-N1-(1-(2-(2-adamantylamino)-O H oxoethyl)-2-oxo-1 ,2-dihydropyrid in-3-y1)-5-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-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-o A NH2 o 11-\LAN11-\1 (4-methyl-2-(trifluoromethyl)thiazole-5-F3c 1 H carboxamido)-5-oxohexanediamide 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
\

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--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-(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

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-N
HNhi carboxamido)hexanediamide o 11-133: :c)(S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-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

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

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
\

11-141 o (S)-N1-(1-(2-(2-adamantylamino)-2-N
H oxoethyl)-2-oxo-1 ,2-d ihydropyrid in-3-yI)-H N6-methyl-2-(4-methyl-1,2,3-thiadiazole-5-sN 1111ANIN
N"\ 1 H carboxamido)-5-oxohexanediamide N

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-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

11-145 o (S)-N1-(1-(2-(2-adamantylami no)-2-oxoethyl)-2-oxo-1 ,2-d ihydropyrid in-3-yI)-2-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 -(24(1 R,2R,4S)-bicyclo[2.2.1 ]heptan-2-N NEIrel%cri_ ylamino)-2-oxoethyl)-2-oxo-1 ,2-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-H II oxoethyl)-2-oxo-1 ,2-d ihydropyrid in-3-yI)-2-N NNVINE1-===IL
I H (3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide o 11-148 (S)-2-(benzofuran-2-carboxamido)-N1 -(1-(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)--- bicyclo[2.2.1]heptan-2-ylamino)-2-o NH
c 0 H yI)-2-oxo-1,2-dihydropyndin-3-y1)-jj o N NvI
I H (3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide o 11-150 oy(S)-2-(benzofura n-2-carboxamido)-5-oxo-N1 -(2-oxo-1 -(2-oxo-2-((1 R,2S,4R)-1 ,7,7-o 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-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)-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

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 -N (S)-N1-(1-(2-((1 S,2R,4R)-H 1-- bicyclo[2.2.1]heptan-2-ylamino)-2-o 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-(trifl uoromethyl)th iazole-5-carboxamido)-2-j oxo-N6-(2-0x0-1-(2-oxo-2-((1R,2S,4R)-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 _____________________________________________ 11-160 (S)-2-(2,5-dichlorothiophene-3-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-CI ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 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

Ns ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 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 11-163 (S)-N1 -methyl-5-(1-methy1-1 H-pyrazo le-5-N carboxamido)-2-oxo-N6-(2-oxo-1 -(2-oxo-0 :cAH 0 ((1R,2S,4R)-1,7,7-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-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-oxopropy1)-2-oxo-1,2-dihydropyridin-3-y1)-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 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-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

(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-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 H H
d ihydro pyrid in-3-y1)-N6-methy1-2-(4--LcNj N H co2H methylpyrimidine-5-carboxamido)-5-oxohexanediamide 11-174 0 (2S)-N1-(1-(2-(4-aminoadamantane-N,N-H
0 r H
0 dimethy1-1-carboxamide)-2-oxoethyl)-2-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-H

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 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 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 (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-N N1\11 H
I H ethylbenzofuran-2-carboxamido)-5-oxohexanediamide :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 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-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 11-186 0 N (S)-N1 -(1 -(2-(2-carboxy-2-amino-5-V
0 ,F1 0 (trifluoromethypadamantane)-2-oxoethyl)-Nj)L N 2-oxo-1,2-dihydropyridin-3-yI)-N6-methyl-HN CF3 5-oxo-2-(3-oxo-1 ,2,3,4-tetra hydroisoquinoli ne-6-carboxamido)hexaned iamide 11-187 N (S)-N1-(1-(2-(5-ethyladamantane-2-V

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-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-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-V
ylamino)-2-oxoethyl)-2-oxo-1,2-0 c H 0 H
0 N NN H dihydropyridin-3-ylamino)-6-/ I H (methylamino)-1,5,6-trioxohexan-2-yI)-1H-pyrrole-2,4-dicarboxamide 11-193 0 Li (S)-N1-(1-(2-(1-acetylamino-4-0 0 aminoadamantane)-2-oxoethyl)-2-oxo-1,2-0 dihY droP yridin-3-y1)-N6-methy1-5-oxo-2-(5-:"-OAH N u-INaElj sulfamoylfuran-3-carboxamido)hexanediamide 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 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 11-196 0 õ, (S)-N1-(1-(2-(4-aminoadamantane-1-0 carboxamide)-2-oxoethyl)-2-oxo-1,2-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-methy1-5-1\1 oxohexanediamide o 11-202 N (S)-2-(4-cyclopropy1-1,2,3-thiadiazole-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-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

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)-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)-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)-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 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 Ac0JJNR6 -H
o 4b;
Step 2B: performing coupling reaction of the compound 4b with a compound 5 o H2NN_L R3 to obtain a compound 6b o NI' R6 H
PG3,N NN_L,R3 H
10 6b;
Step 3B: deprotecting an amino protecting group PG3to obtain a compound 7b Ac0JJNR6 iiz7 0 H
N -Li\i_l_ R3 7b;
15 Step 4B: performing coupling reaction of the compound 7b with a carboxylic acid (R2-CO2H 8) to obtain a compound 9b AcOjN-R6 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 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 to Hunder a basic condition such as treating with K2CO3, and then 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 Na3PO4 02 N AN OH >

2-Adamantylamine EDC, DIPEA, DMF
10% Pd/C

H Me0H H
H2 N N < ________ 02 N N
N N

1 Preparation of compound ZED1657 o , 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 H

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 H

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

H2N ti ,1 N a HATU, DMF
I DIPEA

AcOJl..N Ac0 N
H H

H H 1) TFA, DCM H H

N N-AN N Bocl\I I\1AN-IN
I H H
2) 3-MethylbenzoN-furan-2-carboxylic acid HATU, DIPEA, DMF
1 K2CO3' Me0H

HO N
N
H
0 H H 0 Dess-Martin 0 H periodinane H

N

DMF H

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

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

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 H OJI N
H

H H

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 N

H

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

H H

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 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 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 .. 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

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 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 j)-L N
H

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 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 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 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 oll N
H

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 H

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 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)11_\_11 N
H

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 (21)- N
0 cNN H 0 H 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

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 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

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-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

H H
S N N N
N
(97riNegill42-r--geigla-2-VerrOggilxe -gt-CYair)1;OgriVdi OilgtdoraPxYgdergati 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

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

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 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 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

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 N

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 34 Preparation of compound 11-28 o 0 )N

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 36 Preparation of compound 11-30 0llN

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 38 Preparation of compound 11-32 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 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 40 Preparation of compound 11-34 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 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 42 Preparation of compound 11-36 N

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 N
0 j)-() H 0 N

(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 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

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 46 Preparation of compound 11-40 0j)-N
H

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 oil N
H

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 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-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 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

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 52 Preparation of compound 11-46 oll N

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 N

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 54 Preparation of compound 11-48 0 )C:N

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

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 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-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 58 Preparation of compound 11-52 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 oil N

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 60 Preparation of compound 11-54 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

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 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

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 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

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 66 Preparation of compound 11-61 N
N

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 C:1A N
0 c H 0 H H

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 68 Preparation of compound 11-63 0 )-L() .. N

H H
0,1\1 N N

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 (according to ZED3264).
Yield: 76 mg, 65% (last step) ESI-MS: 622.3 [M+H]
69 Preparation of compound 11-64 -L(:) N
0 c) H 0 H 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 70 Preparation of compound 11-65 oll N

Me0 C

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 72 Preparation of compound 11-67 )L NIH

I

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 AN
H

H H

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 74 Preparation of compound 11-69 c)-N
H

H H

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 AN
H

H H

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 76 Preparation of compound 11-71 oil N0 H
0j H H

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 AN
H

H H

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 78 Preparation of compound 11-73 :cAN
H

H H CN

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 oil N
H
0d 0 H H CO2Me 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 80 Preparation of compound 11-87 H

H H

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

H H

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 82 Preparation of compound 11-90 JA N 1) H

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

H

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 84 Preparation of compound 11-94 cA N
H

H H.1/43....

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 N

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 86 Preparation of compound 11-96 o H

H

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

H

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 88 Preparation of compound 11-98 N
j)-L H 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 N
0 (::1 .. il H 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 90 Preparation of compound 11-100 o1 N
0 N N, I 1\1 , H

(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 0j)-LN
0d 0 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 92 Preparation of compound 11-103 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 94 Preparation of compound 11-105 0)-N
H

H o H

(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
' ____________________________________ ,..-DMF, DIPEA

i10% Pd/C
Me0H

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 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 N
H
0 j)(::1 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 98 Preparation of compound 11-108 o11 N
H

, 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 H

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 2024-03-07 100 Preparation of compound 11-110 N
0 )-F1 0 N

(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 )-L() N

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 2024-03-07 102 Preparation of compound 11-112 N
jA(:) H 0 H H

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 oil N

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 2024-03-07 104 Preparation of compound 11-114 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 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 2024-03-07 106 Preparation of compound 11-116 0)- N H

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 H
0d 0 H H

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 o )c H202, LiOH
_______________________________ ..- ___________________ ..-Boc 'N OtBu Et3N, CH2C Boc 'N Me0H
OtBu Boc 'N OtBu eoco eoca oc 11 1) Ac20, NEt3 2) TFA/DCM
DMAP, DCM 3) Boc20 DI PEA, DMF

AV NH2 H2N,a,N,c1 AV

HATUDMF

H H . _____ Boc 1\1 N N N Boc 'N OtBu , H H DIPEA

1) TFA/DCM 16 2) 3-MethylbenzoN-furan-2-carboxylic acid HATU, DIPEA, DMF

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 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 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 Preparation of compound 16 o 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 )NH2 H H

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 2024-03-07 109 Preparation of compound 11-119 o )-N
H

:cH 0 H

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)-N
H
INjN

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

111 Preparation of compound 11-121 o o N.A=
H

H H

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 0j)r -N
H

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

113 Preparation of compound 11-123 :c)-N
H

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)-L N H2 H H

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

115 Preparation of compound 11-125 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 () - NH2 0 i_1 0 H

--....,,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

117 Preparation of compound 11-127 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

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

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 Ni0 N
H

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-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

121 Preparation of compound 11-131 N
H

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 0j-LN
H

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

123 Preparation of compound 11-133 N
H

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

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

125 Preparation of compound 11-135 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 N

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

127 Preparation of compound 11-137 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 N

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

129 Preparation of compound 11-139 N

N )-LI\IN
NOAH

/
(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 N

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

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 N

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

133 Preparation of compound 11-143 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 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

135 Preparation of compound 11-145 o ).,1\ jo N H2 H
N'SN NN

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-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 0 -L()) 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

137 Preparation of compound 11-147 o cA NH

H H.,..iizzi_ 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 H

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

139 Preparation of compound 11-149 o H

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

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

141 Preparation of compound 11-151 o :cANHO2 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 OA
N
H

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-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

143 Preparation of compound 11-153 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 N

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

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 N

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-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

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-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 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

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

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

151 Preparation of compound 11-161 0)-L

H

H
N' NNH

(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-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)-N
H

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-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

153 Preparation of compound 11-163 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 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

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

157 Preparation of compound 11-167 N

H

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 .A N
H

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

159 Preparation of compound 11-169 N
0 c)- H 0 H H

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 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

161 Preparation of compound 11-171 o cA N
H

H

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 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

163 Preparation of compound 11-173 oll N
N
N
1\11 (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 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 (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

165 Preparation of compound 11-175 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

167 Preparation of compound 11-177 o N (17 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).

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

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 -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

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 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

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

H
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

175 Preparation of compound 11-185 oll N-H

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

1\1/

(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

177 Preparation of compound 11-187 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

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

179 Preparation of compound 11-189 o N

H
H
b-(S)-2-(4-amino-1,2,5-oxadiazole-3-carboxamido)-N1-(1-(2-(bicyclo[1.1.1]pentan-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

\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-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

181 Preparation of compound 11-191 o o N

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

(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

183 Preparation of compound 11-193 o OJA
N
H

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

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

185 Preparation of compound 11-195 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 OAN
H

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

187 Preparation of compound 11-197 o N

/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

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

189 Preparation of compound 11-199 oll N

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 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

191 Preparation of compound 11-201 oil H

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

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

193 Preparation of compound 11-203 :c)-No H

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 oil N
H

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

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

197 Preparation of compound 11-207 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 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

199 Preparation of compound 11-209 oA
N

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

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

201 Preparation of compound 11-211 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 N
j)L H

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 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

Compound Compound TG2 [nM] TG2 [nM]

Date Recue/Date Received 2024-03-07 Date Recue/Date Received 2024-03-07 Date Recue/Date Received 2024-03-07 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 : H
%

H
NN N 8 NENi A
N
\
Ref. 3 (A8, ZED1047) Ref. 6 o o o c)F-N
?, /
H

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

Date Recue/Date Received 2024-03-07

204 Date Recue/Date Received 2024-03-07

205 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 Date Recue/Date Received 2024-03-07

207 Date Recue/Date Received 2024-03-07

208 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 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

[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

Claims

1. A compound of the general formula (I):

H
L (1) R2N N Nv R3 wherein L represents ¨L1¨ or ¨L1-L2¨; preferably ¨L1-L2¨;
Ll represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, ¨NW"¨, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRNICH(CH3)¨;

RI represents '' R4 ; ieL
R2 represents RN

- _________ r Rii 0 R8 S R8 1 j--- -- 1 _____________________________________ r Rii s R8 \ / - - N

R10 09 9 , R10 R9 /
' R9 R10 9 RN RN RN RN RN
RN
R11 N R8 R11 N R11 N N Ri 1 N
i __________ r --1 jt1 / ( R11 N R8 I _______________________________________________________________________ t , Ro Rlo 's = R9 Rlo R9 Rlo RN Rlo t Rlo N R8 R1.1 ON_ R11 0 R8 -_ ,Oi____. R8 .. -- ) R

, , ; ' N 1 i---- \ / 0) Rlo Rlo Rlo R8 \N-.
, , RN RN
, , R10 R11 S ii (3\ i2\1ZR9 1 __ t - R11 S R8 - _ 1 Si...._ R8 - _ _. .N R11 N, Rlo Rlo Rlo /
, , RN

N plo p 10 N DN
N' -----' ' 's -=-=- 'N' N N ------ ,N R13 'N --- f 'N-rµ u R14 N \-) N=N -------- R14 , Date Recue/Date Received 2024-03-07 R12 R12 N R12 0 .7) 13 S ./
fr.<1 R13 N/.) R13 ------------------------- 11 1) R13 -- \ 1 , TR -- \ i R13 N. R14 N. R14 NI14. 10 \N \i \Ria , RN

1\1 A 13 iv- R12 R12 ,--, -- \ 1 T.-10 \Ri4 ______ p R12 AI

N-----\ 14 13 R

R..

µ, Nz___R14. N R9 NI ,R9 S r_KIR9 r i R10 r = i R1c, N. , <,- --,-.

R10 N _______________ - \ --7----R10 (21) -, ' , R9 S N/ I NI 1 N- S)- -..___ _R1 0 i8 S N , - N , - 0 1\

1\I I Tt.
0--N R81\1 R8--_//o I
N
H

, N
, i ' , , , N N
---NNH ----CNN
--- 1 -- ________ ---NS
______ \I ( \I ( 8 j sN
N
( 1\1 , NI j 7C) d\ij N N
--- __________ ---, ____________ - --CO ---eN0 ---eN0 c \c\1 1=1 NiNj 70 CiN N , , , H S
-- -7 --r:----- \I
, , , , H
S--- -N - - -c_-\ -1N----J
-N
, N N
N
___(---- 0_,õõ___ N) - - k-- _er----H H , , Date Recue/Date Received 2024-03-07 ---___ , , , , N .
-, i 1\i /
., N -, -, 1\1 / , N
, N
., N
1 If1\r Nr N . N
N 1\1 , , N ., -, N N
N Il I\I
., . N N .'-!NN
.N i IV' . N , N N
-',-, N I I
1\1 N
, --N ',-- --, i I I
1\1- NN Nle , N .
r-N
' . N N ., N N
I\1 j --r f 1\1 1\1 N N
, . N , N N , , N N
'-r N 'T ' 1 NI\I 1\11e I\IN
, N N , N N . N N
-T , 'T , 1 N
1\1 . N N , N N
i I\1 I
, . N
'-! N .'-!NN -,r1\1N
I I I\I IN1 , I I -r N I\IN NN
, , . N N , -, N
'-! -',r I N If Nle 1\1 -I\r Date Recue/Date Received 2024-03-07 NIV '',NIV
Il I
1=1 1=1 N N
-, NIV
I
NN
., N N
-', N
I\Ir N
N Nle , N -, N ''N
NI N ,N
1=1 -1\I ' I -rN
NN I\INI NI\I
'N NN-'N N N-'1\1 , ---r ' NN
I
NI-I\IN N'Nle leIV
H
N .
H H ;
;
, -- -- ..
N NH
H, ;
N ______ \ 0 N,N N __ \ N
- \ / -- \ /N
--- __ _ , , , , NI_ NI_ ' NI_ __IV _NI
-- \ /1\1 -\I _________________ /
; ; ________ ;
/_1\1 ' _NI ' __NI
\ - __________________________ /c1 -- _________________ /K, \\ ; \ /
N // ;
; ; ;
Date Recue/Date Received 2024-03-07 N N
\I
\ /n N,N N=N N,N N,N N,N
- \ /
--- ______________________ , \ ____________________________________________ - \ rµ( , _ -,\I-1\/
2/ \\_ , _NI N N N N ' , -\I
/
_1/
- \I
- .\\µ.4\
-- _____________________________________________________________ \
) N ¨N \=\ N
NJ \
¨14 ¨1<1 or wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ 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;
Date Recue/Date Received 2024-03-07 Ra, R13, Rc, Rd, and Re represent independently of each other -H, -F, -CI, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C21-15, -CON H2, -CON HCH3, -CON(CH3)2, -CON HC2F1s, -CH2CO2H, -CH2CO2CH3, -CH2CO2C21-15, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2Hs, -NHCOCH3, -NHCOC21-15, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-15, -NHSO2CHF2, -NHSO2CF3, or -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-C3F1s, -cyclo-C4H7, -cyclo-051-19, -cyclo-C6H11, -CH2-cyclo-C31-15, -CH2-cyclo-C4H7, -CH2-cyclo-C51-19, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, or -CH2CH2N(CH3)2, or -NR6R7 is -N(C2F15)2, - -N - -N - -o N rO
__N( ).
R6, R6, R10, R11, R12, R13, and R14 represent independently of each other -H, -F, -CI, -Br, -1, -OH, -CN, -NO2, -CH3, -C21-15, -C3H7, -CH (CH3)2, -C4H9, -CH2-CH(CH3)2, -CH (CH3)-C2Hs, -C(CH3)3, -cyclo-C31-15, -CH2-cyclo-C31-15, -CH2OH, -CH2F, -CH F2, -C F3, -CH2CI, -CH2Br, -CH21, -CH2-CH2F, -CH2-CH F2, -C H2-C F3, -CH2-CH2C1, -CH2-CH2Br, -CH2-CH21, -OCH3, -0C21-15, -0C3H7, -OCH(CH3)2, -0C(CH3)3, -0C4H9, -OCH F2, -OCF3, -0C H2CF3, -0C2F5, -0C H2OCH3, -O-CyCIO-C3H5, -OCH2-CyClo-C3H5, -0-C2H4-CyClo-C3H5, -CHO, -COCH3, -COCF3, -00C21-15, -00C3H7, -COCH (CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2Hs, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -00C-CH3, -00C-CF3, -00C-C2Hs, -00C-C3H7, -00C-CH (CH3)2, -00C-C(CH3)3, -NH2, -NHCH3, -NHC21-15, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -1\1(C3H7 )2, -1\1[C H (C H3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC21-15, -NHCOC3H7, -N HCOCH (CH3)2, -NHCOC(CH3)3, -CON H2, -CON HCH3, -CON HC21-15, -CONHC3H7, -CON HCH(CH3)2, -CONH-cyclo-C31-15, -CONHC(CH3)3, -CON
(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -502NH2, -SO2NHCH3, -SO2NHC2Hs, -SO2NHC3H7, -SO2NHCH (CH3)2, -SO2NH-cyclo-C3Hs, -502N HC(CH3)3, -502N(CH3)2, -502N(C2H5)2, Date Recue/Date Received 2024-03-07 -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -N1-1502C3H7, -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, = ri\( /N r r r , - -N
r r N NH N N- 1\( )\1 , or \ ____ ;
or R8 and R9 or R9 and R1 can form together one of the following five-membered or six-membered rings:

, or ''-%" ;
or R12 and R13 or R13 and R14 can form together one of the following five-membered or six-membered rings:
o o o -0 ,,o , 'N
j u H or I
RN represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-051-19, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-051-19, -CH2F, -CH F2, -C F3, -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, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-051-19, -COOCH3, -COOC2H5, -COOC3H7, -COOCH (CH3)2, -COOC(CH3)3, -COOCH2Ph, -502CH3, -502CF3, -502C2H5, -502C3H7, -SO2CH
(CH3)2, -502-cyclo-C3H5, or -502C(CH3)3;
RI" represents -H, -CH3, or -CH2CH3;
Date Recue/Date Received 2024-03-07 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.

2. The compound according to claim 1, wherein R2 represents RN

- r R11 0 R8 1_ _/---- - - ISr RS R11 S s il R
____ R8 ir R10 __ R9 9 , R10 R9 ' R8 R10 9 RN RN RN RN
R11 N R8 R11 N Rii N _..... N Rii 0 R

--1 t ir I ,;N
/ R9 Rio µs ' R9 Rio R8 Rio , , , ' Rio Rio i i 0 Rto ii S
--, R (3)4\iz 8 ) R -- R8 _ Rii S Rs R,, I i----Rio R8 IN¨ , (:)1-2-Z c, Rio RN RN RN RN
S 8 il R10 N RN
N
-- __________ R --___ .N Rit __N, NN N,N Rio \----- ---f 'N--)¨N ---- 'N
NA
wo R10 /
/ / /

N -R N ---------------- l'i1/21 R13 R13 ------------- fI
Ri3 .. N/.) R13 .. R13 --- 'N Li,.,,,,.,....,,j \-) \N
NA , \R14 , N R14.
, N Ria , N Ria , N Ria , RN

0 .y _13 -- --\R14 S , R13 \ 1 --10 R14 \\RT1:1 -;---0 I --R 13 R9 µ. N N Ria r - ),-:-) s r_II
R14 R10 N - \___,-------R10 g RN

il R9 S , -\i\R/ 9 I R9 1 , _ r 7rwo )---7-1 - s)---R i in v --/-= D 10 N, N ¨ix o - R8 , S , - R8 Ni_Nfl S ,-N N ,- 0 ---R8 Nt_ki -1\1 a N
H

N
, , , , , , Date Recue/Date Received 2024-03-07 w Fp.
x , / , / i i i i i /
CD
/ / / / / / i i i i i , ) C / ¨ ¨ Z_ CD
0 \ Z Z
rrisi 0 = Z)N. rri \ 0) eiN cn riN z ( Z---- z r z'--- ( --D) / \ _/ Z \ / \ /
Zj Z--( Zj( 0------ \ ----";"-- --- cn ca" z zµ / z z z z cz 0 \ c z c cn - =
cp -0 Z Z Z // \ / \ /
(D
- - - - - -(D

N) /

/
N) -P
O
(t) , , , , , z , , 0 , , , , , -.1 z_ z o7 = N cn N cn7 zI-' ' ' , , ' , , z z z z zj \----- cn , , , ' _ / ___________________________________________ z // c> 6 y \
3 /.z /.(z z z " "_ _ _ . _ ,, , , (z--, \ _____________ , \ _______________ ,z \ , \ õz (z____\_. N.) z / \ __ y z_z \ z z _______________________________________________________________________________ ____________ _ _ _ _ _ , , , , , , , , , (z--, ,:x0 ,-70, ,,,z ,cn Iz ;NJ
z--( z-I( z / 0" z I , , , , , , ' , . .
z /(i)- z---, , , , z ¨ / ________________________ ¨ z=z ; z_ _ \--"
z z \
, / \ //z \ z z \ z \z /z \ / , , , , , i , i : 0- , z 0 N cp7 zi cn N = N z_ ___z--\ , z z , z z zj z z i \ 1 c z 0 v z Z---N
z"'"--- cn _ _ . N , --1 N r-N
. N N N N
-.
'I\',( le NI
le INN
, , , . N N . N N
N
'T
1\11=1 i 1\11e I\IN
, N N ., N N . N N
--! N T '-!
N
I
le . N N . N N . N
I
I\1 I
\%\KI
NN .'-!NN .,,rNN
I I j 1=1 1\1-/ N , I
el I\IN KIN
' , , N , , N ,, N
--!
I If N Nr NI le 'N
1=1 ''---Il I j 1=1 1\1--/
, , N -, N N
, -r -----, I
NN
, , , , N N N
. -', Ill N I NI
N Nr le . N -, N ''N
'I\1' N ,N i KI
-1\1 ' NIV I
i\INI NNI
'N i\ININ Ntej --r .
N
'-! N
I
NI,IeN N'Nre , NN
H
N .
H H , , Date Recue/Date Received 2024-03-07 _ .
H
H , H , ;
N \ 0 N,N N N_ 0\1 - -;
;
N N ' N N N

c ___________ ; ;
- _____________ - ____ -- >j // ;
N ; N
¨ \I
-, - -, Is\I / ;
' N,N N=N N,N N,N N,N
- N
; ________________________________________________ ;
N \ N \ _ __ N 1 __ \ _ N __ \ N /S: -- \ /1\1 -- \ /(1\1 -_rs/?
;
N ______________________________ N= N \ ; _______ N ___ N ;
---1 --' ;
__N _c_N N N _c N ;
- - \ 2\1 \ // Cr= r\? ___________ 14 ;
N /_N /__N ; ____N __N ;
-- --' ; ;
; ;
Date Recue/Date Received 2024-03-07 _7¨\I --\1 \N
\ __________ Ki \N
-- ,/
N __________ 1 \
or wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and R" ; and preferably with 1 to 3 of the substituents R11 ¨
R13 and the substituents R9 ¨ R14 and R" have the meanings as defined in claim 1.

3. The compound according to claim 1, wherein R2 represents RN

- r Rii 0 R8 R8 j--- -,S
- r R11 S R8 N __ -\__--R8 R10 __________ 09 9 , R10 __ R9 r ' R9 R10 RN RN RN RN RN
RN
/
R11 KI R8 R11 Ki R11 KI ii R11 Ki _ - il 8 R
1 ____________ r -1 jt1 1 ,;N
( -\_4 1 i- 1 , R9 Rlo µs ' R9 Rlo D9 Rlo , , '' , , , -... II R8 R11 0 R10 R11 0 R8 -_,sc 0 1..__.. D8 1 __ i---- / C!)NZ - R8 Rlo Rlo Rlo R8 RN RN
, , wo R11 S S il R11 N
R11 S R8 --1 R8 ---- '/N
c8 1 1 i---- \--i\I
"..".- 1=1 N

, ' RN

N R10 p10 N, pN
N' , 's -=-=- N's N N DN i1 'N-1` N\

A Ri3 rr-%) R13 N/.) R13 - - R
ir /-1 R13 \ 1 , ,,,,J _ _ \-) \Ri-)R
N Ru N R14 N R14 10 14 10 14 RN

1j 1 A p13 1\1 R13 ,7 - - 13 13 \R14 ___, 7 L j N-----\\IR
----O \T' s \R14 -"------- -'----=---\R- 14 Date Recue/Date Received 2024-03-07 RN RN RN
, ii R9 Ni ,,R9 DR:
_____________________________ S r._11R9 r I R10 _ r -1 R10 1\1_ ..../
<.õ, /---, Rio R1ON-5.) - ""\ -7---010 C)) -, " , , , , R8 R8 S,, -_NIT , , i\..../_, NI Ni i . S)- -S - - N , - N ,--R81\I il N6:
0-N R8--<1''' R8 H
N
\ \ \ N
, 6 , , , , , -CO S N S
- -d\jj 1.1 j N
i i N N
., . N N ., -Tr"------.
N - ---:..------, -=:----I N N
-1\r ------------ ' H , NH cììc:ìIìììi.
-, ' N NH
, H , N_ or , wherein the unsubstituted bicyclic residues can be substituted with 1 to 5 of the substituents R9 ¨ R14 and R" ; and preferably with 1 to 3 of the substituents R11 ¨
R13 and the substituents R9 ¨ R14 and R" have the meanings as defined in claim 1.

4. The compound according to claim 1, wherein the compound has the formula (lb) Date Recue/Date Received 2024-03-07 0 H 147 o R2"N N IN'L'R3 I
(lb) wherein L represents ¨L1¨ or _Li-.L 2-, preferably ¨L1-L2¨;
Ll represents ¨CH2¨, ¨CH2CH2¨, ¨CH2CH2CH2¨, ¨CH2C0¨, or ¨CH2CH2C0¨;
L2 represents a bond, _NRNI_, ¨NRN1CH2¨, ¨NRN1CH2CH2¨, or ¨NRN1CH(CH3)¨;
R2 represents RN
w 1 0 Ra - _ S R8 w 1 S Ra .. _ _ NI
1_ R8 \ / <
R1 o R9 9 R10 R9 /
' R9 R10 <9 RN RN RN RN
R11 ii R9 R11 ri R11 Ki Ki R11 0 R11 0 8 \ / ------N ----1 '8N
-1 t.R
i R9 R1 o ss , 1---R9 R10 R9 R10 , , , ' R10 R10 , -_, R8 ,o) Iv¨ ....

1 i----sN---R10 R9 ,C, \NI- = R9 R10 , , , , RN
RN RN
RN
S N wo,N_RN , NI R1 o NI
) ) - - _________ R9 - - _c,( =N R11 KI,N
N \-------NI
R1 o R1 o N DN ir'''''''l wa il1 R13 ri"----') wa N

' -- 'N-'` \ N
\I=N1 ------\R14 NI- R14 N =R14 NI-RN

R12 NI ._.,/ RN
0 --../,,. ._ S --,/, . _ r N/-1 R13 - - \ 1 R13 - - \ 1 R13 -- \ 1 z;T3 R13 II 9 N\-114 10 -\R14 10 -\R14 10 R14 ( R
-RN

) 13 S
TR

..,R r"--- 1R 13 N \IR14 N R14 R ._ Date Recue/Date Received 2024-03-07 RN RN
H , il R9 N -- R1()N µi 1\17--R14 N R9 \ S - 0) , , H
\ / / /--, R10 -/
rj--. R10 OQ
-------N
/
1 N ''''' / S:C -N \ 1 I\1 N ...õ...õ.1 N N , NN \N

' , ; R8 R8 S ,- , R8 N/,..Ii S - N -, .
N R
\i\I - - Sµr\i" - R81\I I N6" - R8-1\1 8 b-N
or N 5 ;,-R8--co I
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 substituted by one or more of Ra, Rb, Rc, Rd, and Re;
Ra, Rb, Rc, Rd, and Re represent independently of each other -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -0O2C21-16, -CON H2, -CONHCH3, -CON(CH3)2, -CONHC2H6, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H6, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H6, -NHCOCH3, -NHCOC21-16, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C21-16, -NHSO2CHF2, -NHSO2CF3, or -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-C31-16, -cyclo-C4H7, -cyclo-C61-16, -cyclo-C6H11, -CH2-cyclo-C3H6, -CH2-cyclo-C4H7, -CH2-cyclo-C61-16, -CH2-cyclo-C6H11, -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, Date Recue/Date Received 2024-03-07 -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, - -N - -1\( ) .
or -NR8R7 is -N(C2F13)2, - -N - -NO
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, -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, -COC(CH3)3, -COOCH3, -COOC2H3, -COOC3H7, -COOCH (CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2F-13, -502C3H7, -SO2CH (CH3)2, or -502C(CH3)3;
RN,' represent -H, -CH3, or -CH2CH3;
and R8 - R14 have the meanings as defined in 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.

5. The compound according to any one of claims 1 - 4, wherein Ll represents -CH2-, or -CH2C0-;
L2 represents a bond, -NRI41-, -NRN1CH2-, or -NRN1CH(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, Rd, and Re;
and Ra, Rb, Rc, Rd, Re and RI" have the same meanings as defined in claim 1.

6. The compound according to any one of the claims 1 - 5, wherein R2 represents _ _ r 0 R8 R11 0 R8 _ _ S R8 R11 5 R8 -R8 \ , -\__--- \ , ,,,,)-R10 __________ og , Rg R10 g ' R9 R8 \NI-= , RN RN
i i Rio Rii S II D8 il I
(<1-ZR8 _ _ R11 5 R8 - _ ISI___ R8 - - ),c ir .. - - < =N i---- i N
Rio Rio Rio Rio , ; , , ; , Date Recue/Date Received 2024-03-07 RN RN

I
R11 N N Rlo R10 ,,N RN N I\1 ---c¨N N N-' N
- - 'D s ir.<1 R13 L I,.. x j ri---'1 R14 N.

RN

R12 0 ,... I. S A r.,13 11-) R13 --V;IFR16 - -\ N \R14 \R14 - - ----1\1 N. R14 10 10 10 1\1----/') 13 '-/------- \s) NIV--R14 - - 1 \ TR ciR13 r I
s r_KIR9 N--Mv4 x) R14 R10 N ______ - \ --,----R10 : S
Ny -_ r 7_, R10 / / N----/ 10 \ I N''''''-/- -, iv 1) R8 ---, R8 S ,- 'R8 Ni----I S ,- . N - N
N R8 , -R81\1 11 Ndli - R8-1\1 R8 \N-_-- b-or and R8 ¨ R14 and R" have the meanings as defined in claim 1 or 2.

7. The compound according to any one of the claims 1 ¨ 6, wherein the compound has any one of the formulae (IV-a) ¨ (IV-o) and (V-a) ¨ (V-d):
0 .

(D)L 711-H
0 ,(1, 0 Rc H Rb R2J'L NH NH,A ,I_L2 Rb "Lr.i N -L_ . 1 N
R2 im H j\I L2 Ra Ra (IV-a) (IV-b) o 0 NI'R R6 NI' 0 :cAH 0 0 Z-LH Rb Ra R2 im 0 H H
AK' N -L_ . L A N N N L2 Rc H j\V1 2 Ra R2 H Rd Rc b (IV-d) (IV-c) Date Recue/Date Received 2024-03-07 o o N - R6 0 11R6 Rb Ra N -H Rb Ra H Rc c H
R2 N R2 N i H
Rd H
(IV-a) (IV-f) o Rd 0 Rb Ra H 0 :cA H 0 Rc R2 " H
A m N L2 R2 IN N A m N L2 N
H H
Rd (IV-g) (IV-h) o 0 ll N - R6 R6 H
Ra N -Rb H
0 Cij)-L 0 0 :c )- 0 H Rc H

R2 )- N -)-L N R2A N IncL2 H
Rd H
(IV-i) (IV+
o o f-N - :*-Q N - R6 2 0 :cA H 0 :c H
A

H H
N

R2A N A m H H
(IV-k) (IV-1) o o 0,ANFIR6 (:)).L ..R6 Nil 0 c 0 0 R2 c 0 )-LNH NH,AN .,rL2 R2)-LNH NH,AN L2 (IV-m) (IV-n) o o 0)LN FIR6 -H

R2 N H :c)-Ei 0 c N NV11-2"-R3 - -rr L2 0 I \I H

(IV-o) (V-a) Date Recue/Date Received 2024-03-07 o o o o R6 NI' H H

H H
S N)-L L2 S H L2 N AN.r ."-R3 \ , H
R1c, R1c, (V-c) (V-b) o H

N N -)-LN -R3 --/--- \

R1c, ¨
(V-d) and R2, R3; R6, R8; Rs; R10, R11, R12, R13, Ra; R13, Rc; Rd L
anCI - . 2 have the same meanings as defined in claim 1.

8. The compound according to any one of the claims 1 ¨ 7, wherein R2 represents o o o Br 0 0 0- " 0 -- CI
o qB -P---- -- Br _____________ ¨ r , Br , \ /
H2-Nrsi , S S S S
-_ Br ' Br S S ---pi, ) p _____________ y Br - - C1 r , Br Br S y S ,S a ___tr S
-- -_ -- - -. Br \ / S Br _CI \ , Br CI Br , Br , a , Me0 Br , , S
S Br N_Cl CI__ CI Br_ Br HN
NC
, --\
, , 0 õ-/ I 0 N ,-- s, H2N N M e 0 - ¨ 'C\ : l'INI - - - 2 - - ¨ ¨
(/ - - - ¨ / ) 0 --- - - i H , 0 0-- N¨

, , S...õ, st.Br st.C1 --_Br --_CI Br_ISBr --N /, , , --.1 I----CF3 S
- -.1 i___ / __ Br __ - - N S
y CI

Br Date Recue/Date Received 2024-03-07 sIra __ S ph S __ --st.OMe I H H
NI H
NI
I N N N
, \ /
0 H 'N < 'N N' N' NII--- 1_,N \/ /\\ N \\
ri \LNI )L14 \ N , N
.,NO2 .,CO2H
'--, '- 'NH yI I I
1,1=1 CO2Me -,CO2Me 1 Al (D H H
N H
N C_ -- r- -- N
--- HN --- --.._--'- : N-_\
C_2:- - --..o.--.--- ___________________________________________________________________ \ --Br'' HN--' \/ , , 0 % 0 .C-N---- 1-n_ -- \
N-=
N---- --'----LS/ \s--z--N
' , -- \ 0 ,-------r , , 0 F ' , , H \
S
S S N N
-- \ -- \ -- \
Br -- \ --- \ I
íJ
H
H N
N H S
--- __ N N
OH
---I-3k;

H N 1\r'N
-- - ! - S,õ--1 I / N ,7"TT''' 1õ-N II
NN N.. N.) ll\S-1\4 si\1=--N
S 1\l õ
...õ...___ / N ,-NI
\"\
'\ \N NI \NI N N H N

N6õ- N ,---cili 0-N , Or and Date Recue/Date Received 2024-03-07 R6 represents ¨H, ¨CH3, ¨CH(CH3)2, ¨CH2CH2CH3, ¨CH2CH=CH2, ¨CH2CH2CH2CH3, ¨CH2CH(CH3)2, ¨C(CH3)3, ¨CH2CH2CH2CH2CH3, ¨cyclo-C3H3, ¨cyclo-C31-19, ¨cyclo-C6H1 1 or ¨CH2¨cyclo-C3H3.

9. The compound according to claim 1 selected from the group consisting of:
Compound Name 11-2: (S)-2-(benzofuran-2-carboxamido)-N1 -(1 -(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 11-3: (S)-N1 -(1 -(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-yl)-N6-methyl-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-4: (S)-2-(3-chlorobenzofuran-2-carboxamido)-N1 -(1 -(242-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 11-5: (S)-2-(4-bromobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 11-6: (S)-2-(4-bromobenzofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 11-7: (S)-2-(benzo[b]thiophene-2-carboxamido)-N1 -(1 -(242-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 11-8: (S)-2-(5-bromobenzo[b]thiophene-2-carboxamido)-N1 -(1 -(242-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 11-9: (S)-2-(1H-indole-2-carboxamido)-N1 -(1 -(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 0-1 0: (S)-2-(4,5-difluoro-1H-indole-2-carboxamido)-N1 -(1 -(242-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide 0-1 1: (S)-N1 -(1 -(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-yl)-N6-methyl-2-(3-methyl-1H-indole-2-carboxamido)-5-oxohexanediamide 0-1 2: (S)-2-(1H-benzo[d]imidazole-2-carboxamido)-N1 -(1 -(242-adamantylamino)-2-oxoethyl)-2-oxo-1 ,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide Date Recue/Date Received 2024-03-07 11-1 3: (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 11-1 4: (S)--(2-bromo-4-methylthiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-1 5: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide 11-1 6: (S)-2-(4-bromo-2-(trifluoromethyl)thiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-1 7: (S)-2-(2,4-dichlorothiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-1 8: (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 11-1 9: (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 11-20: (S)-2-(2,4-dimethylthiazole-5-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-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 Date Recue/Date Received 2024-03-07 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 11-38: (S)-2-(4,5-dimethylthiazole-2-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 11-39: (S)-2-(4-bromothiazole-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-40: (S)-2-(4-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-41: (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 11-42: (S)-2-(3-bromothiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-43: (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 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-dibromo-3-methoxythiophene-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-47: (S)-2-(4-bromofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-48: (S)-2-(4,5-dibromofuran-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-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-acetylpyrrolidine-2-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11-51: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide Date Recue/Date Received 2024-03-07 11-52: (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 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-dihydropyridin-3-y1)-N6-methy1-24(S)-1-methylpyrrolidine-2-carboxamido)-5-oxohexanediamide 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)-2-((25,45)-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-dihydropyridin-3-y1)-N6-methy1-5-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 11-66: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(6-methylimidazo[2,1-b]thiazole-5-Date Recue/Date Received 2024-03-07 carboxamido)-5-oxohexanediamide 11-67: (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 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 11-74: (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 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-adamantyl)ethanamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-90: (S)-N1-(1-(2-((1R,25,45)-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-24(1S,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide 11-94: (S)-N1-(1-(2-((1R,2R,45)-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-ylam ino)-2-oxoethyl)-2-oxo-1,2-Date Recue/Date Received 2024-03-07 dihydropyridin-3-y1)-N6-methy1-2-(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-oxohexanediamide 11-98: (25)-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 11-99: (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-y1)hexanediamide 11-100: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-24(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide 11-101: (S)-N1-methy1-5-(3-methylbenzofuran-2-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-24(1S,25,35,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide 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)-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-108: (25)-N1-(14(3-hydroxy-1-adamantyl)methyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 0-109: (25)-N1-(14(3-bromo-1-adamantyl)methyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-110: (S)-N1-(1-(2-adamantylmethyl)-2-oxo-1,2-dihydropyridin-3-y1)-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide 11-111: (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(nicotinam ido)-5-Date Recue/Date Received 2024-03-07 oxohexanediamide 11-112: (S)-2-(isonicotinamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 8-113: (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 8-115: (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 8-117: (S)-N1-allyl-N6-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-(3-methylbenzofuran-2-carboxamido)-2-oxohexanediamide 8-118: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-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 11-122: (S)-2-(benzofuran-2-carboxamido)-N141-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxo-N6-phenylhexanediamide 11-123: (S)-2-(benzofuran-2-carboxamido)-N6-benzyl-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-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide 11-125: (S)-2-(2,5-dichlorothiophene-3-carboxamido)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide Date Recue/Date Received 2024-03-07 11-126: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide 11-127: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide 11-128: (25)-N1-(1-(2-((1R,2R,45)-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 11-129: (25)-N1-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(4-methyl-2-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide 11-130: (25)-N1-(1-(2-((1R,2R,45)-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 11-1 31 : (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 11-132: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1H-1,2,3-triazole-4-carboxamido)hexanediamide 11-133: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,3-triazole-4-carboxamido)-5-oxohexanediamide 11-134: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1H-1,2,4-triazole-3-carboxamido)hexanediamide 11-1 35: (S)-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-1,2,4-triazole-3-carboxamido)-5-oxohexanediamide 11-1 36: (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 (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-1 38 dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-3-carboxamido)-5-oxohexanediamide 11 39 (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-4-Date Recue/Date Received 2024-03-07 carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-140 dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-141 dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-142 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,5-thiadiazole-3-carboxamido)hexanediamide (S)-2-(4-iodo-1-methy1-1H-pyrazole-5-carboxamido)-N1-(1-(2-(2-11-143 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-144 dihydropyridin-3-y1)-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-11-145 dihydropyridin-3-y1)-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-((1R,2R,45)-11-146 bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-147 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-carboxamido)-5-oxohexanediamide (S)-2-(benzofuran-2-carboxamido)-N1-(1-(2-((1S,2R,4R)-11-148 bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-149 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(3-methylbenzofuran-carboxamido)-5-oxohexanediamide (S)-2-(benzofuran-2-carboxamido)-5-oxo-N1-(2-oxo-1-(2-oxo-2-11-150 ((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-yl)hexanediamide (S)-2-(3-methylbenzofuran-2-carboxamido)-5-oxo-N1-(2-oxo-1-(2-11-151 oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide (S)-N1-(1-(2-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-152 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide 11-153 (S)-N1-(1-(2-((1R,2R,45)-bicyclo[2.2.1]heptan-2-ylamino)-2-Date Recue/Date Received 2024-03-07 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1H-pyrazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-154 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-(trifluoromethyl)thiazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-155 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(2,5-dichlorothiophene-3-carboxamido)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-156 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-157 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-1,2,3-triazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylam ino)-2-11-158 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(1-methy1-pyrazole-5-carboxamido)-5-oxohexanediamide (S)-N1-methy1-5-(4-methy1-2-(trifluoromethyl)thiazole-5-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-11-159 trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide (S)-2-(2,5-dichlorothiophene-3-carboxam ido)-N6-methy1-5-oxo-N1-11-160 (2-oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide (S)-N1-methy1-5-(4-methy1-1,2,3-thiadiazole-5-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-11-161 trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide (S)-N1-methy1-5-(1-methy1-1H-1,2,3-triazole-5-carboxamido)-2-oxo-N6-(2-oxo-1-(2-oxo-2-((1R,2S,4R)-1,7,7-11-162 trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide (S)-N1-methy1-5-(1-methy1-1H-pyrazole-5-carboxamido)-2-oxo-N6-11-163 (2-oxo-1-(2-oxo-2-((1R,25,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)ethyl)-1,2-dihydropyridin-3-y1)hexanediamide (25)-244-ten-butyl-I H-pyrrole-3-carboxamido)-N6-methyl-N1-(1-(2-11-164 (1-adamantylamino)ethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (25)-2-(4-cyano-1-methy1-1H-pyrrole-2-carboxam ido)-N6-methyl-N1-11-165 (1-(3-(1-adamantylamino)propy1)-2-oxo-1,2-dihydropyridin-3-y1)-oxohexanediamide Date Recue/Date Received 2024-03-07 (S)-N1-(1-(3-(2-adamantylam ino)-3-oxopropy1)-2-oxo-1,2-11-166 dihydropyridin-3-y1)-2-(5-methoxyoxazole-2-carboxamido)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-167 dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide (S)-2-(2-acetyloxazole-4-carboxamido)-N1-(1-(2-11-168 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-169 dihydropyridin-3-y1)-N6-methy1-2-(3-methylbenzofuran-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-170 dihydropyridin-3-y1)-2-(2-isopropyloxazole-5-carboxamido)-N6-methy1-5-oxohexanediamide (25)-2-(benzofuran-2-carboxamido)-N1-(1-(2-(bicyclo[3.2.1]octan-8-11-171 ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (25)-N1-(1-(2-(bicyclo[3.2.1]octan-8-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-172 dihydropyridin-3-y1)-2-(3,5-dimethylisoxazole-4-carboxamido)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(5-carboxy-2-aminoadamantane)-2-oxoethyl)-2-oxo-11-173 1,2-dihydropyridin-3-y1)-N6-methy1-2-(4-methylpyrimidine-5-carboxamido)-5-oxohexanediamide (25)-N1-(1-(2-(4-aminoadamantane-N,N-dimethy1-1-carboxamide)-2-11-174 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,3,4-tetrahydronaphthalene-2-carboxamido)hexanediamide (S)-2-((S)-1,4-diazabicyclo[2.2.2]octane-2-carboxamido)-N6-tert-11-175 butyl-N1-(1-(2-(2-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-5-oxohexanediamide (S)-N1-tert-buty1-5-(1H-indole-3-carboxam ido)-N6-(1-(2-(2-11-176 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-oxohexanediamide (S)-N1-tert-butyl-N6-(1-(2-(2-adamantylam ino)-2-oxoethyl)-2-oxo-11-177 1,2-dihydropyridin-3-y1)-5-(6-methylimidazo[2,1-b]thiazole-3-carboxamido)-2-oxohexanediamide (S)-2-(benzo[d]thiazole-2-carboxamido)-N1-(1-(2-((1S,2R,4R)-11-178 bicyclo[2.2.1]heptan-2-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopentyl-5-oxohexanediamide 11 179 (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1Theptan-2-ylamino)-2--oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopenty1-2-Date Recue/Date Received 2024-03-07 (imidazo[2,1-b]thiazole-6-carboxamido)-5-oxohexanediamide (S)-N1-(1-(24(1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylamino)-2-11 180 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-cyclopenty1-2-(4--hydroxy-6-(trifluoromethoxy)quinoline-3-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-181 dihydropyridin-3-y1)-2-(cinnoline-3-carboxamido)-N6-cyclohexy1-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-182 dihydropyridin-3-y1)-N6-cyclohexy1-2-(3-ethylbenzofuran-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-183 dihydropyridin-3-y1)-N6-cyclohexy1-2-(1-ethy1-1H-indole-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-184 dihydropyridin-3-y1)-N6-cyclohexy1-2-(2-methy1-1,8-naphthyridine-3-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-185 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,3,4-tetrahydroquinoline-6-carboxamido)hexanediamide (S)-N1-(1-(2-(2-carboxy-2-amino-5-(trifluoromethyl)adamantane)-2-11-186 oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)hexanediamide (S)-N1-(1-(2-(5-ethyladamantane-2-amino)-2-oxoethyl)-2-oxo-1,2-11-187 dihydropyridin-3-y1)-N6-methy1-2-(1,6-naphthyridine-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[2.1.1]hexan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-188 dihydropyridin-3-y1)-N6-methy1-2-(2,6-naphthyridine-1-carboxamido)-5-oxohexanediamide (S)-2-(4-amino-1,2,5-oxadiazole-3-carboxamido)-N1-(1-(2-11-189 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-190 dihydropyridin-3-y1)-2-(6-(dimethylamino)benzofuran-2-carboxamido)-N6-methy1-5-oxohexanediamide (S)-2-(2-acetam idothiazole-5-carboxamido)-N1-(1-(2-11-191 (bicyclo[1.1.1]pentan-1-ylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N4-(1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-11-192 1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-y1)-1H-pyrrole-2,4-dicarboxamide Date Recue/Date Received 2024-03-07 (S)-N1-(1-(2-(1-acetylam ino-4-aminoadamantane)-2-oxoethyl)-2-11-193 oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(5-sulfamoylfuran-3-carboxamido)hexanediamide (S)-2-(benzofuran-5-carboxamido)-N1-(1-(2-(1-acetylam ino-4-11-194 aminoadamantane)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-2-(benzofuran-6-carboxamido)-N1-(1-(2-(4-aminoadamantane-1-11-195 carboxamide)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-N1-(1-(2-(4-aminoadamantane-1-carboxamide)-2-oxoethyl)-2-11-196 oxo-1,2-dihydropyridin-3-y1)-N6-methy1-2-(3-(1-methylcyclopropy1)-1,2,4-oxadiazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-197 dihydropyridin-3-y1)-N6-methy1-2-(5-methy1-1,2,4-oxadiazole-3-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-198 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,3-thiadiazole-4-carboxamido)hexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-199 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,2,4-thiadiazole-5-carboxamido)hexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-200 dihydropyridin-3-y1)-N6-methy1-5-oxo-2-(1,3,4-thiadiazole-2-carboxamido)hexanediamide (S)-N1-(1-(2-(bicyclo[1.1.1]pentan-1-ylam ino)-2-oxoethyl)-2-oxo-1,2-11-201 dihydropyridin-3-y1)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N6-methy1-5-oxohexanediamide (S)-2-(4-cyclopropy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-11-202 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-2-(4-isopropy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-11-203 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-2-(4-ethy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-11-204 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide (S)-2-(4-formy1-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2-(2-11-206 adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methy1-5-oxohexanediamide 11 206 (S)-2-(4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxamido)-N1-(1-(2--(2-adamantylam ino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-Date Recue/Date Received 2024-03-07 methy1-5-oxohexanediamide (S)-N1-(1-(2-(1-adamantylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-11-207 y1)-N6-methy1-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(((1S,2R,55)-6,6-dimethylbicyclo[3.1.1Theptan-2-11-208 yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-N6-methyl-2-(1-methyl-1H-imidazole-2-carboxamido)-5-oxohexanediamide (S)-N1-(1-(2-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1Theptan-2-11-209 yl)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-y1)-2-(1H-imidazole-4-carboxamido)-N6-methyl-5-oxohexanediamide (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.

10. A pharmaceutical composition comprising a compound of any one of the claims 1 ¨ 9 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluent.

11. Compound according to any one of the claims 1 ¨ 9 for use in medicine.

12. Compound according to any one of the claims 1 ¨ 9 or the pharmaceutical composition according to claim 9 for use 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.

13. Compound for use, or the pharmaceutical composition for use according to claim 12, wherein the autoimmune and inflammatory diseases comprise multiple sclerosis, celiac disease, Duhring-Brocq-disease (dermatitis herpetiform is), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus psoriasis, and gingivitis; wherein the vascular diseases comprise atherosclerosis, thrombosis, vascular stiffness;
wherein the fibrotic diseases affect 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; wherein the liver diseases comprise alcoholic hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, non-alcoholic fatty Date Recue/Date Received 2024-03-07 liver disease, liver cirrhosis, autoimmune hepatitis or liver inflammation;
wherein the cholestatic liver diseases comprise primary biliary cholangitis and primary sclerosing cholangitis; wherein the cancer comprises glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, wherein the neurodegenerative diseases comprise Parkinson's disease, Huntington's disease, or Alzheimer's disease, wherein the ocular diseases comprise glaucoma, cataracts, macular degeneration, or uveitis; and wherein the skin disorders comprise acne, psoriasis, scarring, and skin aging.

14. Compound for use, or the pharmaceutical composition for use according to any one of the claims 12 and 13 in the treatment or prophylaxis of celiac disease.

15. A method for producing the compound of formula (lb) according to claim 1 or 3 comprising:
Step 1B: providing a compound 4b Ac0JJNR6 -N
H
o 4b;
Step 2B: performing coupling reaction of the compound 4b with a compound 5 o to obtain a compound 6b Ac0 N_ R6 H
PG3 N N N - L 'R3 -H
6b;
Step 3B: deprotecting an amino protecting group PG3to obtain a compound 7b Date Recue/Date Received 2024-03-07 o Ac0 N _ R6 lie 0 H
N IVL'R3 H2N
7b;
Step 4B: performing coupling reaction of the compound 7b with a carboxylic acid (R2-CO2H 8) to obtain a compound 9b Ac0 N , R6 0 iie 0 H
R2-LN NN-L'R3 H
9b;
Step 5B: performing oxidation reaction of the compound 9b to produce the compound of the formula (lb) o o H
R2 A N NN -L'R3 H (lb);
wherein L, R2, R3, R6and R7 have the same meanings as defined in claim 1, and PG3 is an amino protecting group.
Date Recue/Date Received 2024-03-07