Macrocycles as inhibitors of proteasome subunit beta type 5

Abstract

The present invention relates to certain macrocyclic compounds of formula (I) and pharma- ceutically acceptable salts thereof, which are useful for the treatment or prevention of diseases associated with and / or caused by the proteasome or immunoproteasome, selected from cancer, infectious diseases, inflammatory diseases, and autoimmune diseases. [Formula 1] TIFF2024534613001006.tif71170

Description

Detailed Description of the Invention

[0001] The present invention relates to certain macrocyclic compounds of formula (I) and pharmaceutically acceptable salts thereof, which are useful for the treatment or prevention of diseases treatable by proteasome inhibition, selected from cancer, infectious diseases, inflammatory diseases, and autoimmune diseases.

[0002] [ka]

[0003] [Background of the invention] The proteasome is a multicatalytic proteinase complex with a highly regular, ring-shaped 20S core structure. The core structure is composed of four rings of 28 distinct subunits, two rings composed of seven alpha subunits, and two rings composed of seven beta subunits. Proteasomes are distributed throughout eukaryotic cells at high concentrations and cleave peptides in an ATP / ubiquitin-dependent process via a non-lysosomal pathway. There are two isoforms of the proteasome: the constitutive proteasome and the immunoproteasome, which is constitutively expressed in hematopoietic cells and can be induced in non-immune cells by inflammatory cytokines or oxidative stress. Both are distinct in their subunit composition. The constitutive proteasome has three subunits with chymotrypsin-like (beta5), caspase-like (beta1), and trypsin-like (beta2) enzymatic activities. In the immunoproteasome, these subunits are replaced by the beta5i, beta1i, and beta2i catalytic subunits, which have different substrate selectivity and increased proteolytic activity compared to their constitutive counterparts. An essential function of the immunoproteasome is the processing of class I MHC peptides for antigen presentation.

[0004] The proteasome forms a crucial component of the ubiquitin-proteasome system (UPS) and the corresponding cellular protein quality control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction, and apoptosis.

[0005] The proteasome plays a central role in the cellular protein degradation pathway. Protein degradation is particularly important in cancer cells, which have high protein turnover, and high protein turnover is usually associated with the formation of misfolded proteins. Inhibition of the proteasome in these cells leads to the accumulation of misfolded proteins, which activate the caspase cascade and thus contribute to apoptosis. Another event induced by proteasome inhibition that contributes to cell death is the inhibition of the pro-survival NFkB pathway and the induction of pro-apoptotic proteins. Therefore, proteasome inhibition leads to apoptosis in cells with high protein turnover, such as tumor cells and myeloma cells. Furthermore, plasma cells, which have high protein turnover due to repeated antibody secretion, are sensitive to proteasome inhibition. Therefore, proteasome inhibition has been shown to have a significant impact on autoantibody-mediated autoimmune diseases such as systemic lupus erythematosus (SLE) and myasthenia gravis (MG). Because proteasome inhibitors are effective in targeting antibody-producing B cells, they are also being evaluated as a treatment for antibody-mediated allograft rejection. Inhibition of the protozoan proteasome by proteasome inhibitors has been shown to be effective in treating malaria by selectively killing Plasmodium falciparum while sparing human cells. Furthermore, proteasome inhibitors have shown potential as antibiotics against, for example, Mycobacterium tuberculosis.

[0006] The object of the present invention is to provide novel compounds and / or pharmaceutically acceptable salts thereof as proteasome subunit beta5 inhibitors, as well as compositions containing at least one of these compounds and / or pharmaceutically acceptable salts thereof as a pharmaceutically active substance. The novel compounds and / or pharmaceutically acceptable salts thereof as proteasome subunit beta5 inhibitors can be used as pharmaceutically active agents, particularly for the prevention and / or treatment of diseases associated with and / or caused by proteasome subunit beta5, selected from cancer, neurodegenerative diseases, infectious diseases, and inflammatory diseases. The object of the present invention is solved by the teachings of the independent claims. Further advantageous features, aspects, and details of the present invention are apparent from the dependent claims, the description, and the examples of the present application.

[0007] [Description of the Invention] The present invention relates to compounds of general formula (I) or to the enantiomers, stereoisomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, hydrates, solvates, acid salt forms, tautomers, racemates or pharmaceutically acceptable salts thereof of said compounds,

[0008] [ka]

[0009] During the ceremony, A is -CO-N(R N6 )―,

[0010] [ka] , represents;

[0011] B is -H, -NH(R 2 ), -N(R 2 )(RN 5 ),

[0012] [ka] represents;

[0013] L is -CO-, -CO-NH-, -CO-N(R N3 )- or -CO-O-; R 1 -H, -(CH2) p -R 7 , -(CH2) p -NH-R 7 , -(CH2) p -R 9 , or -(CH2) p -NR N4 -R 9 represents; R 2 -H, -R 8 , -R 11 , -L 1 -R 11 , -L 1 -(CH2) r -R 8 , -L 1 -R 10 , -L 1 -(C2H4O) s -R 11 , -L 1 -(CH2) t -OR 11 , -L 1 -(CH2) t -NH-(CH2) r -R 8 , -L 1 -(CH2) t -O-(CH2) r -R 8 , -L 1 -(CH2) t -NHR 8 , -L 1 -(CH2) t -NH-CO-R 8 , -L 1 -(CH2) t -NH-SO2-R 8 , -L 1 -(CH2) t -NR N6 R 10 , -L 1-(CH2) t -O-(CH2) u -NR N6 R 10 , -L 1 -(CH2) r -R 14 , -CO-C(R 12 )(R 13 )-R 10 , -CO-C(R 12 )(R 13 )-R 8 , or -CO-C(R 12 )(R 13 )-(CH2) u -R 8 represents; L 1 represents a bond, -CO-, -CO2-, -CONH-, or -SO2-; R 3 ~R 6 represent, independently of each other, -H, -CH3, -OCH3, -F, or -Cl; Or, R 5 and R 6 together

[0014] [ka] Forming;

[0015] R 8 and R 9 are independent of each other. C6~C 14 Aryl, C1-C 10 Heteroaryl, C3-C8 carbocyclyl, C1-C9 heterocyclyl, C4-C 11 Bicyclic carbocyclyl, C4-C 11 Bridged Carbocyclyl, C1-C 10 Bicyclic heterocyclyl, C1-C 10 Bridged heterocyclyl, C7-C 16 -Spiroalkyl, C5-C 14 -spiroheterocyclyl, wherein all the aforementioned ring systems are Z 1 , Z 2 , Z 3, Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , Z 10 , Z 11 , Z 12 , R N1 and R N2 and C1~C 10 Heteroaryl, C1-C9 heterocyclyl, C1-C 10 Bicyclic heterocyclyl, C1-C 10 Bridged Heterocyclyl, C5-C 14 - the spiroheterocyclyl ring system contains at least one heteroatom N, O, and S; The C3-C8 carbocyclyl, C1-C9 heterocyclyl, C1-C 10 Bicyclic heterocyclyl, C4-C 11 Bridged Carbocyclyl, C1-C 10 Bicyclic heterocyclyl, C1-C 10 Bridged heterocyclyl, C7-C 16 -Spiroalkyl, C5-C 14 - the spiroheterocyclyl ring system can be partially saturated or unsaturated; R 7 and R 10 are each independently -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CN, -C(CH3)2-CN, -CH2-C(CH3)2-CN, -CH2-CF3, -CH2-C(CH3)2-NH2,

[0016] [ka] , cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H 11 , cyclo-CH 13 , -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H 11, -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C6H 13 , -C7H 15 , -C8H 17 , -Ph, -CH2-Ph, -CH2-CH2-Ph, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH2, -C(CH3)=CH-CH3, -CH2-CH=C(CH3)2, -CO-CH=C(CH3)2, -CH2-C≡CH, -C2H4-C≡CH, -CH2-C≡C-CH3, -CH2-OCF3, -C2H4-OCF3, -C3H6-OCF3, -CH2-OCHF2, -C2H4-OCHF2, -C3H6-OCHF2, -CH2-OCH3, -C2H4-OCH3, -C3H6-OCH3, -CH2-OC2H5, -C2H4-OC2H5, -C3H6-OC2H5, -CH2-OH, -C2H4-OH, -C3H6-OH, -CH2-COOH, -C2H4-COOH, -C3H6-COOH, -C(CH3)2-CN, -C(CH3)2-OH, -C(CH3)2-CH2-OH, -C(C2H5)2-CH2-OH, -C(CH2-OH)2-CH3, -C(CH2-OH)2-C2H5, -C(CH3)2-CH2-SH, -C(C2H5)2-CH2-SH, -C(CH2-SH)2-CH3, -CO-O-C(CH3)3, or -C(CH2-SH)2-C2H5;

[0017] R 11 is -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CN, -C(CH3)2-CN, -CH2-C(CH3)2-CN, -CH2-CF3, -CH2-C(CH3)2-NH2,

[0018]

Chem.

[0019] R 12 and R 13represent, independently of one another, -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -Ph, -CH2-Ph, -COOH, -NH2, -NHCO2(CCH3)3, -CH2-NH2, -CHF2, -F, -CF3, -OCF3, -OCHF2, -OH, -OCH3, -OC2H5, -OC3H7, and -OCH(CH3)2; or R 12 and R 13 together

[0020] [ka] may be formed;

[0021] R 14 teeth,

[0022] [ka] represents;

[0023] R 15 and R 16 are independent of each other, -X 3 -L 2 -R 17 , or -(OCH2CH2) w -R 17 represents; L 2 is -(CH2) v -, -(CH2CH2-O) w -CH2-, or -(CH2CH2-O) w represents -CH2CH2-; R 17 represents -OH, -SH, -SO3H, -NH2, or -CO2H; R N1 , R N2 , R N3 , and R N4 are, independently of each other, -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CHF2, -CF3,

[0024] [ka] , cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H 11 , cyclo-CH 13 , -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H 11 , -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C6H 13 , -CH 15 , -CH 17 , -Ph, -CH2-Ph, -CH2-CH2-Ph, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH2, -CH2-CH=C(CH3)2, -CH2-C≡CH, - C2H4-C≡CH, -CH2-C≡C-CH3, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7 , -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH 3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO3H, or -R 15 represents;

[0025] R N5 and R N6 represent, independently of one another, -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, cyclo-C3H5, -COOC(CH3)3, or -COOCH2Ph; X 1 is -(CH2) m - represents; X 2 is -(CH2) n - represents; X3 represents a bond, -O-, -NH-, or -S-; Z 1 ~Z 14 are independent of each other,

[0026] [ka] , cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H 11 , cyclo-CH 13 , -R 16 , -H, -OH, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -O-cyclo-C4H7, -O-cyclo-C5H9, -O-cyclo-C6H 11 , -OCH2CH(CH3)2, -OCH2-cyclo-C3H5, -OCH2-cyclo-C4H7, -OCH2-cyclo-C5H9, -OCH2-cyclo-C6H 11、-OPh、-OCH2-Ph、-OCPh3、-CH2-OCH3、-C2H4-OCH3、-C3H6-OCH3、-CH2-OC2 H5、-C2H4-OC2H5、-C3H6-OC2H5、-CH2-OC3H7、-C2H4-OC3H7、-C3H6-OC3H7、 -CH2-O-シクロ-C3H5、-C2H4-O-シクロ-C3H5、-C3H6-O-シクロ-C3H5、-CH2-OCH(CH3 )2、-C2H4-OCH(CH3)2、-C3H6-OCH(CH3)2、-CH2-OC(CH3)3、-C2H4-OC(CH3)3 、-C3H6-OC(CH3)3、-CH2-OC4H9、-C2H4-OC4H9、-C3H6-OC4H9、-CH2-OPh、-C 2H4-OPh、-C3H6-OPh、-CH2-OCH2-Ph、-C2H4-OCH2-Ph、-C3H6-OCH2-Ph、-SH 、-SCH3、-SC2H5、-SC3H7、-S-シクロ-C3H5、-SCH(CH3)2、-SC(CH3)3、-F、-Cl、-Br、-I、-CN、-COCH3、-COC2H5、-COC3H7、-CO-シクロ-C3H5、-COCH(CH3)2、-COC( CH3)3、-COOH、-COOCH3、-COOC2H5、-COOC3H7、-COO-シクロ-C3H5、-COOCH(CH3 )2、-COOC(CH3)3、-OOC-CH3、-OOC-C2H5、-OOC-C3H7、-OOC-シクロ-C3H5、-OOC -CH(CH3)2、-OOC-C(CH3)3、-CONH2、-CONHCH3、-CONHC2H5、-CONHC3H7、-CONH-シクロ-C3H5、-CONH[CH(CH3)2]、-CONH[C(CH3)3]、-CON(CH3)2、-CON(C2H5 )2、-CON(C3H7)2、-CON(シクロ-C3H5)2、-CON[CH(CH3)2]2、-CON[C(CH3)3]2、 -NHCOCH3、-NHCOC2H5、-NHCOC3H7、-NHCO-シクロ-C3H5、-NHCO-CH(CH3)2、-NHC O-C(CH3)3、-NHCO-CH(NH2)CH2-COOH、-NHCO-CH(NH2)CH2CH2-COOH、-NHCO-OCH3、-NHCO-OC2H5、-NHCO-OC3H7、-NHCO-O-シクロ-C3H5、-NHCO-OCH(CH3)2、-NHCO-OC(CH3)3、-NH2、-NHCH3、-NHC2H5、-NHC3H7、-NH-シクロ-C3H5、-NHCH(CH3)2、-NHC(CH3)3、-N(CH3)2、-N(C2H5)2、-N(C3H7)2、-N(シクロ-C3H5)2、-N [CH(CH3)2]2、-N[C(CH3)3]2、-SOCH3、-SOC2H5、-SOC3H7、-SO-シクロ-C3H5、-SOCH(CH3)2、-SOC(CH3)3、-SO2CH3、-SO2C2H5、-SO2C3H7、-SO2-シクロ-C3H5、 -SO2CH(CH3)2、-SO2C(CH3)3、-SO3H、-SO3CH3、-SO3C2H5、-SO3C3H7、-SO3-シクロ-C3H5、-SO3CH(CH3)2、-SO3C(CH3)3、-SO2NH2、-SO2NHCH3、-SO2NHC2H5 、-SO2NHC3H7、-SO2NH-シクロ-C3H5、-SO2NHCH(CH3)2、-SO2NHC(CH3)3、-SO2N (CH3)2、-SO2N(C2H5)2、-SO2N(C3H7)2、-SO2N(シクロ-C3H5)2、-SO2N[CH(CH3) 2]2、-SO2N[C(CH3)3]2、-OS(=O)CH3、-OS(=O)C2H5、-OS(=O)C3H7、-OS(=O) -シクロ-C3H5、-OS(=O)CH(CH3)2、-OS(=O)C(CH3)3、-S(=O)(=NH)CH3、-S(=O) (=NH)C2H5、-S(=O)(=NH)C3H7、-S(=O)(=NH)-シクロ-C3H5、-S(=O)(=NH)CH(CH3)2、-S(=O)(=NH)C(CH3)3、-NH-SO2-CH3、-NH-SO2-C2H5、-NH-SO2-C3H7、 -NH-SO2-シクロ-C3H5、-NH-SO2-CH(CH3)2、-NH-SO2-C(CH3)3、-O-SO2-CH3、-O-SO2-C2H5、-O-SO2-C3H7、-O-SO2-シクロ-C3H5、-O-SO2-CH(CH3)2、-O-SO2- C(CH3)3、-OCH2F、-OCHF2、-OCF3、-CH2-OCF3、-C2H4-OCF3、-C3H6-OCF3、-C H2-OCHF2、-C2H4-OCHF2、-C3H6-OCHF2、-OC2F5、-CH2-OC2F5、-C2H4-OC2F5、-C3H6-OC2F5、-O-COOCH3、-O-COOC2H5、-O-COOC3H7、-O-COO-シクロ-C3H5、-O-COOCH(CH3)2、-O-COOC(CH3)3、-NH-CO-NH2、-NH-CO-NHCH3、-NH-CO-NHC2H5、-NH-CO-NHC3H7、-N H-C(=NH)-NH2、-NH-CO-N(C3H7)2、-NH-CO-NH[CH(CH3)2]、-NH-CO-NH[C(CH3)3]、-NH-CO-N(CH3)2、-NH-CO-N(C2H5)2、-NH-CO-NH-シクロ-C3H5、-NH-CO-N(シクロ-C3H5)2、-NH-C、 ON[CH(CH3)2]2、-NH-C(=NH)-NHCH3、-NH-C(=NH)-NHC2H5、-NH-C(=NH)-NHC3H7、-O-CO-NH--C3H5、-NH-C(=NH)-NH--C3H5、-NH-C(=NH)-NH--C3H5、-NH-C(=NH)-NH[CH(CH3)2]、-O-CO-NH[CH(CH3)2]、 -NH-C(=NH)-NH[C(CH3)3]、-NH-C(=NH)-N(CH3)2、-NH-C(=NH)-N(C2H5)2、-NH-C(=NH)-N(C3H7)2、-NH-C(=NH)-N(C3H5)2、-O-CO-NHC3H7、-NH-C(=NH)-N[CH(CH3)2]2、-NH-C(=NH )-N[C(CH3)3]2、-O-CO-NH2、-O-CO-NHCH3、-O-CO-NHC2H5、-O-CO-NH[C(CH3)3]、-O-CO-N( CH3)2、-O-CO-N(C2H5)2、-O-CO-N(C3H7)2、-O-CO-N(シクロ-C3H5)2、-O-CO-N[CH(CH3)2]2、-O -CO-N[C(CH3)3]2、-O-CO-OCH3、-O-CO-OC2H5、-O-CO-OC3H7、-O-CO-O-シクロ-C3H5、-O-CO-OC H(CH3)2、-O-CO-OC(CH3)3、-CH2F、-CHF2、-CF3、-CH2-CH2F、-CH2-CHF2、-CH2-CF3、シクロ-C8H 15、-Ph、-CH2-Ph、-CH2-CH2-Ph、-CH=CH-Ph、-CPh3、-CH3、-C2H5、-C3H7、-CH(CH3)2、-C4H9、-CH2-CH(CH3)2、-CH(CH3)-C2H5、-C(CH3)3、-C5H 11 、-CH(CH3)-C3H7、-CH2-CH(CH3)-C2H5、-CH(CH3)-CH(CH3)2、-C(CH3)2-C2H5、-CH2-C(CH3)3、-CH(C2H5)2、-C2H4-CH(CH3)2、-C6H 13 、-C7H 15 、-C8H 17、-C3H6-CH(CH3)2、-C2H4-CH(CH3)-C2H5、-CH(CH3)-C4H9、-CH2-CH(CH3)-C3H7、-CH(CH3)-CH2-CH(CH3)2、-CH(CH3)-CH(CH3)-C2H5、-CH2-CH(CH3)-CH(CH3)2、-CH2-C(CH3)2-C2H5、-C(CH3)2-C3H7、-C(CH3)2-CH(CH3)2、-C2H4-C(CH3)3、-CH(CH3)-C(CH3)3、-CH=CH2、-CH2-CH=CH2、-C(CH3)=CH2、-CH=CH-CH3、-C2H4-CH=CH2、-CH2-CH=CH-CH3、-CH=CH-C2H5、-CH2-C(CH3)=CH2、-CH(CH3)-CH=CH、-CH=C(CH3)2、-C(CH3)=CH-CH3、-CH=CH-CH=CH2、-C3H6-CH=CH2、-C2H4-CH=CH-CH3、-CH2-CH=CH-C2H5、-CH=CH-C3H7、-CH=CH-CH=CH-CH3、-C2H4-C(CH3)=CH2、-CH2-CH(CH3)-CH=CH2、-CH(CH3)-CH2-CH=CH2、-CH2-CH=C(CH3)2、-CH2-C(CH3)=CH-CH3、-CH(CH3)-CH=CH-CH3、-CH=CH-CH(CH3)2、-CH=C(CH3)-C2H5、-C(CH3)=CH-C2H5、-C(CH3)=C(CH3)2、-C(CH3)2-CH=CH2、-CH(CH3)-C(CH3)=CH2、-C4H8-CH=CH2、-C3H6-CH=CH-CH3、-C2H4-CH=CH-C2H5、-CH2-CH=CH-C3H7、-CH=CH-C4H9、-C3H6-C(CH3)=CH2、-C2H4-CH(CH3)-CH=CH2、-CH2-CH(CH3)-CH2-CH=CH2、-C2H4-CH=C(CH3)2、-CH(CH3)-C2H4-CH=CH2、-C2H4-C(CH3)=CH-CH3、-CH2-CH(CH3)-CH=CH-CH3、-CH(CH3)-CH2-CH=CH-CH3、-CH2-CH=CH-CH(CH3)2、-CH2-CH=C(CH3)-C2H5、-CH2-C(CH3)=CH-C2H5、-CH(CH3)-CH=CH-C2H5、-CH=CH-CH2-CH(CH3)2、-CH=CH-CH(CH3)-C2H5、-CH=C(CH3)-C3H7、-C(CH3)=CH-C3H7、-CH2-CH(CH3)-C(CH3)=CH2、-C[C(CH3)3]=CH2、-CH(CH3)-CH2-C(CH3)=CH2、-CH(CH3)-CH(CH3)-CH=CH2、-CH=CH-C2H4-CH=CH2、-C(CH3)2-CH2-CH=CH2、-CH2-C(CH3)=C(CH3)2、-CH(CH3)-CH=C(CH3)2、-C(CH3)2-CH=CH-CH3、-CH=CH-CH2-CH=CH-CH3、-CH(CH3)-C(CH3)=CH-CH3、-CH=C(CH3)-CH(CH3)2、-C(CH3)=CH-CH(CH3)2、-C(CH3)=C(CH3)-C2H5、-CH=CH-C(CH3)3、-C(CH3)2-C(CH3)=CH2、-CH(C2H5)-C(CH3)=CH2、-C(CH3)(C2H5)-CH=CH2、-CH(CH3)-C(C2H5)=CH2、-CH2-C(C3H7)=CH2、-CH2-C(C2H5)=CH-CH3、-CH(C2H5)-CH=CH-CH3、-C(C4H9)=CH2、-C(C3H7)=CH-CH3、-C(C2H5)=CH-C2H5、-C(C2H5)=C(CH3)2、-C[CH(CH3)(C2H5)]=CH2、-C[CH2-CH(CH3)2]=CH2、-C2H4-CH=CH-CH=CH2、-CH2-CH=CH-CH2-CH=CH2、-C3H6-C≡C-CH3、-CH2-CH=CH-CH=CH-CH3、-CH=CH-CH=CH-C2H5、-CH(CH3)-CH2-C≡CH、-CH(CH3)-C≡C-CH3、-C2H4-CH(CH3)-C≡CH、-CH=CH-CH=C(CH3)2、-CH2-CH(CH3)-CH2-C≡CH、-CH=CH-C(CH3)=CH-CH3、-CH=C(、 CH3)-CH=CH-CH3, -CH2-CH(CH3)-C≡CH, -C(CH3)=CH-CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -C2H4-C ≡CH, -CH2-C≡C-CH3, -C≡C-C2H5, -C3H6-C≡CH, -C2H4-C≡C-CH3, -CH2-C≡C-C2H5, -C≡C-C3H7, -CH(CH3)-C ≡CH, -C4H8-C≡CH, -C2H4-C≡C-C2H5, -CH2-C≡C-C3H7, -C≡C-C4H9, -C≡C-CH2-CH(CH3)2, -CH(CH3)-C2H4- C≡CH, -CH2-CH(CH3)-C≡C-CH3, -C(CH3)(C2H5)-C≡CH, -CH(CH3)-CH2-C≡C-CH3, -CH(CH3)-C≡C-C2H5, -C H2-C≡C-CH(CH3)2, -C≡C-CH(CH3)-C2H5, -CH2-C≡CC≡C-CH3, -CH(C2H5)-C≡C-CH3, -C(CH3)2-C≡C-CH3, - CH(C2H5)-CH2-C≡CH, -CH2-CH(C2H5)-C≡CH, -C(CH3)2-CH2-C≡CH, -CH2-C(CH3)2-C≡CH, -CH(CH3)-CH(C H3)-C≡CH, -CH(C3H7)-C≡CH, -CH2-CH(C≡CH)2, -C≡CC≡CH, -CH2-C≡CC≡CH, -C≡CC≡C-CH3, -CH(C≡CH)2, -C 2H4-C≡CC≡CH, -CH2-C≡C-CH2-C≡CH, -C≡C-C2H4-C≡CH, -C≡CC(CH3)3, -C≡C-CH2-C≡C-CH3, -C≡CC≡C-C2H5,

[0027] [ka] represents;

[0028] Z 3 and Z 4 together

[0029] [ka] may be formed;

[0030] Z 13 and Z 14 together

[0031] [ka] may be formed;

[0032] m is an integer selected from 0, 1, 2, 3, 4, 5, or 6; n is an integer selected from 0, 1, 2, 3, 4, 5, or 6; p is an integer selected from 0, 1, 2, 3, 4, 5, or 6; r is an integer selected from 0, 1, 2, 3, or 4; s is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; t is an integer selected from 1, 2, 3, or 4; u is an integer selected from 1, 2, 3, or 4; v is an integer selected from 0, 1, 2, 3, 4, 5, or 6; w is an integer selected from 0, 1, 2, or 3.

[0033] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. The compounds of the present invention may form salts with organic or inorganic acids or bases. Examples of acids suitable for forming such acid addition salts include 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, and china acid. acid), mandelic acid, o-methylmandelic acid, hydrogen benzenesulfonic acid, picric acid, adipic acid, o-tolyltartaric acid, tartronic acid, (o,m,p)-toluic acid, naphthylaminesulfonic 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 of the compound of formula (I) with a sufficient amount of the desired acid to produce the salt by conventional methods well known to those skilled in the art.

[0034] When the compound of the present invention has an acidic group, it can also form salts with inorganic or organic bases.Examples of suitable inorganic or organic bases include, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, lysine or arginine, etc.Salts can be prepared by conventional methods using methods well known in the art, for example, by treating a solution of the compound of general formula (I) with a solution of an acid selected from the above group.

[0035] As used herein, the term "C6 to C 14"-aryl" refers to aromatic residues or, more particularly, aromatic carbocyclic residues having one, two or three aromatic rings, preferably phenyl and naphthyl, where these phenyl and naphthyl residues are Z 1 ~Z 12 However, the term "can be substituted" does not include the substituent Z 1 From Z 12 It is clear to those skilled in the art that the term refers to the replacement of a hydrogen atom with one of the following: C6-C 14 The number of carbon atoms in the substituent Z refers only to the carbon atoms in the aromatic ring system (aryl). 1 ~Z 12 does not contain carbon atoms.

[0036] Preferred C6 to C 14 -aryl groups and substituted C6-C 14 Examples of -aryl residues are

[0037] [ka]

[0038] [ka] is.

[0039] As used herein, the term "C1-C 10 -heteroaryl" refers to an aromatic residue having one or more heteroatoms such as O, S, N, and especially N, preferably

[0040] [ka]

[0041] [ka]

[0042] [ka]

[0043] [ka]

[0044] [ka] refers to,

[0045] where these residues are R N1 , R N2 , Z 1 ~Z 12 However, the term "can be substituted" does not include the substituent R N1 , R N2 , Z 1 From Z 12 It will be clear to those skilled in the art that the term refers to the replacement of a hydrogen atom with one of the substituents R. Furthermore, only those hydrogen atoms present in the residue are substituents R. N1 , R N2 , Z 1 From Z 12 It will be clear to those skilled in the art that in the case of secondary amine groups in these heteroaryl residues, the hydrogen atoms of the secondary amine groups can be substituted by the substituent R N1 or R N2 Therefore, since the oxadiazole group has only one hydrogen atom, only one hydrogen atom is replaced by Z. 1 From Z 12 It can be substituted with one substituent selected from C1 to C 10 The number of carbon atoms in the aromatic heterocyclic ring system (heteroaryl) refers only to the carbon atoms in the substituent R N1 , R N2 , Z 1 ~Z 12 does not contain carbon atoms.

[0046] Preferred substituted C1-C 10 Examples of -heteroaryl residues are

[0047] [ka]

[0048] [ka]

[0049] [ka] is.

[0050] As used herein, C3-C8-carbocyclyl includes cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H 11 , cyclo-CH 13 , and cyclo-CH 15 where these residues are Z 1 ~Z 12 1 to 5 substituents selected from, preferably Z 1 , Z 2 , Z 3 , Z 4 and Z 5 However, the term "can be substituted" does not include the substituent Z 1 From Z 12 , preferably Z 1 , Z 2 , Z 3 , Z 4 and Z 5 It is clear to those skilled in the art that the number of carbon atoms C3 to C8 refers only to the carbon atoms of the cycloalkyl residue, and the substituent Z 1 From Z 12 does not contain carbon atoms.

[0051] Examples of preferred substituted C3-C8-cycloalkyl residues are

[0052] [ka]

[0053] [ka] is.

[0054] The term "C1-C9-heterocyclyl" as used herein includes saturated or partially unsaturated heterocyclic residues having 1 to 9 ring carbon atoms, but does not include aromatic residues, and also includes bicyclic saturated or partially unsaturated residues having 1 to 9 ring carbon atoms, but preferably not fully aromatic residues in which the entire bicyclic ring system is aromatic, but may include a partially aromatic ring system in which one ring of the bicyclic ring system is aromatic.

[0055] Examples of preferred substituted C1-C9-heterocyclyl residues are

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] [ka]

[0060] [ka] and

[0061] where these residues are R N1 , R N2 , Z 1 ~Z 12However, the term "can be substituted" does not include the substituent R N1 , R N2 , Z 1 From Z 12 It will be clear to those skilled in the art that the term refers to the replacement of a hydrogen atom with one of the substituents R. Furthermore, only those hydrogen atoms present in the residue are considered to be substituents R. N1 , R N2 , Z 1 From Z 12 It will be clear to those skilled in the art that in the case of secondary amine groups in these heteroaryl residues, the hydrogen atoms of the secondary amine groups can be substituted by the substituent R N1 or R N2 Therefore, the oxirane group (also called the ethylene oxide group) has only three hydrogen atoms, so only three hydrogen atoms are Z 1 From Z 12 The number of carbon atoms C1 to C9 refers only to the carbon atoms of the heterocyclic ring system (heterocyclyl), and the substituent R N1 , R N2 , Z 1 ~Z 12 does not contain carbon atoms.

[0062] As used herein, C4-C 11 The bicyclic carbocyclyl is represented by the general formula (a1):

[0063] [ka]

[0064] wherein A1 and A3 independently represent a C1-C7 alkylene; and C5~C 11 Bicyclic carbocycles are Z 1 ~Z 12 and optionally substituted with 1 to 5 substituents selected from Z 1 and Z 2and may have 0 to 2 double bonds.

[0065] Preferred C4 to C 11 Examples of bicyclic carbocycles are

[0066] [ka] is.

[0067] As used herein, C1-C 10 The bicyclic heterocyclyl may be represented by the general formula (a2):

[0068] [ka]

[0069] wherein A1 and A3 independently represent a C1-C5 alkylene, and at least one carbon atom of the C1-C5 alkylene is replaced with a heteroatom selected from O, N, and S; and B1 and B2 independently represent CH or N; C5~C 11 Bicyclic carbocycles are Z 1 From Z 12 , R N1 and R N2 and optionally substituted with 1 to 5 substituents selected from Z 1 , Z 2 , and R N1 and may have 0 to 3 double bonds.

[0070] Preferred C5~C 11 Examples of bicyclic heterocycles are:

[0071] [ka] is.

[0072] As used herein, C4-C 11 The bridged carbocyclyl may be represented by the general formula (b1):

[0073] [ka]

[0074] wherein A1, A2, and A3 independently represent a C1-C3 alkylene; and B1 and B2 independently represent CH, or B1 and B2 form a bond; C4~C 11 The bridged carbocyclyl ring is Z 1 From Z 12 and optionally substituted with 1 to 5 substituents selected from Z 1 and Z 2 and may have 0 to 2 double bonds.

[0075] [ka]

[0076] [ka]

[0077] As used herein, C1-C 10 The bridged heterocyclyl may be represented by the general formula (b2):

[0078] [ka]

[0079] wherein A1, A2, and A3 independently represent a C1-C3 alkylene, and at least one carbon atom of the C1-C3 alkylene is substituted with a heteroatom selected from O, N, and S; and B1 and B2 independently represent CH, or N; C5~C 11 A bridged heterocyclyl ring is Z 1 From Z 12 , R N1 and R N2 and may be optionally substituted with 1 to 5 substituents selected from Z 1 , Z 2 , and R N1 and may have 0 to 2 double bonds.

[0080] [ka]

[0081] [ka]

[0082] As used herein, C7-C 16 -spiroalkyl may be represented by the general formula (b3):

[0083] [ka]

[0084] wherein A1 and A2 independently represent a C2-C7 alkylene; and C7~C 16 Spiroalkyl is Z 1 ~Z 12 and optionally substituted with 1 to 5 substituents selected from Z 1 ~Z 3 By or Z 5 ~Z 7 and may have 0 to 2 double bonds.

[0085] As used herein, the term "C7-C 16"-spiroalkyl" refers to a spirocarbocyclic moiety, wherein the spirocarbocyclic moiety is a Z 1 , Z 2 , Z 3 , Z 5 , Z 6 and Z 7 However, the term "can be substituted" does not include the substituent Z 1 , Z 2 , Z 3 , Z 5 , Z 6 and Z 7 It will be clear to those skilled in the art that the substituent Z refers to the replacement of a hydrogen atom with one of the following: 1 , Z 2 , Z 3 , Z 5 , Z 6 and Z 7 Two of the C7 to C8 carbon atoms can together represent an oxygen atom, forming a carbonyl moiety with the carbon atom of the spiroalkyl residue to which they are both attached. 16 The number of carbon atoms in refers only to the carbon atoms in the spiro ring system, not including the carbon atoms of the substituents. Thus, a spiro[4,5]decyl residue has C, regardless of whether this spiro residue has five pentyl substituents. 10 - Counts as a spiroalkyl.

[0086] Preferred C7~C 16 -spiroalkyl groups and substituted C7-C 16 Examples of -spiroalkyl groups are

[0087] [ka]

[0088] [ka] and;

[0089] Preferred Substituent Z 5 , Z 6 and Z7 is -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -OH, -OCH3, -OC2H5, -OC3H7, -NH2, -N(CH3)2, -F, -Cl, -Br, -I, -CN, -CH2F, -CHF2, -CF3, -OCHF2, -OCF3, and more preferably Z 5 , Z 6 , and Z 7 At least one of the groups is not -H.

[0090] Of course, Z 5 ~Z 7 instead of Z 1 ~Z 3 can be replaced by and Z 1 ~Z 3 is Z 5 ~Z 7 has the same meaning as defined in As used herein, "C5-C 14 -spiroheterocyclyl" may be represented by general formula (b4):

[0091] [ka]

[0092] wherein A1 and A2 independently represent a C2-C6 alkylene, and at least one carbon atom of the C2-C6 alkylene is replaced with a heteroatom selected from O, N, and S; and C5~C 14 The spiroheterocyclyl ring is Z 1 From Z 12 , R N1 and R N2 and may be optionally substituted with 1 to 5 substituents selected from, preferably R N1 , Z1 and Z 2 and may have 0 to 2 double bonds.

[0093] As used herein, the term "C5-C 14"-spiroheterocyclyl" refers to a spiro radical having one, two or three heteroatoms, e.g., O, S, N, in the spiro ring system, where these spiroheterocyclic radicals are Z 1 From Z 12 , R N1 and R N2 and preferably R N1 , Z 1 , Z 2 , Z 3 , Z 5 , Z 6 and Z 7 However, the term "can be substituted" does not include the substituent R N1 , Z 5 , Z 6 and Z 7 It is clear to those skilled in the art that the replacement of a hydrogen atom with one of C5 to C 14 The number of carbon atoms in refers only to the carbon atoms in the spiro ring system, not including the carbon atoms of the substituents. Thus, an azaspiro[4,5]decyl residue is counted as a C9-spiroalkyl, regardless of whether the azaspiro[4,5]decyl residue has five isopropyl substituents.

[0094] Preferred C5~C 14 -spiroheterocyclyl groups and substituted C5-C 14 Examples of -spiroheterocyclyl groups are

[0095] [ka]

[0096] [ka]

[0097] [ka]

[0098] [ka]

[0099] [ka]

[0100] [ka] and

[0101] wherein Y and X are independently -O-, -NH-, or -NR N1 -, -SO-, or -SO2-, preferably -NH-, or -NR N1 - represents Z 5 and Z 6 are each independently -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -OH, -OCH3, -OC2H5, -OC3H7, -NH2, -N(CH3)2, -F, -Cl, -Br, -I, -CN, -CH2F, -CHF2, -CF3, -OCHF2, or -OCF3, and more preferably Z 5 and Z 6 At least one of the is not -H.

[0102] Of course, Z 5 and Z 6 Instead of Z 1 and Z 2 can be replaced by Z 1 and Z 2 is Z 5 and Z 6 has the same meaning as defined in R 8 , R 9 , and R 14 With respect to the above, examples of preferred 4-membered heterocyclic groups and substituted 4-membered heterocyclic groups are:

[0103] [ka] and;

[0104] Preferably Z 1 From Z 4 are each independently -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -OH, -OCH3, -OC2H5, -OC3H7, -NH2, -N(CH3)2, -F, -Cl, -Br, -I, -CN, -CH2F, -CHF2, -CF3, -OCHF2, or -OCF3, and more preferably Z 1 From Z 4 At least one of the is not -H.

[0105] R N1 Preferred substituents for are -R 15 , -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CHF2, -CF3

[0106] [ka] , cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H 11 , cyclo-CH 13 , -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H 11 , -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C6H 13 , -CH 15 , -CH 17, -Ph, -CH2-Ph, -CH2-CH2-Ph, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH2, -CH2-CH=C(CH3)2, -CH2-C≡CH, - C2H4-C≡CH, -CH2-C≡C-CH3, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7 , -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, or -SO3H.

[0107] Preferred 4-membered heterocyclyl groups are

[0108] [ka] is.

[0109] R 8 or R 9 Examples of preferred 5-membered heterocyclyl groups and substituted 5-membered heterocyclyl groups for are substituted or unsubstituted ring systems of 5 atoms containing at least one heteroatom, such as, for example, O, S, SO, SO, N, NO, where these 5-membered heterocyclic residues are R N1 , R N2 , Z 1 , Z 2 , Z 3 and Z 4 The substituent Z may be substituted with 1 to 4 substituents selected from 1 , Z 2 , Z 3 and Z 4Two of the Z substituents may together represent an oxygen atom and together with the ring carbon atom of the heterocycle to which they are both attached form a carbonyl moiety, or together with the ring sulfur atom to which they are attached form a sulfoxide moiety, or both Z substituents may represent oxygen and together with the ring sulfur atom to which they are attached form a sulfone moiety. N1 When the first Z substituent contains a nitrogen atom substituted by R N1 The five-membered heterocyclic residue is represented by the substituent R N1 , R N2 If the group contains two nitrogen atoms both substituted with one of N1 and the second Z substituent represents R N2 The same definition applies to the substituent R 9 applies to, but any substituent of the 5-membered heterocyclyl residue is Z 1 From Z 4 instead of Z 5 From Z 7 The only difference is that R 9 With respect to any substituent Z 1 is Z 5 is replaced by Z 2 is Z 6 is replaced by Z 3 is Z 7 and Z are replaced by 4 is hydrogen.

[0110] R 8 or R 9 Examples of preferred 5-membered heterocyclic groups and substituted 5-membered heterocyclic groups for

[0111] [ka]

[0112] [ka] and

[0113] Here, the aforementioned 5-membered heterocyclic group is R N1 , Z1 , Z 2 , Z 3 , and Z 4 It can be substituted with 1 to 4 substituents selected from: R 8 or R 9 With respect to the above, examples of preferred 6-membered heterocyclic groups and substituted 6-membered heterocyclic groups are:

[0114] [ka]

[0115] [ka] and

[0116] Here, the aforementioned 6-membered heterocyclic group is Z 1 , Z 2 , Z 3 , and Z 4 The substituent Z may be substituted with 1 to 4 substituents selected from 1 From Z 4 Preferred residues for are disclosed above.

[0117] R 8 or R 9 Examples of preferred "monounsaturated 4-membered heterocyclyl" groups and substituted "monounsaturated 4-membered heterocyclyl" groups with respect to are substituted or unsubstituted ring systems of 4 atoms containing at least one heteroatom, such as, for example, O, S, SO, SO, N, NO, where these 4-membered heterocyclic residues are N1 , R N2 , Z 1 , Z 2 , Z 3 and Z 4 However, the term "can be substituted" does not include the substituent R N1 , R N2 , Z 1 , Z 2 , Z 3 or Z 4It will be clear to those skilled in the art that the substitution of a hydrogen atom with one of the following is intended. Furthermore, only hydrogen atoms present in a monounsaturated 4-membered heterocyclic residue can be substituted with the substituent R N1 , R N2 , Z 1 , Z 2 , Z 3 and Z 4 It will be apparent to those skilled in the art that the substituent Z can be substituted by 1 , Z 2 , Z 3 and Z 4 Two of the Z substituents may together represent an oxygen atom and together with the ring carbon atom of the heterocycle to which they are both attached form a carbonyl moiety, or together with the ring sulfur atom to which they are attached form a sulfoxide moiety, or both Z substituents may represent oxygen and together with the ring sulfur atom to which they are attached form a sulfone moiety. N1 When the first substituent contains a nitrogen atom substituted by R N1 The monounsaturated four-membered heterocyclic residue is represented by the substituent R N1 , R N2 If the alkyl group contains two nitrogen atoms both substituted with one of N1 and the second Z substituent represents R N2 Represents.

[0118] R 8 or R 9 Preferred examples of monounsaturated 4-membered heterocyclic groups and substituted 4-membered heterocyclic groups for

[0119] [ka] is.

[0120] Preferably Z 1 From Z 4represent, independently of one another, -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -OH, -OCH3, -OC2H5, -OC3H7, -NH2, -N(CH3)2, -F, -Cl, -Br, -I, -CN, -CH2F, -CHF2, -CF3, -OCHF2, or -OCF3.

[0121] R N1 Preferred substituents for are -R 15 , -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CHF2, -CF3

[0122] [ka] , cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H 11 , cyclo-CH 13 , -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H 11 , -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C6H 13 , -CH 15 , -CH 17, -Ph, -CH2-Ph, -CH2-CH2-Ph, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH2, -CH2-CH=C(CH3)2, -CH2-C≡CH, - C2H4-C≡CH, -CH2-C≡C-CH3, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7 , -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, or -SO3H.

[0123] R 8 or R 9 Examples of preferred "monounsaturated 5-membered heterocyclyl" groups and substituted "monounsaturated 5-membered heterocyclyl" groups with respect to refer to substituted or unsubstituted ring systems of 5 atoms containing at least one heteroatom, such as, for example, O, S, SO, SO, N, NO, and one double bond, where these monounsaturated 5-membered heterocyclic residues are N1 , R N2 , Z 1 , Z 2 , Z 3 and Z 4 The substituent R N1 , R N2 , Z 1 , Z 2 , Z 3 and Z 4Two of the Z substituents may together represent an oxygen atom and together with the ring carbon atom of the heterocycle to which they are both attached form a carbonyl moiety, or together with the ring sulfur atom to which they are attached form a sulfoxide moiety, or both Z substituents may represent oxygen and together with the ring sulfur atom to which they are attached form a sulfone moiety. N1 When the first substituent contains a nitrogen atom substituted by R N1 The monounsaturated five-membered heterocyclic residue is represented by the substituent R N1 , R N2 When the alkyl group contains two nitrogen atoms both substituted by R, the first substituent is R N1 and the second Z substituent represents R N2 Represents.

[0124] R 3 Preferred examples of monounsaturated 5-membered heterocyclic groups and substituted 5-membered heterocyclic groups are:

[0125] [ka]

[0126] [ka]

[0127] [ka] and

[0128] Here, the aforementioned monounsaturated 5-membered heterocyclic group is R N1 , R N2 , Z 1 , Z 2 , Z 3 , and Z 4 It can be substituted with 1 to 4 substituents selected from: R 8 and R 9 are preferably, independently of one another, the following spiroheterocyclyl or C5-C 14 / N0-N2 / O0-O2 / S0-S1 - represents a spiroheterocyclyl residue: spiro[2,3]heterohexyl, spiro[2,4]heteroheptyl, spiro[2,5]heteroctyl, spiro[2,7]heteronyl, spiro[3,3]heteroheptyl, spiro[3,4]heteroctyl, spiro[3,5]heteronyl, spiro[3,6]heterodecyl, spiro[4,4]heteronyl, spiro[4,5]heterodecyl, spiro[4,6]heterundecyl, spiro[5,5]heterundecyl, spiro[5,6]heterododecyl, spiro[6,6]heterotridecyl, where the aforementioned spiroheterocyclyl or C5-C 14 / N0-N2 / O0-O2 / S0-S1-spiroheterocyclyl residue is attached to the rest of the molecule via a ring carbon atom, where the aforementioned spiroheterocyclyl or C5-C 14 / N0~N2 / O0~O2 / S0~S1-spiroheterocyclyl residues are R N1 , R N2 , Z 1 , Z 2 , Z 3 , Z 5 , Z 6 and Z 7 and optionally substituted with 1 to 3 substituents selected from the spiroheterocyclyl or C5-C 14 The heteroatoms of the / N0-N2 / O0-O2 / S0-S1-spiroheterocyclyl residue are preferably -O-, -NH-, -NR N1 -, -NR N2 -, -SO-, and -SO2-.

[0129] More preferably, R 8 and R 9 are each independently preferably the following spiroheterocyclyl or C5-C 14 / N0~N2 / O0~O2 / S0~S1 - represents spiroheterocyclyl residues: azaspiro[3,3]heptyl, azaspiro[3,4]octyl, azaspiro[3,5]nonyl, azaspiro[3,6]decyl, azaspiro[4,4]nonyl, azaspiro[4,5]decyl, azaspiro[4,6]undecyl, azaspiro[5,5]undecyl, azaspiro[5,6]dodecyl, azaspiro[6,6]tridecyl, diazaspiro[3,3]heptyl, Diazaspiro[3,4]octyl, diazaspiro[3,5]nonyl, diazaspiro[3,6]decyl, diazaspiro[4,4]nonyl, diazaspiro[4,5]decyl, diazaspiro[4,6]undecyl, diazaspiro[5,5]undecyl, diazaspiro[5,6]dodecyl, diazaspiro[6,6]tridecyl, triazaspiro[3,5]nonyl, triazaspiro[3,6]decyl, triazaspiro[4,5]decyl, triazaspiro[4,5]decyl Oxazaspiro[4,6]undecyl, triazaspiro[5,5]undecyl, triazaspiro[5,6]dodecyl, triazaspiro[6,6]tridecyl, oxazaspiro[3,3]heptyl, oxazaspiro[3,4]octyl, oxazaspiro[3,5]nonyl, oxazaspiro[3,6]decyl, oxazaspiro[4,4]nonyl, oxazaspiro[4,5]decyl, oxazaspiro[4,6]undecyl, oxazaspiro[5,5]undecyl undecyl, oxazaspiro[5,6]dodecyl, oxazaspiro[6,6]tridecyl, oxadiazaspiro[3,5]nonyl, oxadiazaspiro[3,6]decyl, oxadiazaspiro[4,5]decyl, oxadiazaspiro[4,6]undecyl, oxadiazaspiro[5,5]undecyl, oxadiazaspiro[5,6]dodecyl, oxadiazaspiro[6,6]tridecyl, wherein the aforementioned spiroheterocyclyl or C5-C 14 / N0-N2 / O0-O2 / S0-S1-spiroheterocyclyl residues are attached to the rest of the molecule via a ring carbon atom, where the aforementioned spiroheterocyclyl or C5-C 14 / N0~N2 / O0~O2 / S0~S1-spiroheterocyclyl residues are R N1 , R N2 , Z 1 , Z 2 , Z 3, Z 5 , Z 6 and Z 7 is optionally substituted with 1 to 3 substituents selected from:

[0130] Furthermore, R 8 and R 9 more preferably represent, independently of one another, the following residues: substituted or unsubstituted 4-membered carbocyclyl, substituted or unsubstituted 5-membered carbocyclyl, substituted or unsubstituted 6-membered carbocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, substituted 4-membered heterocyclyl, substituted 5-membered heterocyclyl, substituted 6-membered heterocyclyl, 4-membered nitrogen heterocyclyl, 5-membered nitrogen heterocyclyl, 6-membered nitrogen heterocyclyl, substituted 4-membered nitrogen heterocyclyl, substituted 5-membered nitrogen heterocyclyl, substituted 6-membered nitrogen heterocyclyl, spiro[2,3]heterohexyl, spiro[2,4]heteroheptyl, spiro[2,5]heteroctyl, spiro[2,7]heterononyl, spiro[3,3]heteroheptyl, spiro[3,4]heteroctyl, spiro[3,5]heterononyl, spiro[3,6]heterodeoxy Sil, spiro[4,4]heterononyl, spiro[4,5]heterodecyl, spiro[4,6]heterundecyl, spiro[5,5]heterondecyl, spiro[5,6]heterododecyl, spiro[6,6]heterotridecyl, substituted spiro[2,3]heterohexyl, substituted spiro[2,4]heteroheptyl, substituted spiro[2,5]heteroctyl, substituted spiro[2,7]heterononyl, substituted spiro[2,3]heterohexyl spiro[3,3]heteroheptyl, substituted spiro[3,4]heteroctyl, substituted spiro[3,5]heteronyl, substituted spiro[3,6]heterodecyl, substituted spiro[4,4]heteronyl, substituted spiro[4,5]heterodecyl, substituted spiro[4,6]heterundecyl, substituted spiro[5,5]heterundecyl, substituted spiro[5,6]heterododecyl, substituted spiro[6,6]heterotridecyl, Azaspiro[3,3]heptyl, azaspiro[3,4]octyl, azaspiro[3,5]nonyl, azaspiro[3,6]decyl, azaspiro[4,4]nonyl, azaspiro[4,5]decyl, azaspiro[4,6]undecyl, azaspiro[5,5]undecyl, azaspiro[5,6]dodecyl, azaspiro[6,6]tridecyl, substituted azaspiro[3,3]heptyl , substituted azaspiro[3,4]octyl, substituted azaspiro[3,5]nonyl, substituted azaspiro[3,6]decyl, substituted azaspiro[4,4]nonyl, substituted azaspiro[4,5]decyl, substituted azaspiro[4,6]undecyl, substituted azaspiro[5,5]undecyl, substituted azaspiro[5,6]dodecyl, substituted azaspiro[6,6]tridecyl, diazaspiro[3,3 ]heptyl, diazaspiro[3,4]octyl, diazaspiro[3,5]nonyl, diazaspiro[3,6]decyl, diazaspiro[4,4]nonyl, diazaspiro[4,5]decyl, diazaspiro[4,6]undecyl, diazaspiro[5,5]undecyl, diazaspiro[5,6]dodecyl, diazaspiro[6,6]tridecyl, substituted diazaspiro[3,3]heptyl ethyl, substituted diazaspiro[3,4]octyl, substituted diazaspiro[3,5]nonyl, substituted diazaspiro[3,6]decyl, substituted diazaspiro[4,4]nonyl, substituted diazaspiro[4,5]decyl, substituted diazaspiro[4,6]undecyl, substituted diazaspiro[5,5]undecyl, substituted diazaspiro[5,6]dodecyl, substituted diazaspiro[6,6]tridecyl, Triazaspiro[3,5]nonyl, triazaspiro[3,6]decyl, triazaspiro[4,5]decyl, triazaspiro[4,6]undecyl, triazaspiro[5,5]undecyl, triazaspiro[5,6]dodecyl, triazaspiro[6,6]tridecyl, substituted triazaspiro[3,5]nonyl, substituted triazaspiro[3,6]decyl, substituted triazaspiro[4,5]decyl, substituted triazaspiro[4,6]undecyl, substituted triazaspiro[5,5]undecyl, substituted triazaspiro[5 ,6]dodecyl, or substituted triazaspiro[6,6]tridecyl, oxazaspiro[3,3]heptyl, oxazaspiro[3,4]octyl, oxazaspiro[3,5]nonyl, oxazaspiro[3,6]decyl, oxazaspiro[4,4]nonyl, oxazaspiro[4,5]decyl, oxazaspiro[4,6]undecyl, oxazaspiro[5,5]undecyl, oxazaspiro[5,6]dodecyl, oxazaspiro[6,6]tridecyl, substituted oxazaspiro[3,3]heptyl, substituted oxa Oxazaspiro[3,4]octyl, substituted oxazaspiro[3,5]nonyl, substituted oxazaspiro[3,6]decyl, substituted oxazaspiro[4,4]nonyl, substituted oxazaspiro[4,5]decyl, substituted oxazaspiro[4,6]undecyl, substituted oxazaspiro[5,5]undecyl, substituted oxazaspiro[5,6]dodecyl, substituted oxazaspiro[6,6]tridecyl, oxadiazaspiro[3,5]nonyl, oxadiazaspiro[3,6]decyl, oxadiazaspiro[4,5]decyl, oxadia ...oxadiazaspiro[4,6]undecyl, oxadiazaspiro[4,6]dodecyl, substituted oxazaspiro[4,6]tridecyl, oxadiazaspiro[3,5]nonyl, oxadiazaspiro[3,6]decyl, oxadiazaspiro[4,5]decyl, oxadiazaspiro[4,4]nonyl, oxadiazaspiro[4,6]undecyl, oxadiazaspiro[4,6]undecyl, oxa oxadiazaspiro[4,6]undecyl, oxadiazaspiro[5,5]undecyl, oxadiazaspiro[5,6]dodecyl, oxadiazaspiro[6,6]tridecyl, substituted oxadiazaspiro[3,5]nonyl, substituted oxadiazaspiro[3,6]decyl, substituted oxadiazaspiro[4,5]decyl, substituted oxadiazaspiro[4,6]undecyl, substituted oxadiazaspiro[5,5]undecyl, substituted oxadiazaspiro[5,6]dodecyl, or substituted oxadiazaspiro[6,6]tridecyl; wherein the aforementioned substituted or unsubstituted spiroheterocyclyl or C5-C 14 / N0-N2 / O0-O2 / S0-S1-spiroheterocyclyl residues are attached to the remainder of the molecule via a ring carbon atom, where the aforementioned substituted or unsubstituted spiroheterocyclyl or C5-C 14 / N0~N2 / O0~O2 / S0~S1-spiroheterocyclyl residues are Z 1 , Z 2 , Z 3 , Z 5 , Z 6 and Z 7 The aforementioned substituted or unsubstituted spiroheterocyclyl or C5-C 14 The heteroatoms in the / N0-N2 / O0-O2 / S0-S1-spiroheterocyclyl residue are preferably -O-, -NH-, -NR N1 -, -SO-, and -SO2-.

[0131] Preferably Z 5 , Z 6 , and Z 7 represent, independently of one another, -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -OH, -OCH3, -OC2H5, -OC3H7, -NH2, -N(CH3)2, -F, -Cl, -Br, -I, -CN, -CH2F, -CHF2, -CF3, -OCHF2, or -OCF3.

[0132] If present, R N1 is preferably:-R 15 , -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CHF2, -CF3

[0133] [ka] , cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H 11 , cyclo-CH 13 , -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H 11, -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C6H 13 , -CH 15 , -CH 17 , -Ph, -CH2-Ph, -CH2-CH2-Ph, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH2, -CH2-CH=C(CH3)2, -CH2-C≡CH, -C 2H4-C≡CH, -CH2-C≡C-CH3, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, - selected from COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, or -SO3H.

[0134] The term "4-membered nitrogen heterocyclyl" refers to the residue "4-membered heterocyclyl" as defined above, wherein at least one heteroatom is a nitrogen atom and the residue is attached to the remainder of the molecule through at least one nitrogen ring atom, and wherein Z 1 is Z 5 is replaced by Z 2 is Z 6 is replaced by Z 3 is Z 7 is replaced by, and Z 4 is hydrogen.

[0135] The term "5-membered nitrogen heterocyclyl" refers to the residue "5-membered heterocyclyl" as defined above, wherein at least one heteroatom is a nitrogen atom and the residue is attached to the remainder of the molecule through at least one nitrogen ring atom, and wherein Z 1 is Z 5 is replaced by Z 2 is Z 6 is replaced by Z 3 is Z 7 is replaced by, and Z 4 is hydrogen.

[0136] The term "6-membered nitrogen heterocyclyl" refers to the residue "6-membered heterocyclyl" as defined above, wherein at least one heteroatom is a nitrogen atom and the residue is attached to the remainder of the molecule through at least one nitrogen ring atom, and wherein Z 1 is Z 5 is replaced by Z 2 is Z 6 is replaced by Z 3 is Z 7 is replaced by, and Z 4 is hydrogen.

[0137] Even more desirable R 8 or R 9 is selected from the following residues:

[0138] [ka]

[0139] [ka]

[0140] [ka]

[0141] [ka]

[0142] [ka]

[0143] [ka]

[0144] [ka]

[0145] [ka]

[0146] [ka]

[0147] [ka]

[0148] [ka]

[0149] where Y is -O-, -NH-, or -NR N1 -, -NR N2 represents -, -SO-, or -SO2-, and preferably represents -NH- or -NR N1 -, where the substituent Z 5 , Z 6 and Z 7 has the meaning defined herein. Of course, the substituent Z 5 , Z 6 and Z 7 is a substituent Z 1 , Z 2 , Z 3can be replaced by and Z 1 , Z 2 , Z 3 has the meaning defined herein.

[0150] As used herein, the term "spiro nitrogen cyclyl" refers to a C-C 14 - C5-C comprising or including a spiroheterocyclyl residue 14 / refers to an N1-N3-spiro nitrogen cyclyl residue, where the heteroatom is nitrogen, i.e., Y is NH, NR N1 or NR N2 The term "C5~C 14 / N1-N3" means that the spiro ring system consists of 5 to 14 carbon atoms and 1 to 3 nitrogen atoms. Furthermore, the spiro nitrogen cyclyl residue is N1 , R N2 , Z 1 , Z 2 , Z 3 , Z 5 , Z 6 and Z 7 However, the term "can be substituted" does not include the substituent R N1 , R N2 , Z 1 , Z 2 , Z 3 , Z 5 , Z 6 or Z 7 It will be clear to those skilled in the art that the substituent Z refers to the replacement of a hydrogen atom with one of the following: 5 , Z 6 and Z 7 Two of these may together represent an oxygen atom, forming a carbonyl moiety with the carbon atom of the spiro nitrogen cyclyl residue to which they are both attached. 14 / N1-N3-spiro nitrogen cyclyl residues are characterized in that the spiro nitrogen cyclyl residue is bonded via a nitrogen atom of the spiro ring system rather than via a carbon atom of the spiro ring system. 14-For spiroheterocyclyl residues, the heteroatom Y is nitrogen and the C5-C 14 - means that the spiroheterocyclyl residue is attached to the rest of the molecule through this nitrogen atom (the nitrogen atom is Y). C5-C 14 / When the N1-N3-spiro nitrogen cyclyl residue contains a second nitrogen atom, the substituent R N1 , R N2 Thus, the designation "N2" refers to the first nitrogen atom through which the spiro nitrogen cyclyl residue is attached and which forms the group of the spiro ring system.

[0151] [ka] The spiro nitrogen cyclyl residue contains a third nitrogen atom, and both nitrogen atoms are substituents Z. 1 , Z 2 , Z 3 , Z 5 , Z 6 and Z 7 When substituted by one of N2 and the second Z substituent on the third nitrogen atom represents R N1 Thus, the designation "N3" refers to the first nitrogen atom through which the spiro nitrogen cyclyl residue is attached and which forms the group of the spiro ring system.

[0152] [ka] and

[0153] [ka] Therefore, C5~C 14 / N1-N3-spiro nitrogen cyclyl residues can contain one, two, or three nitrogen atoms in the spiro ring system. 14 / N1 to N2" are the substituents Z 1 , Z 2 , Z 3 , Z5 From Z 7 does not include C and N atoms.

[0154] As used herein, the term "nitrogen heterocyclyl" refers to a C5-C heterocyclyl as disclosed above. 14 - C5-C comprising or including a spiroheterocyclyl residue 14 / N1-N3 / O0-O2 / S0-S1-refers to a nitrogen heterocyclyl residue, where the heteroatom is nitrogen, i.e., Y is NH, NR N1 or NR N2 The term "C5~C 14 / N1-N3 / O0-O2 / S0-S1" means that the spiro ring system consists of 5 to 14 carbon atoms, 1 to 3 nitrogen atoms, 0 to 2 oxygen atoms, and 0 to 1 sulfur atom. Furthermore, the nitrogen heterocyclyl residue can be represented by R N1 , R N2 , Z 1 , Z 2 , Z 3 , Z 5 , Z 6 and Z 7 However, the term "can be substituted" does not include the substituent Z 1 , Z 2 , Z 3 , Z 5 , Z 6 or Z 7 It will be clear to those skilled in the art that the substituent Z refers to the replacement of a hydrogen atom with one of the following: 5 , Z 6 and Z 7 Two of these may together represent an oxygen atom, forming a carbonyl moiety together with the carbon atom of the nitrogen heterocyclyl residue to which both oxygen atoms are attached. 14 The / N1-N3 / O0-O2 / S0-S1-nitrogen heterocyclyl residue is characterized in that the nitrogen heterocyclyl residue is attached via a nitrogen atom of the spiro ring system, rather than via a carbon atom of the spiro ring system. This is the same as the C5-C 14-For spiroheterocyclyl residues, the heteroatom Y is nitrogen and the C5-C 14 - means that the spiroheterocyclyl residue is attached to the rest of the molecule through this nitrogen atom (the nitrogen atom is Y). C5-C 14 / N1~N3 / O0~O2 / S0~S1-nitrogen heterocyclyl residues are substituted with the substituent Z 1 , Z 2 , Z 3 , Z 5 , Z 6 , and Z 7 When the Z substituent contains a second nitrogen atom substituted by one of R N2 Thus, the designation "N2" refers to the first nitrogen atom through which the spiro nitrogen cyclyl residue is attached and which forms the group of the spiro ring system.

[0155] [ka] The nitrogen heterocyclyl residue contains a third nitrogen atom, and both nitrogen atoms are substituents Z. 5 , Z 6 and Z 7 When substituted by one of N2 and the second Z substituent on the third nitrogen atom represents R N1 Thus, the designation "N3" refers to the first nitrogen atom through which the nitrogen heterocyclyl residue is attached and which is a group of spirocyclic ring systems.

[0156] [ka] and

[0157] [ka] The designation "S1" refers to the group -S-, -SO-, or -SO2- in the spiro ring system. The designation "S0" means that there is no sulfur in the nitrogen heterocyclyl residue. The designation "O1" refers to the group -O-, and the designation "O2" refers to two groups -O- that are not directly bonded to each other, while "O0" indicates that there is no oxygen in the spiro ring system. Thus, C5-C 14 The N1-N3 / O0-O2 / S0-S1 nitrogen heterocyclyl residue may contain a total of six heteroatoms, while there should be no more than three heteroatoms in total in the spiro ring system. Furthermore, it is preferred that the heteroatoms in the spiro ring system are not directly bonded to each other. 14 The number of atoms in "N1~N3 / O0~O2 / S0~S1" is determined by the substituent R N1 , R N2 , Z 1 From Z 3 , Z 5 From Z 7 It does not include C, O, S, and N atoms from

[0158] Preferably, there is one nitrogen atom, or two nitrogen atoms, or one nitrogen atom and one sulfur atom, or one nitrogen atom and one sulfoxide moiety, or one nitrogen atom and one sulfone moiety, or one nitrogen atom and one oxygen atom, or one nitrogen atom and two oxygen atoms, or one oxygen atom and two nitrogen atoms in the spiro ring system.

[0159] R 8 and R 9 are each independently preferably the following spiro nitrogen cyclyl, nitrogen heterocyclyl, C5-C 14 / N1~N3-spiro nitrogen cyclyl or C5~C 14 / N1~N3 / O0~O2 / S0~S1 - represent nitrogen heterocyclyl residues: 4-membered nitrogen heterocyclyl, 5-membered nitrogen heterocyclyl, 6-membered nitrogen heterocyclyl, 5-membered dinitrogen heterocyclyl, 6-membered dinitrogen heterocyclyl, spiro[2,3]heterohexyl, spiro[2,4]heteroheptyl, spiro[2,5]heterooctyl, spiro[2,7]heterononyl, spiro[3,3]heteroheptyl , spiro[3,4]heterooctyl, spiro[3,5]heteronyl, spiro[3,6]heterodecyl, spiro[4,4]heteronyl, spiro[4,5]heterodecyl, spiro[4,6]heterundecyl, spiro[5,5]heterondecyl, spiro[5,6]heterododecyl, spiro[6,6]heterotridecyl, wherein the spiro nitrogen cyclyl and nitrogen heterocyclyl are C5-C 14 / N1~N3-spiro nitrogen cyclyl, or C5~C 14 / N1-N3 / O0-O2 / S0-S1-nitrogen heterocyclyl residues are attached to the rest of the molecule via a ring nitrogen atom, where spiro nitrogen cyclyl, nitrogen heterocyclyl, C5-C 14 / N1~N3-spiro nitrogen cyclyl or C5~C 14 / N1~N3 / O0~O2 / S0~S1-nitrogen heterocyclyl residues are R N1 , R N2 , Z 1 , Z 2 , Z 3 , Z 5 , Z 6 and Z 7 is optionally substituted with 1 to 3 substituents selected from:

[0160] The term "5-membered dinitrogen heterocyclyl" refers to the residue "5-membered heterocyclyl" as defined above, where the two heteroatoms are nitrogen atoms and the residue is attached to the rest of the molecule via the nitrogen ring atom, where Z 1 is Z 5 is replaced by Z 2 is Z 6 is replaced by Z 3 is Z 7 is replaced by, and Z 4 is hydrogen.

[0161] The term "6-membered dinitrogen heterocyclyl" refers to the residue "6-membered heterocyclyl" as defined above, where the two heteroatoms are nitrogen atoms and the residue is attached to the rest of the molecule via the nitrogen ring atom, where Z 1 is Z 5 is replaced by Z 2 is Z 6 is replaced by Z 3 is Z 7 is replaced by, and Z 4 is hydrogen.

[0162] Furthermore, the aforementioned spiro nitrogen cyclyl, nitrogen heterocyclyl, C5-C 14 / N1~N3-spiro nitrogen cyclyl or C5~C 14 / N1-N3 / O0-O2 / S0-S1-Nitrogen heterocyclyl residues contain at least one nitrogen atom through which they are attached to the rest of the molecule and can be any of oxygen (-O-), sulfoxide (-SO-), sulfone (-SO2-), carbonyl (-CO-), nitrogen (-NR N1 -), and may contain one or two further moieties selected from:

[0163] Preferred Substituent Z 5 , Z 6 and Z 7 represent, independently of one another, -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -OH, -OCH3, -OC2H5, -OC3H7, -NH2, -NHCH3, -N(CH3)2, -F, -Cl, -Br, -I, -CN, -CH2F, -CHF2, -CF3, -OCHF2, or -OCF3.

[0164] R N1 and R N1 are preferably, independently of each other:-R 15 , -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CHF2, -CF3

[0165] [ka] , cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H 11 , cyclo-CH 13 , -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H 11 , -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C6H 13 , -CH 15 , -CH 17 , -Ph, -CH2-Ph, -CH2-CH2-Ph, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH2, -CH2-CH=C(CH3)2, -CH2-C≡CH, -C2 H4-C≡CH, -CH2-C≡C-CH3, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -C and -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, or -SO3H.

[0166] More preferably R 8 and R 9 are independently selected from the following spiro nitrogen cyclyl, nitrogen heterocyclyl, C5-C 14 / N1~N3-spiro nitrogen cyclyl, or C5~C 14 / N0-N2 / O0-O2 / S0-S1-represents a nitrogen heterocyclyl residue: a 4-membered nitrogen heterocyclyl bonded to the rest of the molecule through a nitrogen atom, a 5-membered nitrogen heterocyclyl bonded to the rest of the molecule through a nitrogen atom, a 6-membered nitrogen heterocyclyl bonded through a nitrogen atom, a substituted 4-membered nitrogen heterocyclyl bonded through a nitrogen atom, a substituted 5-membered nitrogen heterocyclyl bonded through a nitrogen atom, a substituted 6-membered nitrogen heterocyclyl bonded through a nitrogen atom, a 5-membered dinitrogen heterocyclyl bonded through a nitrogen atom, a 6-membered dinitrogen heterocyclyl bonded through a nitrogen atom, a substituted 5-membered dinitrogen heterocyclyl bonded through a nitrogen atom, a substituted 6-membered dinitrogen heterocyclyl bonded to the rest of the molecule through a nitrogen atom, wherein the aforementioned spiro nitrogen cyclyl, nitrogen heterocyclyl, C5-C 14 / N1~N3-spiro nitrogen cyclyl, or C5~C 14 / N1~N3 / O0~O2 / S0~S1-nitrogen heterocyclyl residues are R N1 , R N2 , Z 1 , Z 2 , Z 3 , Z 5 , Z 6 and Z 7 is optionally substituted with 1 to 3 substituents selected from:

[0167] Even more preferably, R 8 and R 9 are independently selected from the following spiro nitrogen cyclyl, nitrogen heterocyclyl, C5-C 14 / N1~N3-spiro nitrogen cyclyl, or C5~C 14 / N1~N3 / O0~O2 / S0~S1 - represents nitrogen heterocyclyl residues: azaspiro[3,3]heptyl bonded through a nitrogen atom, azaspiro[3,4]octyl bonded through a nitrogen atom, azaspiro[3,5]nonyl bonded through a nitrogen atom, azaspiro[3,6]decyl bonded through a nitrogen atom, azaspiro[4,4]nonyl bonded through a nitrogen atom, azaspiro[4,5]decyl bonded through a nitrogen atom, azaspiro[4,6]undecyl bonded through a nitrogen atom, azaspiro[4,6]undecyl bonded through a nitrogen atom [5,5]undecyl, azaspiro[5,6]dodecyl bonded through a nitrogen atom, azaspiro[6,6]tridecyl bonded through a nitrogen atom, substituted azaspiro[3,3]heptyl bonded through a nitrogen atom, substituted azaspiro[3,4]octyl bonded through a nitrogen atom, substituted azaspiro[3,5]nonyl bonded through a nitrogen atom, substituted azaspiro[3,6]decyl bonded through a nitrogen atom, substituted azaspiro[4,4]nonyl bonded through a nitrogen atom, substituted azaspiro[4,5]decyl bonded through a nitrogen atom, substituted azaspiro[4,4]nonyl bonded through a nitrogen atom, substituted azaspiro[4,5]decyl bonded through a nitrogen atom, Substituted azaspiro[4,6]undecyl bonded through a nitrogen atom, substituted azaspiro[5,5]undecyl bonded through a nitrogen atom, substituted azaspiro[5,6]dodecyl bonded through a nitrogen atom, substituted azaspiro[6,6]tridecyl bonded through a nitrogen atom, diazaspiro[3,3]heptyl bonded through a nitrogen atom, diazaspiro[3,4]octyl bonded through a nitrogen atom, diazaspiro[3,5]nonyl bonded through a nitrogen atom, diazaspiro[3,6]decyl bonded through a nitrogen atom, diazapiro[3,5]nonyl bonded through a nitrogen atom, diazapiro[3,6]decyl bonded through a nitrogen atom, Azaspiro[4,4]nonyl, diazaspiro[4,5]decyl bonded through a nitrogen atom, diazaspiro[4,6]undecyl bonded through a nitrogen atom, diazaspiro[5,5]undecyl bonded through a nitrogen atom, diazaspiro[5,6]dodecyl bonded through a nitrogen atom, diazaspiro[6,6]tridecyl bonded through a nitrogen atom, substituted diazaspiro[3,3]heptyl bonded through a nitrogen atom, substituted diazaspiro[3,4]octyl bonded through a nitrogen atom, substituted diazaspiro[3,5]nonyl, substituted diazaspiro[3,6]decyl bonded through a nitrogen atom, substituted diazaspiro[4,4]nonyl bonded through a nitrogen atom, substituted diazaspiro[4,5]decyl bonded through a nitrogen atom, substituted diazaspiro[4,6]undecyl bonded through a nitrogen atom, substituted diazaspiro[5,5]undecyl bonded through a nitrogen atom, substituted diazaspiro[5,6]dodecyl bonded through a nitrogen atom, substituted diazaspiro[6,6]tridecyl bonded through a nitrogen atom, triazaspiro[3 ,5]nonyl, triazaspiro[3,6]decyl bonded through a nitrogen atom, triazaspiro[4,5]decyl bonded through a nitrogen atom, triazaspiro[4,6]undecyl bonded through a nitrogen atom, triazaspiro[5,5]undecyl bonded through a nitrogen atom, triazaspiro[5,6]dodecyl bonded through a nitrogen atom, triazaspiro[6,6]tridecyl bonded through a nitrogen atom, substituted triazaspiro[3,5]nonyl bonded through a nitrogen atom, substituted triazaspiro[3,6]bonded through a nitrogen atom ]decyl, substituted triazaspiro[4,5]decyl bonded through a nitrogen atom, substituted triazaspiro[4,6]undecyl bonded through a nitrogen atom, substituted triazaspiro[5,5]undecyl bonded through a nitrogen atom, substituted triazaspiro[5,6]dodecyl bonded through a nitrogen atom, substituted triazaspiro[6,6]tridecyl bonded through a nitrogen atom, oxazaspiro[3,3]heptyl bonded through a nitrogen atom, oxazaspiro[3,4]octyl bonded through a nitrogen atom, oxazaspiro[3,5]octyl bonded through a nitrogen atom, oxazaspiro[3,6]octyl bonded through a nitrogen atom, oxazaspiro[3,7]octyl bonded through a nitrogen atom, oxazaspiro[3,8]octyl bonded through a nitrogen atom, oxazaspiro[3,9]oct ...4]octyl bonded through a nitrogen atom, oxazaspiro[3,5]octyl bonded through a nitrogen atom, oxazaspiro[3,5]octyl bonded through a nitrogen atom, oxazaspiro[3,5]octyl bonded through a nitrogen Pyro[3,5]nonyl, oxazaspiro[3,6]decyl bonded through a nitrogen atom, oxazaspiro[4,4]nonyl bonded through a nitrogen atom, oxazaspiro[4,5]decyl bonded through a nitrogen atom, oxazaspiro[4,6]undecyl bonded through a nitrogen atom, oxazaspiro[5,5]undecyl bonded through a nitrogen atom, oxazaspiro[5,6]dodecyl bonded through a nitrogen atom, oxazaspiro[6,6]tridecyl bonded through a nitrogen atom, substituted oxazaspiro[3,3]heptyl, substituted oxazaspiro[3,4]octyl bonded through a nitrogen atom, substituted oxazaspiro[3,5]nonyl bonded through a nitrogen atom, substituted oxazaspiro[3,6]decyl bonded through a nitrogen atom, substituted oxazaspiro[4,4]nonyl bonded through a nitrogen atom, substituted oxazaspiro[4,5]decyl bonded through a nitrogen atom, substituted oxazaspiro[4,6]undecyl bonded through a nitrogen atom, substituted oxazaspiro[5,5]undecyl bonded through a nitrogen atom, substituted oxazaspiro[5,6]dodecyl bonded through a nitrogen atom, substituted oxazaspiro[6,6]tridecyl bonded through a nitrogen atom, oxadiazaspiro[3,5]nonyl bonded through a nitrogen atom, oxadiazaspiro[3,6]decyl bonded through a nitrogen atom, oxadiazaspiro[4,5]decyl bonded through a nitrogen atom, oxadiazaspiro[4,6]undecyl bonded through a nitrogen atom, oxadiazaspiro[5,5]undecyl bonded through a nitrogen atom, oxadiazaspiro[5,6]dodecyl bonded through a nitrogen atom, oxadiazaspiro[6,6]tridecyl bonded through a nitrogen atom, substituted oxadiazaspiro[3,5]nonyl bonded through a nitrogen atom, substituted oxadiazaspiro[3,6]decyl bonded through a nitrogen atom, substituted oxadiazaspiro[4,5]decyl bonded through a nitrogen atom, substituted oxadiazaspiro[4,6]undecyl bonded through a nitrogen atom, substituted oxadiazaspiro[5,5]undecyl bonded through a nitrogen atom, substituted oxadiazaspiro[5,6]dodecyl bonded through a nitrogen atom, substituted oxadiazaspiro[6,6]tridecyl bonded through a nitrogen atom, wherein the aforementioned substituted spiro nitrogen cyclyl, substituted nitrogen heterocyclyl, substituted C5-C, 14 / N1-N3-spiro nitrogen cyclyl or substituted C5-C 14 / N1~N3 / O0~O2 / S0~S1-nitrogen heterocyclyl residues are R N1 , R N2 , Z 5 , Z 6 and Z 7Furthermore, the above-mentioned substituted or unsubstituted spiro nitrogen cyclyl, substituted or unsubstituted nitrogen heterocyclyl, substituted or unsubstituted C5-C 14 / N1-N3-spiro nitrogen cyclyl or substituted or unsubstituted C5-C 14 / N1-N3 / O0-O2 / S0-S1-Nitrogen heterocyclyl residues contain at least one nitrogen atom through which they are attached to the rest of the molecule and include oxygen (-O-), sulfoxide (-SO-), sulfone (-SO2-), carbonyl (-CO-), and nitrogen (-NR N2 -), and may contain one or two further moieties selected from:

[0168] Even more preferably, R 8 and R 9 are independently selected from the following spiro nitrogen cyclyl, nitrogen heterocyclyl, C5-C 14 / N1~N3-spiro nitrogen cyclyl, or C5~C 14 / N1~N3 / O0~O2 / S0~S1-represents a nitrogen heterocyclyl residue:

[0169] [ka]

[0170] [ka]

[0171] [ka]

[0172] [ka]

[0173] [ka]

[0174] [ka]

[0175] where Y is -O-, -NH-, or -NR N1 -, -NR N2 represents -, -SO-, or -SO2-, and preferably represents -NH- or -NR N1 -, where the substituent Z 5 , Z 6 and Z 7 has the meaning defined herein. 5 , Z 6 and Z 7 is a substituent Z 1 , Z 2 , and Z 3 may be replaced by

[0176] Preferably, Z 5 , Z 6 and Z 7 are each independently -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -OH, -OCH3, -OC2H5, -OC3H7, -NH2, -NH(CH3), -N(CH3)2, -F, -Cl, -Br, -I, -CN, -CH2F, -CHF2, -CF3, -OCHF2, or -OCF3, and more preferably -NH2, -NH(CH3), or -N(CH3)2.

[0177] Preferred are compounds of formula (I), wherein R 8 and R 9 are independent of each other.

[0178] [ka]

[0179] [ka]

[0180]

change

[0181]

change

[0182]

change

[0183]

change

[0184]

change

[0185]

change

[0186]

change

[0187]

change

[0188]

change

[0189]

change

[0190]

change

[0191] [ka]

[0192] [ka]

[0193] [ka]

[0194] [ka]

[0195] [ka]

[0196] [ka]

[0197] [ka]

[0198] [ka] represents:

[0199] where R N1 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , Z 10 , Z 11 and Z 10has the same meaning as defined in formula (I). More preferably, it is a compound of formula (I) wherein R 8 and R 9 are independent of each other;

[0200] [ka]

[0201] [ka] represents

[0202] where R N1 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , and Z 10 has the same meaning as defined in formula (I). Preferably, a compound of general formula (I) or an enantiomer, stereoisomer, mixture of enantiomers, diastereomer, mixture of diastereomers, hydrate, solvate, acid salt form, tautomer, racemate or a pharmaceutically acceptable salt thereof of said compound,

[0203] [ka]

[0204] During the ceremony, A is -CO-N(R N6 )-,

[0205] [ka] , represents;

[0206] Preferably, A is -CO-NH-, -CO-N(CH3)-

[0207] [ka] represents;

[0208] B is -H, -NH(R 2 ),

[0209] [ka] represents;

[0210] Preferably, B is —H, —NH(R 2 ),

[0211] [ka] represents;

[0212] L represents -CO-, -CO-NH-, -CO-N(CH3)-, or -CO-O-; R 1 -H, -(CH2) p -R 7 , -(CH2) p -NH-R 7 , -(CH2) p -R 9 , or -(CH2) p -N(Ph)-R 9 and preferably represents -(CH2) p -R 7 , -(CH2) p -R 9 , or -(CH2) p -N(Ph)-R 9 represents; R 2 -H, -R 8 , -R 11 , -L 1 -R 11 , -L 1 -(CH2) r -R 8 , -L1 -R 10 , -L 1 -(C2H4O) s -R 11 , -L 1 -(CH2) t -OR 11 , -L 1 -(CH2) t -NH-(CH2) r -R 8 , -L 1 -(CH2) t -O-(CH2) r -R 8 , -L 1 -(CH2) t -NHR 8 , -L 1 -(CH2) t -NH-CO-R 8 , -L 1 -(CH2) t -NH-SO2-R 8 , -CO-(CH2) t -N(CH3)R 10 , -CO-(CH2) t -O-(CH2) u -N(CH3)R 10 , -L 1 -(CH2) t -R 14 , -CO-C(R 12 )(R 13 )-R 10 , -CO-C(R 12 )(R 13 )-R 8 , or -CO-C(R 12 )(R 13 )-(CH2) u -R 8 represents; L 1 represents a bond, -CO-, -CO2-, -CONH-, or -SO2-; R 3 represents -H; R 4 ~R 6 represent, independently of each other, -H, -CH3, or -OCH3; and more preferably -H, -CH3; Or, R 5and R 6 together

[0213] [ka] Forming;

[0214] R 8 and R 9 are independent of each other. C6~C 14 Aryl, C1-C 10 Heteroaryl, C3-C8 carbocyclyl, C1-C9 heterocyclyl, C4-C 11 Bicyclic carbocyclyl, C4-C 11 Bridged Carbocyclyl, C1-C 10 Bicyclic heterocyclyl, C1-C 10 Bridged heterocyclyl, C7-C 16 -Spiroalkyl, C5-C 14 -spiroheterocyclyl, wherein all the aforementioned ring systems are Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , Z 10 , Z 11 , Z 12 , R N1 and R N2 and C1~C 10 Heteroaryl, C1-C9 heterocyclyl, C1-C 10 Bicyclic heterocyclyl, C1-C 10 Bridged Heterocyclyl, C5-C 14 - the spiroheterocyclyl ring system contains at least one heteroatom N, O, and S; The C3-C8 carbocyclyl, C1-C9 heterocyclyl, C1-C 10 Bicyclic heterocyclyl, C4-C 11 Bridged Carbocyclyl, C1-C 10Bicyclic heterocyclyl, C1-C 10 Bridged heterocyclyl, C7-C 16 -Spiroalkyl, C5-C 14 - the spiroheterocyclyl ring system can be partially saturated or unsaturated; R 7 and R 10 are each independently -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CN, -C(CH3)2-CN, -CH2-C(CH3)2-CN, -CH2-CF3, -CH2-C(CH3)2-NH2,

[0215] [ka] , cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H 11 , -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H 11, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -Ph, -CH2-Ph, -CH2-CH2-Ph, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH2, -C(CH3)=CH-CH3, -CH2-CH=C(CH3)2, -CO-CH=C(CH3)2, -CH2-C≡CH, -C2H4-C≡CH, -CH2-C≡C-CH3, -CH2-OCF3, -C2H4-OCF3, -C3H6-OCF3, -CH2-OCHF2, -C2H4-OCHF2, -C3H6-OCHF2, -CH2-OCH3, -C2H4-OCH3, -C3H6-OCH3, -CH2-OC2H5, -C2H4-OC2H5, -C3H6-OC2H5, -CH2-OH, -C2H4-OH, -C3H6-OH, -CH2-COOH, -C2H4-COOH, -C3H6-COOH, -C(CH3)2-CN, -C(CH3)2-OH, -C(CH3)2-CH2-OH, -C(C2H5)2-CH2-OH, -C(CH2-OH)2-CH3, -C(CH2-OH)2-C2H5, -C(CH3)2-CH2-SH, -C(C2H5)2-CH2-SH, -C(CH2-SH)2-CH3, -CO-O-C(CH3)3, or -C(CH2-SH)2-C2H5;

[0216] R 11 is -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CN, -C(CH3)2-CN, -CH2-C(CH3)2-CN, -CH2-CF3, -CH2-C(CH3)2-NH2,

[0217]

Chem.

[0218] R 12 and R 13 represent, independently of one another, -H, -CH3, -C2H5, -C3H7, -Ph, -CH2-Ph, -NH2, -NHCO2(CCH3)3, -CH2-NH2, -CHF2, -F, -CF3, -OCF3, -OCHF2, -OH, -OCH3, -OC2H5, and -OC3H7; or R 12 and R 13 together

[0219] [ka] may be formed;

[0220] R 14 teeth,

[0221] [ka] represents;

[0222] R N1 , R N2 , and R N4 are, independently of each other, -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CHF2, -CF3,

[0223] [ka] , cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H 11 , -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H 11 , -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C6H 13 , -CH 15 , -CH 17 , -Ph, -CH2-Ph, -CH2-CH2-Ph, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH2, -CH2-CH=C(CH3)2, -CH2-C≡CH, - C2H4-C≡CH, -CH2-C≡C-CH3, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7 , -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3 )2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO3H, -(CH2) v-COOH, -(CH2) v -OH, -(CH2) v -SH, -(CH2) v -SO3H, or -(CH2CH2-O) w represents -CH2CH2-NH2;

[0224] X 1 is -(CH2) m - represents; X 2 is -(CH2) n - represents; X 3 represents a bond, -O-, -NH-, or -S-; Z 1 ~Z 14 are independent of each other,

[0225] [ka] , cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H 11 , -H, -OH, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -O-cyclo-C4H7, -O-cyclo-C5H9, -O-cyclo-C6H 11 , -OCH2CH(CH3)2, -OCH2-cyclo-C3H5, -OCH2-cyclo-C4H7, -OCH2-cyclo-C5H9, -OCH2-cyclo-C6H 11、-OPh、-OCH2-Ph、-OCPh3、-CH2-OCH3、-C2H4-OCH3、-C3H6-OCH3、-CH2-OC2 H5、-C2H4-OC2H5、-C3H6-OC2H5、-CH2-OC3H7、-C2H4-OC3H7、-C3H6-OC3H7、 -CH2-O-シクロ-C3H5、-C2H4-O-シクロ-C3H5、-C3H6-O-シクロ-C3H5、-CH2-OCH(CH3 )2、-C2H4-OCH(CH3)2、-C3H6-OCH(CH3)2、-CH2-OC(CH3)3、-C2H4-OC(CH3)3 、-C3H6-OC(CH3)3、-CH2-OC4H9、-C2H4-OC4H9、-C3H6-OC4H9、-CH2-OPh、-C 2H4-OPh、-C3H6-OPh、-CH2-OCH2-Ph、-C2H4-OCH2-Ph、-C3H6-OCH2-Ph、-SH 、-SCH3、-SC2H5、-SC3H7、-S-シクロ-C3H5、-SCH(CH3)2、-SC(CH3)3、-F、-Cl、-Br、-I、-CN、-COCH3、-COC2H5、-COC3H7、-CO-シクロ-C3H5、-COCH(CH3)2、-COC( CH3)3、-COOH、-COOCH3、-COOC2H5、-COOC3H7、-COO-シクロ-C3H5、-COOCH(CH3 )2、-COOC(CH3)3、-OOC-CH3、-OOC-C2H5、-OOC-C3H7、-OOC-シクロ-C3H5、-OOC -CH(CH3)2、-OOC-C(CH3)3、-CONH2、-CONHCH3、-CONHC2H5、-CONHC3H7、-CONH-シクロ-C3H5、-CONH[CH(CH3)2]、-CONH[C(CH3)3]、-CON(CH3)2、-CON(C2H5 )2、-CON(C3H7)2、-CON(シクロ-C3H5)2、-CON[CH(CH3)2]2、-CON[C(CH3)3]2、 -NHCOCH3、-NHCOC2H5、-NHCOC3H7、-NHCO-シクロ-C3H5、-NHCO-CH(CH3)2、-NHC O-C(CH3)3、-NHCO-CH(NH2)CH2-COOH、-NHCO-CH(NH2)CH2CH2-COOH、-NHCO-OCH3、-NHCO-OC2H5、-NHCO-OC3H7、-NHCO-O-シクロ-C3H5、-NHCO-OCH(CH3)2、-NHCO-OC(CH3)3、-NH2、-NHCH3、-NHC2H5、-NHC3H7、-NH-シクロ-C3H5、-NHCH (CH3)2、-NHC(CH3)3、-N(CH3)2、-N(C2H5)2、-N(C3H7)2、-N(シクロ-C3H5)2、 -N[CH(CH3)2]2、-N[C(CH3)3]2、-SOCH3、-SOC2H5、-SOC3H7、-SO-シクロ-C3H5、-SOCH(CH3)2、-SOC(CH3)3、-SO2CH3、-SO2C2H5、-SO2C3H7、-SO2-シクロ-C3 H5、-SO2CH(CH3)2、-SO2C(CH3)3、-SO3H、-SO3CH3、-SO3C2H5、-SO3C3H7、-SO3-シクロ-C3H5、-SO3CH(CH3)2、-SO3C(CH3)3、-SO2NH2、-SO2NHCH3、-SO2NH C2H5、-SO2NHC3H7、-SO2NH-シクロ-C3H5、-SO2NHCH(CH3)2、-SO2NHC(CH3)3、 -SO2N(CH3)2、-SO2N(C2H5)2、-SO2N(C3H7)2、-SO2N(シクロ-C3H5)2、-SO2N[C H(CH3)2]2、-SO2N[C(CH3)3]2、-OS(=O)CH3、-OS(=O)C2H5、-OS(=O)C3H7、 -OS(=O)-シクロ-C3H5、-OS(=O)CH(CH3)2、-OS(=O)C(CH3)3、-NH-SO2-CH3、- NH-SO2-C2H5、-NH-SO2-C3H7、-NH-SO2-シクロ-C3H5、-NH-SO2-CH(CH3)2、-NH-SO2-C(CH3)3、-O-SO2-CH3、-O-SO2-C2H5、-O-SO2-C3H7、-O-SO2-シクロ-C3 H5、-O-SO2-CH(CH3)2、-O-SO2-C(CH3)3、-OCH2F、-OCHF2、-OCF3、-CH2-OCF3、-C2H4-OCF3、-C3H6-OCF3、-CH2-OCHF2、-C2H4-OCHF2、-C3H6-OCHF2、-O C2F5、-CH2-OC2F5、-C2H4-OC2F5、-C3H6-OC2F5、-NH-CO-NH2、-NH-CO-NHC H3、-NH-CO-NHC2H5、-NH-CO-NHC3H7、-NH-C(=NH)-NH2、-NH-CO-N(C3H7)2、-NH-CO-NH[CH(CH3)2], -NH-CO-NH[C(CH3)3], -NH-CO-N(CH3)2, -NH-CO-N(C2H5)2, -NH-CO-NH-cyclo-C3H5, -NH-CO-N(cyclo-C3H5)2, -NH-CO-N[CH(CH3)2]2, -O-CO-NH-cyclo-C3H5, -O-CO-NH[CH(CH3)2], -NH-C(=NH)-NH[C(CH3)3], -O-CO-NHC3H7, -O-CO-NH2, -O-CO-NHCH3, -O-CO-NHC2H5, -O-CO-NH[C(CH3)3], -O-CO-N(CH3)2, -O-CO-N(C2H5)2, -O-CO-N(C3H7)2, -O-CO-N(cyclo-C, 3H5)2, -O-CO-N[CH(CH3)2]2, -O-CO-N[C(CH3)3]2, -CH2F, -CHF2, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, cyclo-C8H 15 , -Ph, -CH2-Ph, -CH2-CH2-Ph, -CH=CH-Ph, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH2-CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H 11 , -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C6H 13 , -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH=CH-C2H5, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH, -CH=C(CH3)2, -C(CH3)=CH-CH3, -C3H6-CH=CH2, -C2H4-CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -C2H4-C≡CH, -CH2-C≡C-CH3, -C≡C-C2H5,

[0226]

Chem.

[0227] Z3 and Z 4 together

[0228] [ka] may be formed;

[0229] m is an integer selected from 0, 1, 2, or 3; n is an integer selected from 0, 1, 2, 3, or 4; p is an integer selected from 0, 1, or 2; r is an integer selected from 0, 1, 2, or 3; s is an integer selected from 1, 2, 3, 4, 5, 6, or 7; t is an integer selected from 1 or 2; u is an integer selected from 1 or 2; v is an integer selected from 1, 2, or 3; w is an integer selected from 1, 2, or 3.

[0230] Thus, preferably, a compound of formula (I) or an enantiomer, stereoisomer, mixture of enantiomers, diastereomer, mixture of diastereomers, hydrate, solvate, acid salt form, tautomer, racemate or a pharmaceutically acceptable salt thereof of said compound,

[0231] [ka]

[0232] During the ceremony, A is -CO-N(R N6 )-,

[0233] [ka] , represents;

[0234] B is -H, -NH(R2 ), -N(R 2 )(R N5 ),

[0235] [ka] represents;

[0236] L is -CO-, -CO-NH-, -CO-N(R N3 )- or -CO-O-; R 1 -H, -(CH2) p -R 7 , -(CH2) p -NH-R 7 , -(CH2) p -R 9 , or -(CH2) p -NR N4 -R 9 represents; R 2 -H, -R 8 , -R 11 , -L 1 -R 11 , -L 1 -(CH2) r -R 8 , -L 1 -R 10 , -L 1 -(C2H4O) s -R 11 , -L 1 -(CH2) t -OR 11 , -L 1 -(CH2) t -NH-(CH2) r -R 8 , -L 1 -(CH2) t -O-(CH2) r -R 8 , -L 1 -(CH2) t -NHR 8 , -L 1 -(CH2) t -NH-CO-R 8 , -L 1 -(CH2) t-NH-SO2-R 8 , -L 1 -(CH2) t -NR N6 R 10 , -L 1 -(CH2) t -O-(CH2) u -NR N6 R 10 , -L 1 -(CH2) r -R 14 , -CO-C(R 12 )(R 13 )-R 10 , -CO-C(R 12 )(R 13 )-R 8 , or -CO-C(R 12 )(R 13 )-(CH2) u -R 8 represents; L 1 represents a bond, -CO-, -CO2-, -CONH-, or -SO2-; R 3 ~R 6 represent, independently of each other, -H, -CH3, -OCH3, -F, or -Cl; Or, R 5 and R 6 together

[0237] [ka] may be formed;

[0238] R 8 and R 9 are independent of each other.

[0239] [ka]

[0240] [ka] represents;

[0241] R 7 and R 10 are each independently -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CN, -C(CH3)2-CN, -CH2-C(CH3)2-CN, -CH2-CF3, -CH2-C(CH3)2-NH2,

[0242] [ka] , cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H 11 , cyclo-CH 13 , -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H 11 , -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C6H 13 , -CH 15 , -CH 17, -Ph, -CH2-Ph, -CH2-CH2-Ph, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH2, -C(CH3)=CH-CH3, -CH2-CH=C(CH3)2, -CO-CH=C(CH3)2, -C H2-C≡CH, -C2H4-C≡CH, -CH2-C≡C-CH3, -CH2-OCF3, -C2H4-OCF3, -C3H6-OCF3, -C H2-OCHF2, -C2H4-OCHF2, -C3H6-OCHF2, -CH2-OCH3, -C2H4-OCH3, -C3H6-OCH3, -C represents H2-OC2H5, -C2H4-OC2H5, -C3H6-OC2H5, -CH2-OH, -C2H4-OH, -C3H6-OH, -CH2-COOH, -C2H4-COOH, -C3H6-COOH, -C(CH3)2-CN, -C(CH3)2-OH, -C(CH3)2-CH2-OH, -C(C2H5)2-CH2-OH, -C(CH2-OH)2-CH3, -C(CH2-OH)2-C2H5, -C(CH3)2-CH2-SH, -C(C2H5)2-CH2-SH, -C(CH2-SH)2-CH3, -CO-OC(CH3)3, or -C(CH2-SH)2-C2H5;

[0243] R 11 -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CN, -C(CH3)2-CN, -CH2-C(CH3)2-CN, -CH2-CF3, -CH2-C(CH3)2-NH2,

[0244] [ka] , cyclo-C3H5, cyclo-C4H, cyclo-C5H9, cyclo-C6H 11 , cyclo-CH 13 , -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H 11, -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C6H 13 , -CH 15 , -CH 17 , -Ph, -CH2-Ph, -CH2-CH2-Ph, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C(CH3)=CH-CH3, -CH=C(CH3)2, -C(CH3)=C(CH3)2, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH2, -C(CH3)=CH-CH3, -CH2-CH=C(CH3)2, -C≡CH, - CH2-C≡CH, -C2H4-C≡CH, -CH2-C≡C-CH3, -C≡C-CH3, -C≡C-C2H5, -CH2-OCF3, -C2H4-OC F3, -C3H6-OCF3, -CH2-OCHF2, -C2H4-OCHF2, -C3H6-OCHF2, -CH2-OCH3, -C2H4-OCH3, -C3H6-OCH3, -CH2-OC2H5, -C2H4-OC2H5, -C3H6-OC2H5, -CH2-OH, -C2H4-OH, -C3H6-O H, -C(CH3)2-CH2-OH, -C(C2H5)2-CH2-OH, -C(CH2-OH)2-CH3, -C(CH2-OH)2-C2H5, -C (CH3)2-CH2-SH, -C(C2H5)2-CH2-SH, -C(CH2-SH)2-CH3, or -C(CH2-SH)2-C2H5;

[0245] R 12 and R 13 represent, independently of one another, -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -Ph, -CH2-Ph, -COOH, -NH2, -NHCO2(CCH3)3, -CH2-NH2, -CHF2, -CF3, -OCF3, -OCHF2, -OH, -F, -OCH3, -OC2H5, -OC3H7, or -OCH(CH3)2; or R 12 and R 13 together

[0246] [ka] may be formed;

[0247] R 14 teeth,

[0248] [ka] represents; R 15 and R 16 are independent of each other, -X 3 -L 2 -R 17 , or -(OCH2CH2) w -R 17 represents;

[0249] L 2 is -(CH2) v -, -(CH2CH2-O) w -CH2-, or -(CH2CH2-O) w represents -CH2CH2-; R 17 represents -OH, -SH, -SO3H, -NH2, or -CO2H; R N1 , R N2 , R N3 and R N4 are independent of each other, -R 15 , -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -CHF2, -CF3,

[0250] [ka] , cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H 11 , cyclo-CH 13 , -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5H 11, -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C6H 13 , -CH 15 , -CH 17 , -Ph, -CH2-Ph, -CH2-CH2-Ph, -C2H4-CH=CH2, -CH2-CH=CH-CH3, -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH2, -CH2-CH=C(CH3)2, -CH2-C≡CH, - C2H4-C≡CH, -CH2-C≡C-CH3, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7 , -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, or -SO3H;

[0251] R N5 and R N6 represent, independently of one another, -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, cyclo-C3H5, -COOC(CH3)3, or -COOCH2Ph; X 1 is -(CH2) m - represents; X 2 is -(CH2) n - represents; X 3 represents a bond, -O-, -NH-, or -S-; Z 1 ~Z 14 are independent of each other,

[0252] [ka] , cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H 11 , cyclo-CH 13 , -R 16 , -H, -OH, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -O-cyclo-C4H7, -O-cyclo-C5H9, -O-cyclo-C6H 11 , -OCH2CH(CH3)2, -OCH2-cyclo-C3H5, -OCH2-cyclo-C4H7, -OCH2-cyclo-C5H9, -OCH2-cyclo-C6H 11、-OPh、-OCH2-Ph、-OCPh3、-CH2-OCH3、-C2H4-OCH3、-C3H6-OCH3、-CH2-OC2 H5、-C2H4-OC2H5、-C3H6-OC2H5、-CH2-OC3H7、-C2H4-OC3H7、-C3H6-OC3H7、 -CH2-O-シクロ-C3H5、-C2H4-O-シクロ-C3H5、-C3H6-O-シクロ-C3H5、-CH2-OCH(CH3 )2、-C2H4-OCH(CH3)2、-C3H6-OCH(CH3)2、-CH2-OC(CH3)3、-C2H4-OC(CH3)3 、-C3H6-OC(CH3)3、-CH2-OC4H9、-C2H4-OC4H9、-C3H6-OC4H9、-CH2-OPh、-C 2H4-OPh、-C3H6-OPh、-CH2-OCH2-Ph、-C2H4-OCH2-Ph、-C3H6-OCH2-Ph、-SH 、-SCH3、-SC2H5、-SC3H7、-S-シクロ-C3H5、-SCH(CH3)2、-SC(CH3)3、-F、-Cl、-Br、-I、-CN、-COCH3、-COC2H5、-COC3H7、-CO-シクロ-C3H5、-COCH(CH3)2、-COC( CH3)3、-COOH、-COOCH3、-COOC2H5、-COOC3H7、-COO-シクロ-C3H5、-COOCH(CH3 )2、-COOC(CH3)3、-OOC-CH3、-OOC-C2H5、-OOC-C3H7、-OOC-シクロ-C3H5、-OOC -CH(CH3)2、-OOC-C(CH3)3、-CONH2、-CONHCH3、-CONHC2H5、-CONHC3H7、-CONH-シクロ-C3H5、-CONH[CH(CH3)2]、-CONH[C(CH3)3]、-CON(CH3)2、-CON(C2H5 )2、-CON(C3H7)2、-CON(シクロ-C3H5)2、-CON[CH(CH3)2]2、-CON[C(CH3)3]2、 -NHCOCH3、-NHCOC2H5、-NHCOC3H7、-NHCO-シクロ-C3H5、-NHCO-CH(CH3)2、-NHC O-C(CH3)3、-NHCO-CH(NH2)CH2-COOH、-NHCO-CH(NH2)CH2CH2-COOH、-NHCO-OCH3、-NHCO-OC2H5、-NHCO-OC3H7、-NHCO-O-シクロ-C3H5、-NHCO-OCH(CH3)2、-NHCO-OC(CH3)3、-NH2、-NHCH3、-NHC2H5、-NHC3H7、-NH-シクロ-C3H5、-NHCH(CH3)2、-NHC(CH3)3、-N(CH3)2、-N(C2H5)2、-N(C3H7)2、-N(シクロ-C3H5)2、-N [CH(CH3)2]2、-N[C(CH3)3]2、-SOCH3、-SOC2H5、-SOC3H7、-SO-シクロ-C3H5、-SOCH(CH3)2、-SOC(CH3)3、-SO2CH3、-SO2C2H5、-SO2C3H7、-SO2-シクロ-C3H5、 -SO2CH(CH3)2、-SO2C(CH3)3、-SO3H、-SO3CH3、-SO3C2H5、-SO3C3H7、-SO3-シクロ-C3H5、-SO3CH(CH3)2、-SO3C(CH3)3、-SO2NH2、-SO2NHCH3、-SO2NHC2H5 、-SO2NHC3H7、-SO2NH-シクロ-C3H5、-SO2NHCH(CH3)2、-SO2NHC(CH3)3、-SO2N (CH3)2、-SO2N(C2H5)2、-SO2N(C3H7)2、-SO2N(シクロ-C3H5)2、-SO2N[CH(CH3) 2]2、-SO2N[C(CH3)3]2、-OS(=O)CH3、-OS(=O)C2H5、-OS(=O)C3H7、-OS(=O) -シクロ-C3H5、-OS(=O)CH(CH3)2、-OS(=O)C(CH3)3、-S(=O)(=NH)CH3、-S(=O) (=NH)C2H5、-S(=O)(=NH)C3H7、-S(=O)(=NH)-シクロ-C3H5、-S(=O)(=NH)CH(CH3)2、-S(=O)(=NH)C(CH3)3、-NH-SO2-CH3、-NH-SO2-C2H5、-NH-SO2-C3H7、 -NH-SO2-シクロ-C3H5、-NH-SO2-CH(CH3)2、-NH-SO2-C(CH3)3、-O-SO2-CH3、-O-SO2-C2H5、-O-SO2-C3H7、-O-SO2-シクロ-C3H5、-O-SO2-CH(CH3)2、-O-SO2- C(CH3)3、-OCH2F、-OCHF2、-OCF3、-CH2-OCF3、-C2H4-OCF3、-C3H6-OCF3、-C H2-OCHF2、-C2H4-OCHF2、-C3H6-OCHF2、-OC2F5、-CH2-OC2F5、-C2H4-OC2F5、-C3H6-OC2F5、-O-COOCH3、-O-COOC2H5、-O-COOC3H7、-O-COO-シクロ-C3H5、-O-COOCH(CH3)2、-O-COOC(CH3)3、-NH-CO-NH2、-NH-CO-NHCH3、-NH-CO-NHC2H5、-NH-CO-NHC3H7、-N H-C(=NH)-NH2、-NH-CO-N(C3H7)2、-NH-CO-NH[CH(CH3)2]、-NH-CO-NH[C(CH3)3]、-NH-CO-N(CH3)2、-NH-CO-N(C2H5)2、-NH-CO-NH-シクロ-C3H5、-NH-CO-N(シクロ-C3H5)2、-NH-C、 ON[CH(CH3)2]2、-NH-C(=NH)-NHCH3、-NH-C(=NH)-NHC2H5、-NH-C(=NH)-NHC3H7、-O-CO-NH--C3H5、-NH-C(=NH)-NH--C3H5、-NH-C(=NH)-NH--C3H5、-NH-C(=NH)-NH[CH(CH3)2]、-O-CO-NH[CH(CH3)2]、 -NH-C(=NH)-NH[C(CH3)3]、-NH-C(=NH)-N(CH3)2、-NH-C(=NH)-N(C2H5)2、-NH-C(=NH)-N(C3H7)2、-NH-C(=NH)-N(C3H5)2、-O-CO-NHC3H7、-NH-C(=NH)-N[CH(CH3)2]2、-NH-C(=NH )-N[C(CH3)3]2、-O-CO-NH2、-O-CO-NHCH3、-O-CO-NHC2H5、-O-CO-NH[C(CH3)3]、-O-CO-N( CH3)2、-O-CO-N(C2H5)2、-O-CO-N(C3H7)2、-O-CO-N(シクロ-C3H5)2、-O-CO-N[CH(CH3)2]2、-O -CO-N[C(CH3)3]2、-O-CO-OCH3、-O-CO-OC2H5、-O-CO-OC3H7、-O-CO-O-シクロ-C3H5、-O-CO-OC H(CH3)2、-O-CO-OC(CH3)3、-CH2F、-CHF2、-CF3、-CH2-CH2F、-CH2-CHF2、-CH2-CF3、シクロ-C8H 15、-Ph、-CH2-Ph、-CH2-CH2-Ph、-CH=CH-Ph、-CPh3、-CH3、-C2H5、-C3H7、-CH(CH3)2、-C4H9、-CH2-CH(CH3)2、-CH(CH3)-C2H5、-C(CH3)3、-C5H 11 、-CH(CH3)-C3H7、-CH2-CH(CH3)-C2H5、-CH(CH3)-CH(CH3)2、-C(CH3)2-C2H5、-CH2-C(CH3)3、-CH(C2H5)2、-C2H4-CH(CH3)2、-C6H 13 、-C7H 15 、-C8H 17、-C3H6-CH(CH3)2、-C2H4-CH(CH3)-C2H5、-CH(CH3)-C4H9、-CH2-CH(CH3)-C3H7、-CH(CH3)-CH2-CH(CH3)2、-CH(CH3)-CH(CH3)-C2H5、-CH2-CH(CH3)-CH(CH3)2、-CH2-C(CH3)2-C2H5、-C(CH3)2-C3H7、-C(CH3)2-CH(CH3)2、-C2H4-C(CH3)3、-CH(CH3)-C(CH3)3、-CH=CH2、-CH2-CH=CH2、-C(CH3)=CH2、-CH=CH-CH3、-C2H4-CH=CH2、-CH2-CH=CH-CH3、-CH=CH-C2H5、-CH2-C(CH3)=CH2、-CH(CH3)-CH=CH、-CH=C(CH3)2、-C(CH3)=CH-CH3、-CH=CH-CH=CH2、-C3H6-CH=CH2、-C2H4-CH=CH-CH3、-CH2-CH=CH-C2H5、-CH=CH-C3H7、-CH=CH-CH=CH-CH3、-C2H4-C(CH3)=CH2、-CH2-CH(CH3)-CH=CH2、-CH(CH3)-CH2-CH=CH2、-CH2-CH=C(CH3)2、-CH2-C(CH3)=CH-CH3、-CH(CH3)-CH=CH-CH3、-CH=CH-CH(CH3)2、-CH=C(CH3)-C2H5、-C(CH3)=CH-C2H5、-C(CH3)=C(CH3)2、-C(CH3)2-CH=CH2、-CH(CH3)-C(CH3)=CH2、-C4H8-CH=CH2、-C3H6-CH=CH-CH3、-C2H4-CH=CH-C2H5、-CH2-CH=CH-C3H7、-CH=CH-C4H9、-C3H6-C(CH3)=CH2、-C2H4-CH(CH3)-CH=CH2、-CH2-CH(CH3)-CH2-CH=CH2、-C2H4-CH=C(CH3)2、-CH(CH3)-C2H4-CH=CH2、-C2H4-C(CH3)=CH-CH3、-CH2-CH(CH3)-CH=CH-CH3、-CH(CH3)-CH2-CH=CH-CH3、-CH2-CH=CH-CH(CH3)2、-CH2-CH=C(CH3)-C2H5、-CH2-C(CH3)=CH-C2H5、-CH(CH3)-CH=CH-C2H5、-CH=CH-CH2-CH(CH3)2、-CH=CH-CH(CH3)-C2H5、-CH=C(CH3)-C3H7、-C(CH3)=CH-C3H7、-CH2-CH(CH3)-C(CH3)=CH2、-C[C(CH3)3]=CH2、-CH(CH3)-CH2-C(CH3)=CH2、-CH(CH3)-CH(CH3)-CH=CH2、-CH=CH-C2H4-CH=CH2、-C(CH3)2-CH2-CH=CH2、-CH2-C(CH3)=C(CH3)2、-CH(CH3)-CH=C(CH3)2、-C(CH3)2-CH=CH-CH3、-CH=CH-CH2-CH=CH-CH3、-CH(CH3)-C(CH3)=CH-CH3、-CH=C(CH3)-CH(CH3)2、-C(CH3)=CH-CH(CH3)2、-C(CH3)=C(CH3)-C2H5、-CH=CH-C(CH3)3、-C(CH3)2-C(CH3)=CH2、-CH(C2H5)-C(CH3)=CH2、-C(CH3)(C2H5)-CH=CH2、-CH(CH3)-C(C2H5)=CH2、-CH2-C(C3H7)=CH2、-CH2-C(C2H5)=CH-CH3、-CH(C2H5)-CH=CH-CH3、-C(C4H9)=CH2、-C(C3H7)=CH-CH3、-C(C2H5)=CH-C2H5、-C(C2H5)=C(CH3)2、-C[CH(CH3)(C2H5)]=CH2、-C[CH2-CH(CH3)2]=CH2、-C2H4-CH=CH-CH=CH2、-CH2-CH=CH-CH2-CH=CH2、-C3H6-C≡C-CH3、-CH2-CH=CH-CH=CH-CH3、-CH=CH-CH=CH-C2H5、-CH(CH3)-CH2-C≡CH、-CH(CH3)-C≡C-CH3、-C2H4-CH(CH3)-C≡CH、-CH=CH-CH=C(CH3)2、-CH2-CH(CH3)-CH2-C≡CH、-CH=CH-C(CH3)=CH-CH3、-CH=C(、 CH3)-CH=CH-CH3, -CH2-CH(CH3)-C≡CH, -C(CH3)=CH-CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -C2H4-C ≡CH, -CH2-C≡C-CH3, -C≡C-C2H5, -C3H6-C≡CH, -C2H4-C≡C-CH3, -CH2-C≡C-C2H5, -C≡C-C3H7, -CH(CH3)-C ≡CH, -C4H8-C≡CH, -C2H4-C≡C-C2H5, -CH2-C≡C-C3H7, -C≡C-C4H9, -C≡C-CH2-CH(CH3)2, -CH(CH3)-C2H4- C≡CH, -CH2-CH(CH3)-C≡C-CH3, -C(CH3)(C2H5)-C≡CH, -CH(CH3)-CH2-C≡C-CH3, -CH(CH3)-C≡C-C2H5, -C H2-C≡C-CH(CH3)2, -C≡C-CH(CH3)-C2H5, -CH2-C≡CC≡C-CH3, -CH(C2H5)-C≡C-CH3, -C(CH3)2-C≡C-CH3, - CH(C2H5)-CH2-C≡CH, -CH2-CH(C2H5)-C≡CH, -C(CH3)2-CH2-C≡CH, -CH2-C(CH3)2-C≡CH, -CH(CH3)-CH(C H3)-C≡CH, -CH(C3H7)-C≡CH, -CH2-CH(C≡CH)2, -C≡CC≡CH, -CH2-C≡CC≡CH, -C≡CC≡C-CH3, -CH(C≡CH)2, -C 2H4-C≡CC≡CH, -CH2-C≡C-CH2-C≡CH, -C≡C-C2H4-C≡CH, -C≡CC(CH3)3, -C≡C-CH2-C≡C-CH3, -C≡CC≡C-C2H5,

[0253] [ka] represents;

[0254] Z 3 and Z 4 together

[0255] [ka] may be formed;

[0256] Z 13 and Z 14 together

[0257] [ka] may be formed;

[0258] m is an integer selected from 0, 1, 2, 3, 4, 5, or 6; n is an integer selected from 0, 1, 2, 3, 4, 5, or 6; p is an integer selected from 0, 1, 2, 3, 4, 5, or 6; r is an integer selected from 0, 1, 2, 3, or 4; s is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; t is an integer selected from 1, 2, 3, or 4; u is an integer selected from 1, 2, 3, or 4; v is an integer selected from 0, 1, 2, 3, 4, 5, or 6; w is an integer selected from 0, 1, 2, 3, 4, 5, or 6.

[0259] Even more preferred are compounds of formula (I) wherein R 8 teeth

[0260] [ka]

[0261] [ka] represents;

[0262] where R N1 , Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 has the same meaning as defined in formula (I). More preferred are compounds of formula (I), wherein R 9 teeth

[0263] [ka] represents

[0264] where R N1 , Z 1 , Z 2 , Z 6 , Z 7 , Z 8 , Z 9 , and Z 10 has the same meaning as defined in formula (I). Thus, preferably, a compound of formula (I) or an enantiomer, stereoisomer, mixture of enantiomers, diastereomer, mixture of diastereomers, hydrate, solvate, acid salt form, tautomer, racemate or a pharmaceutically acceptable salt thereof of said compound,

[0265] [ka]

[0266] During the ceremony, A is -CO-N(R N6 )-,

[0267] [ka] , represents;

[0268] B is -H, -NH(R 2 ), -N(R 2 )(R N5 ),

[0269] [ka] represents;

[0270] Preferably, B is -H, -NH(R 2 ), -N(R 2 )(R N5 ),

[0271] [ka] represents;

[0272] L is -CO-, -CO-NH-, -CO-N(R N3 )- or -CO-O-; R 1 -H, -(CH2) p -R 7 , -(CH2) p -NH-R 7 , -(CH2) p -R 9 , or -(CH2) p -NR N4 -R 9 represents; R 2 -H, -R 8 , -R 11 , -L 1 -R 11 , -L 1 -(CH2) r -R 8 , -L 1 -R 10 , -L 1 -(C2H4O) s -R 11 , -L 1 -(CH2) t -OR 11 , -L 1 -(CH2) t -NH-(CH2) r -R 8 , -L 1 -(CH2) t -O-(CH2) r -R 8 , -L 1 -(CH2) t -NHR 8 , -L 1 -(CH2) t -NH-CO-R 8 , -L1 -(CH2) t -NH-SO2-R 8 , -L 1 -(CH2) t -NR N6 R 10 , -L 1 -(CH2) t -O-(CH2) u -NR N6 R 10 , -L 1 -(CH2) r -R 14 , -CO-C(R 12 )(R 13 )-R 10 , -CO-C(R 12 )(R 13 )-R 8 , or -CO-C(R 12 )(R 13 )-(CH2) u -R 8 represents; L 1 represents a bond, -CO-, -CO2-, -CONH-, or -SO2-; R 3 ~R 6 represent, independently of each other, -H, -CH3, -OCH3, -F, or -Cl; Or, R 5 and R 6 together

[0273] [ka] may be formed;

[0274] R 8 teeth,

[0275] [ka]

[0276] [ka] represents;

[0277] R 9 teeth,

[0278] [ka] represents;

[0279] X 1 is -(CH2) m - represents; X 2 is -(CH2) n - represents; X 3 represents a bond, -O-, -NH-, or -S-; and R N1 ~R N6 , R 7 , R 10 ~R 17 , Z 1 ~Z 14 , m, n, o, p, r, s, t, u, v, w have the same meanings as defined herein.

[0280] Preferably, R 15 teeth -CH2-OH, -CH2-CH2-OH, -CH2CH2CH2-OH, -CH2CH2CH2CH2-OH, -CH2CH2CH2CH2CH2-OH, -CH2CH2CH2CH2CH2-OH, -CH2-CO2H, -CH2CH2-CO2H, -CH2CH2CH2-CO2H, -CH2CH2CH2CH2-CO2H, -CH2CH2CH2CH2CH2-CO2H, -CH2CH2CH2CH2CH2-CO2H, -CH2-SH, -CH2CH2-SH, -CH2CH2CH2-SH, -CH2CH2CH2CH2-SH, -CH2CH2CH2CH2CH2-SH, -CH2CH2CH2CH2CH2-SH, -CH2-SO3H, -CH2CH2-SO3H, -CH2CH2CH2-SO3H, -CH2CH2CH2CH2-SO3H, -CH2CH2CH2CH2CH2-SO3H, -CH2CH2CH2CH2CH2-SO3H, -CH2-NH2, -CH2CH2-NH2, -CH2CH2CH2-NH2, -CH2CH2CH2CH2-NH2, -CH2CH2CH2CH2CH2-NH2, -CH2CH2CH2CH2CH2CH2-NH2, -CH2CH2-O-CH2-CH2-OH, -(CH2CH2-O)2-CH2-CH2-OH, -(CH2CH2-O)3-CH2-CH2-OH, -CH2CH2-O-CH2-CH2-CO2H, -(CH2CH2-O)2-CH2-CH2-CO2H, -(CH2CH2-O)3-CH2-CH2-CO2H, -CH2CH2-O-CH2-CH2-SH, -(CH2CH2-O)2-CH2-CH2-SH, -(CH2CH2-O)3-CH2-CH2-SH, -CH2CH2-O-CH2-CH2-SO3H, -(CH2CH2-O)2-CH2-CH2-SO3H, -(CH2CH2-O)3-CH2-CH2-SO3H, -CH2CH2-O-CH2-CH2-NH2, -(CH2CH2-O)2-CH2-CH2-NH2, or -(CH2CH2-O)3-CH2-CH2-NH2.

[0281] More preferably, R 15represents -CH2-NH2, -CH2CH2-NH2, -CH2CH2CH2-NH2, -CH2-SO3H, -CH2CH2-SO3H, -CH2CH2CH2-SO3H, -CH2CH2-O-CH2-CH2-NH2, -(CH2CH2-O)2-CH2-CH2-NH2, or -(CH2CH2-O)3-CH2-CH2-NH2.

[0282] Preferably, R 16 teeth -CH2-OH、-CH2CH2-OH、-CH2CH2CH2-OH、-CH2CH2CH2CH2-OH、-CH2CH2CH2CH2CH2-OH、-CH2CH2CH2CH2CH2-OH、-CH2-CO2H、-CH2CH2-CO2H、-CH2CH2CH2-CO2H、-CH2CH2CH2CH2-CO2H、-CH2CH2CH2CH2CH2-CO2H、-CH2CH2CH2CH2CH2-CO2H、-CH2-SH、-CH2CH2-SH、-CH2CH2CH2-SH、-CH2CH2CH2CH2-SH、-CH2CH2CH2CH2CH2-SH、-CH2CH2CH2CH2CH2-SH、-CH2-SO3H、-CH2CH2-SO3H、-CH2CH2CH2-SO3H、-CH2CH2CH2CH2-SO3H、-CH2CH2CH2CH2CH2-SO3H、-CH2CH2CH2CH2CH2-SO3H、-CH2-NH2、-CH2CH2-NH2、-CH2CH2CH2-NH2、-CH2CH2CH2CH2-NH2、-CH2CH2CH2CH2CH2-NH2、-CH2CH2CH2CH2CH2CH2-NH2、-CH2CH2-O-CH2-CH2-OH、-(CH2CH2-O)2-CH2-CH2-OH、-(CH2CH2-O)3-CH2-CH2-OH、-CH2CH2-O-CH2-CH2-CO2H、-(CH2CH2-O)2-CH2-CH2-CO2H、-(CH2CH2-O)3-CH2-CH2-CO2H、-CH2CH2-O-CH2-CH2-SH、-(CH2CH2-O)2-CH2-CH2-SH、-(CH2CH2-O)3-CH2-CH2-SH、-CH2CH2-O-CH2-CH2-SO3H、-(CH2CH2-O)2-CH2-CH2-SO3H、-(CH2CH2-O)3-CH2-CH2-SO3H、-CH2CH2-O-CH2-CH2-NH2、-(CH2CH2-O)2-CH2-CH2-NH2、-(CH2CH2-O)3-CH2-CH2-NH2、-OCH2-OH、-OCH2CH2-OH、-OCH2CH2CH2-OH、-OCH2CH2CH2CH2-OH、-OCH2CH2CH2CH2CH2-OH、-OCH2CH2CH2CH2CH2-OH、-OCH2-CO2H、-OCH2CH2-CO2H、-OCH2CH2CH2-CO2H、-OCH2CH2CH2CH2-CO2H、-OCH2CH2CH2CH2CH2-CO2H、-OCH2CH2CH2CH2CH2-CO2H、-OCH2-SH、-OCH2CH2-SH、-OCH2CH2CH2-SH、-OCH2CH2CH2CH2-SH、-OCH2CH2CH2CH2CH2-SH、-OCH2CH2CH2CH2CH2-SH、-OCH2-SO3H、-OCH2CH2-SO3H、-OCH2CH2CH2-SO3H、-OCH2CH2CH2CH2-SO3H、-OCH2CH2CH2CH2CH2-SO3H、-OCH2CH2CH2CH2CH2-SO3H、-OCH2-NH2、-OCH2CH2-NH2、-OCH2CH2CH2-NH2、-OCH2CH2CH2CH2-NH2、-OCH2CH2CH2CH2CH2-NH2、-OCH2CH2CH2CH2CH2CH2-NH2、-OCH2CH2-O-CH2-CH2-OH、-O(CH2CH2-O)2-CH2-CH2-OH、-O(CH2CH2-O)3-CH2-CH2-OH、-OCH2CH2-O-CH2-CH2-CO2H、-O(CH2CH2-O)2-CH2-CH2-CO2H、-O(CH2CH2-O)3-CH2-CH2-CO2H、-OCH2CH2-O-CH2-CH2-SH、-O(CH2CH2-O)2-CH2-CH2-SH、-O(CH2CH2-O)3-CH2-CH2-SH、-OCH2CH2-O-CH2-CH2-SO3H、-O(CH2CH2-O)2-CH2-CH2-SO3H、-O(CH2CH2-O)3-CH2-CH2-SO3H、-OCH2CH2-O-CH2-CH2-NH2、-O(CH2CH2-O)2-CH2-CH2-NH2、-O(CH2CH2-O)3-CH2-CH2-NH2、-SCH2-OH、-SCH2CH2-OH、-SCH2CH2CH2-OH、-SCH2CH2CH2CH2-OH、-SCH2CH2CH2CH2CH2-OH、-SCH2CH2CH2CH2CH2-OH、-SCH2-CO2H、-SCH2CH2-CO2H、-SCH2CH2CH2-CO2H、-SCH2CH2CH2CH2-CO2H、-SCH2CH2CH2CH2CH2-CO2H、-SCH2CH2CH2CH2CH2-CO2H、-SCH2-SH、 -SCH2CH2-SH、-SCH2CH2CH2-SH、-SCH2CH2CH2CH2-SH、-SCH2CH2CH2CH2CH2-SH、-SCH2CH2CH2CH2CH2-SH、-SCH2-SO3H、-SCH2CH2-SO3H、-SCH2CH2CH2-SO3H、-SCH2CH2CH2CH2-SO3H、-SCH2CH2CH2CH2CH2-SO3H、-SCH2CH2CH2CH2CH2-SO3H、-SCH2-NH2、-SCH2CH2-NH2、-SCH2CH2CH2-NH2、-SCH2CH2CH2CH2-NH2、-SCH2CH2CH2CH2CH2-NH2、-SCH2CH2CH2CH2CH2CH2-NH2、-SCH2CH2-O-CH2-CH2-OH、-S(CH2CH2-O)2-CH2-CH2-OH、-S(CH2CH2-O)3-CH2-CH2-OH、-SCH2CH2-O-CH2-CH2-CO2H、-S(CH2CH2-O)2-CH2-CH2-CO2H、-S(CH2CH2-O)3-CH2-CH2-CO2H、-SCH2CH2-O-CH2-CH2-SH、-S(CH2CH2-O)2-CH2-CH2-SH、-S(CH2CH2-O)3-CH2-CH2-SH、-SCH2CH2-O-CH2-CH2-SO3H、-S(CH2CH2-O)2-CH2-CH2-SO3H、-S(CH2CH2-O)3-CH2-CH2-SO3H、-SCH2CH2-O-CH2-CH2-NH2、-S(CH2CH2-O)2-CH2-CH2-NH2、-S(CH2CH2-O)3-CH2-CH2-NH2、-NHCH2-OH、-NHCH2CH2-OH、-NHCH2CH2CH2-OH、-NHCH2CH2CH2CH2-OH、-NHCH2CH2CH2CH2CH2-OH、-NHCH2CH2CH2CH2CH2-OH、-NHCH2-CO2H、-NHCH2CH2-CO2H、-NHCH2CH2CH2-CO2H、-NHCH2CH2CH2CH2-CO2H、-NHCH2CH2CH2CH2CH2-CO2H、-NHCH2CH2CH2CH2CH2-CO2H、-NHCH2-SH、-NHCH2CH2-SH、-NHCH2CH2CH2-SH、-NHCH2CH2CH2CH2-SH、-NHCH2CH2CH2CH2CH2-SH、-NHCH2CH2CH2CH2CH2-SH、-NHCH2-SO3H, -NHCH2CH2-SO3H, -NHCH2CH2CH2-SO3H, -NHCH2CH2CH2CH2-SO3H, -NHCH2CH2CH2CH2CH2-SO3H, -NHCH2CH2CH2CH2CH2-SO3H, -NHCH2-NH2, -NHCH2CH2-NH2, -NHCH2CH2CH2-NH2 , -NHCH2CH2CH2CH2-NH2, -NHCH2CH2CH2CH2CH2-NH2, -NHCH2CH2CH2CH2CH2CH2-NH2, -NHCH2CH2-O-CH2-CH2-OH, -NH(CH2CH2-O)2-CH2-CH2-OH, -NH(CH2CH2-O)3-CH2-CH2-OH, -NHCH2CH2- O-CH2-CH2-CO2H, -NH(CH2CH2-O)2-CH2-CH2-CO2H, -NH(CH2CH2-O)3-CH2-CH2-CO2H, -NHCH2 CH2-O-CH2-CH2-SH, -NH(CH2CH2-O)2-CH2-CH2-SH, -NH(CH2CH2-O)3-CH2-CH2-SH, -NHCH2CH2 -O-CH2-CH2-SO3H, -NH(CH2CH2-O)2-CH2-CH2-SO3H, -NH(CH2CH2-O)3-CH2-CH2-SO3H, -NHCH2 Represents CH2-O-CH2-CH2-NH2, -NH(CH2CH2-O)2-CH2-CH2-NH2, or -NH(CH2CH2-O)3-CH2-CH2-NH2. ,

[0283] More preferably, R 16 represents -CH2-NH2, -CH2CH2-NH2, -CH2CH2CH2-NH2, -CH2-SO3H, -CH2CH2-SO3H, -CH2CH2CH2-SO3H, -CH2CH2-O-CH2-CH2-NH2, -(CH2CH2-O)2-CH2-CH2-NH2, or -(CH2CH2-O)3-CH2-CH2-NH2.

[0284] More preferred are compounds of formula (I), wherein A is -CO-NH-, -CO-NCH3-,

[0285] [ka] and; and / or

[0286] X2 represents a bond, -CH2-, -CH2CH2-, or -CH2CH2CH2-; and X1 represents a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-; More preferably, -X2-A-X1- is a compound

[0287] [ka] .

[0288] More preferred are compounds of general formula (I), wherein B is -H, -NH2, -NHCOCH3, -NHCOC(CH3)3, -NHCOC(CN)(CH3)2, -NHCOCH=CH2, -NHCOCH2C(CH3)3, -NHCOPh, -NHCOCH2Ph, -NHCOCH2-NH(CH3), -NHCOCH2-N(CH3)CO2tBu, -NHCOC(CH3)2CH2OH, -NHCOC(CH3)2CH2SH, -NHCOC(CH3)2CH2NH2, -NHCOC(CH3)2CH2F, -NHC OC(CH3)2CF3, -NHCOCF2CH2OH, -NHCOCF2CH2NH2, -NHCOC(CH2CH3)2CH2OH, -NHCOC(CH3)(CH2OH)2, -NHCOCH2OCH2CH2-NH(CH3), -NHCOCH2OCH2CH2-N(CH 3)CO2tBu, -NHCO(CH2CH2O)2CH3, -NHCO2CH2CH3, -NHCO2(CH2CH2O)3CH3, -NHCO2(CH2CH2O)5CH3, -NHCO2(CH2CH2O)7CH3, -NHCO2CH2Ph, -NHCONHCH2CH3 , -NHSO2CH3, -NHSO2CH=CH2, -NHSO2CH2Ph, -NHSO2CH2CH2Ph, -NHSO2CH2CH2CH2Ph, -NHSO2CH2CF3, -NHCH2CF3, -NHCH2(CH3)2NH2, -NHCH2(CH3)2CH2OH,

[0289] [ka]

[0290] [ka]

[0291] [ka]

[0292] [ka]

[0293] [ka]

[0294] [ka] and / or

[0295] R 1 are -CH3, -CH2CH2-CH(CH3)2, -CH2CH2-C≡CH,

[0296] [ka] Represents.

[0297] More preferably, the present invention relates to compounds of formula (I):

[0298] [ka]

[0299] During the ceremony, A is -CO-NH-, -CO-NCH3-

[0300] [ka] represents;

[0301] X2 represents a bond, -CH2-, -CH2CH2-, or -CH2CH2CH2-; X1 represents a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-; B is -H, -NH2, -NHCOCH3, -NHCOC(CH3)3, -NHCOC(CN)(CH3)2, -NHCOCH=CH2, -NHCOCH2C(CH3)3, -NHCOPh, -NHCOCH2Ph, -NHCOCH2-NH(CH3), -NHCOCH2-N(CH3)CO2tBu, -NHCOC(CH3) 2CH2OH, -NHCOC(CH3)2CH2SH, -NHCOC(CH3)2CH2NH2, -NHCOC(CH3)2CH2F, -NHCOC(CH3)2CF3, -NHCOCF2CH2OH, -NHCOCF2CH2NH2, -NHCOC(CH2CH3)2CH2OH, -NHCO2CH2CH3, -NHCOC( CH3)(CH2OH)2, -NHCOCH2OCH2CH2-NH(CH3), -NHCOCH2OCH2CH2-N(CH3)CO2tBu, -NHCO(CH2CH2O)2CH3, -NHCO2(CH2CH2O)3CH3, -NHCO2(CH2CH2O)5CH3, -NHCO2(CH2CH2O)7CH3, -N HCO2CH2Ph-NHCONHCH2CH3, -NHSO2CH3, -NHSO2CH=CH2, -NHSO2CH2Ph, -NHSO2CH2CH2Ph, -NHSO2CH2CH2CH2Ph, -NHSO2CH2CF3, -NHCH2CF3, -NHCH2(CH3)2NH2, -NHCH2(CH3)2CH2OH,

[0302] [ka]

[0303] [ka]

[0304] [ka]

[0305] [ka]

[0306] [ka]

[0307] [ka] represents; and

[0308] R 1 are -CH3, -CH2CH2-CH(CH3)2, -CH2CH2-C≡CH,

[0309] [ka] represents;

[0310] R 3 ~R 6 represent, independently of each other, -H, -CH3, -OCH3, -F, or -Cl; Or, R 5 and R 6 together

[0311] [ka] may be formed.

[0312] More preferably, it is a compound of formula (I):

[0313] [ka]

[0314] In the formula, -X2-A-X1- represents

[0315]

Chemical formula

[0316] B is -H, -NH2, -NHCOCH3, -NHCOC(CH3)3, -NHCOC(CN)(CH3)2, -NHCOCH=CH2, -NHCOCH2C(CH3)3, -NHCOPh, -NHCOCH2Ph, -NHCOCH2-NH(CH3), -NHCOCH2-N(CH3)CO2tBu, -NHCOC(CH3)2CH2OH, -NHCOC(CH3)2CH2SH, -NHCOC(CH3)2CH2NH2, -NHCOC(CH3)2CH2F, -NHCOC(CH3)2CF3, -NHCOCF2CH2OH, -NHCOCF2CH2NH2, -NHCOC(CH2CH3)2CH2OH, -NHCOC(CH3)(CH2OH)2, -NHCOCH2OCH2CH2-NH(CH3), -NHCOCH2OCH2CH2-N(CH3)CO2tBu, -NHCO(CH2CH2O)2CH3, -NHCO2CH2CH3, -NHCO2(CH2CH2O)3CH3, -NHCO2(CH2CH2O)5CH3, -NHCO2(CH2CH2O)7CH3, -NHCO2CH2Ph -NHCONHCH2CH3, -NHSO2CH3, -NHSO2CH=CH2, -NHSO2CH2Ph, -NHSO2CH2CH2Ph, -NHSO2CH2CH2CH2Ph, -NHSO2CH2CF3, -NHCH2CF3, -NHCH2(CH3)2NH2, -NHCH2(CH3)2CH2OH,

[0317]

Chemical formula

[0318]

Chemical formula

[0319] [ka]

[0320] [ka]

[0321] [ka]

[0322] [ka] represents; and

[0323] R 1 are -CH3, -CH2CH2-CH(CH3)2, -CH2CH2-C≡CH,

[0324] [ka] represents;

[0325] R 3 ~R 6 represent, independently of each other, -H, -CH3, -OCH3, -F, or -Cl; Or, R 5 and R 6 together

[0326] [ka] may be formed.

[0327] In some embodiments, the present invention relates to a compound having any one of formulas (II-1) to (II-16):

[0328] [ka]

[0329] [ka]

[0330] where A, B, R 4 , R N1 , R N4 , X 1 , X 2 , Z 1 , Z 2 , and Z 8 has the same meaning as defined above. In some embodiments, the present invention relates to a compound having any one of formulas (III-1) to (III-10):

[0331] [ka]

[0332] [ka]

[0333] where R 8 , R 12 , R 13 , R N1 , and Z 8 has the same meaning as defined above. Preferably, it is a compound of any one of formulas (III-1) to (III-10), wherein R 8 teeth

[0334] [ka]

[0335] [ka] and

[0336] where R N1 , Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 has the same meaning as defined in formula (I). In some embodiments, the present invention relates to a compound having any one of formulas (IV-1) to (IV-10):

[0337] [ka] TIFF2024534613000189.tif128156

[0338] where R 1 , R 2 , R 9 , R 12 , R 13 , Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 has the same meaning as defined above. Preferably, it is a compound of any one of formulas (IV-1) to (IV-3), wherein: R 1 is -(CH2) p -R 9 , or -(CH2) p -NR N4 -R 9 represents; p is an integer selected from 0, 1, 2, or 3; and R 9 and R N4 has the same meaning as defined in formula (I).

[0339] More preferably, it is a compound of any one of formulas (IV-1) to (IV-10), wherein R 9 teeth

[0340] [ka] and

[0341] and Z 1 , Z 2 , Z 6 , Z 7 , Z 8 , Z 9 , Z 10 , and R N1 has the same meaning as defined in formula (I). In some embodiments, the present invention relates to a compound having any one of formulas (V-1) to (V-9):

[0342] [ka]

[0343] where R 2 has the same meaning as defined above. Preferably, it is a compound of any one of formulas (V-1) to (V-9), wherein: R 2 -H, -R 8 , -CO-C(R 12 )(R 13 )-R 8 , -L 1 -(CH2) t -NHR 8 , -L 1 -(CH2) t -NH-CO-R 8 , -L 1 -(CH2) t -NH-SO2-R 8 , or -CO-C(R 12 )(R 13 )-(CH2)-R 8 represents; R 8 teeth,

[0344] [ka]

[0345] [ka] represents

[0346] where R 12 , R 13 , R N1 , Z 1 , Z 2 , Z 6 , Z 7 , Z 8 , Z 9 , and Z 10 has the same meaning as defined above. Preferred are compounds of formula (I), (II-1) to (II-16), where A is -CO-NH-, -CO-NCH3-,

[0347] [ka] represents;

[0348] The compounds of any one of formulas (III-1) to (III-10), (IV-1) to (IV-10), and (V-1) to (V-9) also include these moieties as A.

[0349] Particularly preferred compounds according to the present invention include those represented by Table 1, or an enantiomer, stereoisomer, mixture of enantiomers, diastereomer, mixture of diastereomers, hydrate, solvate, acid salt form, tautomer, racemate, or pharmaceutically acceptable salt thereof of the foregoing compounds.

[0350] [Table 1-1]

[0351] [Table 1-2]

[0352] [Table 1-3]

[0353]

Table 1-4

[0354]

Table 1-5

[0355]

Table 1-6

[0356]

Table 1-7

[0357]

Table 1-8

[0358]

Table 1-9

[0359]

Table 1-10

[0360]

Table 1-11

[0361]

Table 1-12

[0362]

Table 1-13

[0363]

Table 1-14

[0364]

Table 1-15

[0365]

Table 1-16

[0366]

Table 1-17

[0367]

Table 1-18

[0368]

Table 1-19

[0369]

Table 1-20

[0370]

Table 1-21

[0371]

Table 1-22

[0372]

Table 1-23

[0373]

Table 1-24

[0374]

Table 1-25

[0375]

Table 1-26

[0376]

Table 1-27

[0377]

Table 1-28

[0378]

Table 1-29

[0379]

Table 1-30

[0380]

Table 1-31

[0381]

Table 1-32

[0382]

Table 1-33

[0383]

Table 1-34

[0384]

Table 1-35

[0385]

Table 1-36

[0386]

Table 1-37

[0387]

Table 1-38

[0388]

Table 1-39

[0389]

Table 1-40

[0390]

Table 1-41

[0391]

Table 1-42

[0392]

Table 1-43

[0393]

Table 1-44

[0394]

Table 1-45

[0395]

Table 1-46

[0396]

Table 1-47

[0397]

Table 1-48

[0398]

Table 1-49

[0399]

Table 1-50

[0400]

Table 1-51

[0401]

Table 1-52

[0402]

Table 1-53

[0403]

Table 1-54

[0404]

Table 1-55

[0405]

Table 1-56

[0406]

Table 1-57

[0407]

Table 1-58

[0408]

Table 1-59

[0409]

Table 1-60

[0410]

Table 1-61

[0411]

Table 1-62

[0412]

Table 1-63

[0413]

Table 1-64

[0414]

Table 1-65

[0415]

Table 1-66

[0416]

Table 1-67

[0417]

Table 1-68

[0418]

Table 1-69

[0419]

Table 1-70

[0420]

Table 1-71

[0421]

Table 1-72

[0422]

Table 1-73

[0423]

Table 1-74

[0424]

Table 1-75

[0425]

Table 1-76

[0426]

Table 1-77

[0427] Table 1-78

[0428]

Table 1-79

[0429]

Table 1-80

[0430]

Table 1-81

[0431]

Table 1-82

[0432]

Table 1-83

[0433]

Table 1-84

[0434]

Table 1-85

[0435]

Table 1-86

[0436]

Table 1-87

[0437]

Table 1-88

[0438]

Table 1-89

[0439]

Table 1-90

[0440]

Table 1-91

[0441]

Table 1-92

[0442]

Table 1-93

[0443]

Table 1-94

[0444]

Table 1-95

[0445]

Table 1-96

[0446]

Table 1-97

[0447]

Table 1-98

[0448]

Table 1-99

[0449]

Table 1-100

[0450]

Table 1-101

[0451] Table 1-102

[0452]

Table 1-103

[0453]

Table 1-104

[0454]

Table 1-105

[0455]

Table 1-106

[0456] Table 1-107

[0457]

Table 1-108

[0458]

Table 1-109

[0459]

Table 1-110

[0460]

Table 1-111

[0461]

Table 1-112

[0462]

Table 1-113

[0463]

Table 1-114

[0464]

Table 1-115

[0465]

Table 1-116

[0466]

Table 1-117

[0467]

Table 1-118

[0468]

Table 1-119

[0469]

Table 1-120

[0470]

Table 1-121

[0471] Table 1-122

[0472]

Table 1-123

[0473]

Table 1-124

[0474]

Table 1-125

[0475]

Table 1-126

[0476]

Table 1-127

[0477] Table 1-128

[0478]

Table 1-129

[0479] Table 1-130

[0480]

Table 1-131

[0481] Table 1-132

[0482]

Table 1-133

[0483] Table 1-134

[0484] Table 1-135

[0485] [Compound synthesis] The compounds of formula (I) are prepared by the appropriate selection of suitable substituted reagents, with reference to the methods shown in Schemes 1-3 below. Solvents, temperatures, pressures, and other reaction conditions can be readily selected by those skilled in the art. Starting materials are commercially available or readily prepared by those skilled in the art.

[0486] Another aspect of the present invention refers to a method for producing a compound of formula (I), comprising: Step 1A: Intermediate Compound (I-1 * ) to provide:

[0487] [ka]

[0488] In the formula, A, B, R 1 , R 3 , R 4 , R 5 , R 6 , X 1 , and X 2 has the same meaning as defined in formula (I); Step 2A: Intermediate Compound (I-1 * ) by intramolecular amide coupling reaction with the carboxylic acid group and the amine group to obtain a compound of formula (I).

[0489] [ka]

[0490] [ka]

[0491] Optionally, the intermediate compound of Step 1A (I-1 * ) is prepared by step 1A'. Step 1A' includes the following steps a1) to d1): a1) Compound 1 * and Compound 2 * A coupling reaction is carried out between

[0492] [ka] compound 3 * to get

[0493] [ka] b1) Compound 3 * The nitrile (-CN) group of compound 4 is reduced to an aminomethyl (-CHNH) group. * to get

[0494] [ka] c1) Compound 4 * and Compound 5 * Perform a coupling reaction between

[0495] [ka] compound 6 * to get

[0496] [ka] d1) The carboxyl protecting group PG1 and the amine protecting group PG2 are removed to give compound (I-1 * )

[0497] [ka] where

[0498] A * is -NH(R N6 )-,

[0499] [ka] represents;

[0500] L * represents -CO2H; PG1 represents a carboxyl protecting group; PG2 represents an amine protecting group; and A, B, R 1 , R 3 , R 4 , R 5 , R 6 , R N6 , X 1 , X 2 , Z 13 , and Z 14 has the same meaning as defined in formula (I).

[0501] Thus, a method for producing a compound of formula (I) may comprise Step 1A', Step 1A, and Step 2A. Alternatively, the compound of formula (I) may be produced by the following method, and therefore the present invention relates to a method for producing a compound of formula (I), comprising: Step 1B: Intermediate Compound (I-2 * ) to provide:

[0502] [ka]

[0503] where A * is -NH(R N6 )-,

[0504] [ka] represents;

[0505] L * represents -CO2H, and B, R 1 , R3 , R 4 , R 5 , R 6 , R N6 , X 1 , X 2 , Z 13 , and Z 14 has the same meaning as defined in formula (I); Step 2B: Intermediate Compound (I-2 * )L * and A * and carrying out an intramolecular amide coupling reaction between the amino group of the moiety and the compound of formula (I).

[0506] Optionally, the intermediate compound (I-2) in Step 1B * ) is prepared by Step 1B'. Step 1B' comprises the following steps a2) to c2): a2) Compound 5 * and Compound 7 * Perform a coupling reaction between

[0507] [ka] compound 8 * to get

[0508] [ka] b2) Compound 8 * and compound 1a * Perform a coupling reaction between

[0509] [ka] compound 12 * to get

[0510] [ka] c2) Compound 12 *The carboxyl protecting group PG1 and the amine protecting group PG2 in * )

[0511] [ka]

[0512] where A * is -NH(R N6 )-,

[0513] [ka] represents;

[0514] L * represents -CO2H, PG1 represents a carboxyl protecting group; PG2 represents an amine protecting group; and B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R N6 , X 1 , X 2 , Z 13 , and Z 14 has the same meaning as defined in formula (I).

[0515] Thus, the method of producing the compound of formula (I) may comprise Step 1B', Step 1B, and Step 2B.

[0516] [ka]

[0517] Alternatively, the intermediate compound (I-2) in Step 1B may be prepared as follows: * ) is prepared by step 1B''. Step 1B'' comprises the following steps b2') and c2): b2') Compound 7 * and Compound 9 * Perform a coupling reaction between

[0518] [ka] compound 12 * to get

[0519] [ka] c2) Compound 12 * The carboxyl protecting group PG1 and the amine protecting group PG2 of the compound (I-2 * )

[0520] [ka]

[0521] where A * is -NH(R N6 )-,

[0522] [ka] represents;

[0523] L * represents -CO2H, PG1 represents a carboxyl protecting group; PG2 represents an amine protecting group; and B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R N6 , X 1 , X 2 , Z 13 , and Z 14 has the same meaning as defined in formula (I).

[0524] Thus, the method for producing the compound of formula (I) may comprise Step 1B'', Step 1B, and Step 2B. Alternatively, the intermediate compound of Step 1B (I-2 * ) is prepared by Step 1B''', which includes the following steps b2'') and c2): b2'') Compound 1a * , compound 10a * (R 1 -CHO), compound 11 * and ammonia water (NH3) by Ugi reaction.

[0525] [ka] compound 12 * to get

[0526] [ka] c2) Compound 12 * The carboxyl protecting group PG1 and the amine protecting group PG2 of the compound (I-2 * )

[0527] [ka] ,

[0528] where A * is -NH(R N6 )-,

[0529] [ka] represents;

[0530] L * represents -CO2H, PG1 represents a carboxyl protecting group; PG2 represents an amine protecting group; and B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R N6 , X 1 , X 2 , Z 13 , and Z 14 has the same meaning as defined in formula (I).

[0531] Thus, the method of producing the compound of formula (I) may comprise Step 1B''', Step 1B, and Step 2B. Preferably, the process for producing a compound of formula (I) comprises: Steps 1B', 1B'', and 1B'': Step 1B', including steps a2), b2), and c2); Step 1B'', including steps b2') and c2); Step 1B''', including steps b2'') and c2); Step 1B, and Step 2B may include:

[0532] Alternatively, the compound of formula (I) may be produced by the following process, and the present invention therefore refers to a process for producing a compound of formula (I), including: Step 1C: Intermediate Compound (I-3 * ) to provide:

[0533] [ka]

[0534] where A, B, R 1 , R 3 , R 4 , R 5 , R 6 , X 1 , and X 2has the same meaning as defined in formula (I); Step 2C: Intermediate Compound (I-3 * ) and R 1 -CHO 10 * and performing an intramolecular Ugi reaction with aqueous ammonia (NH3) to obtain the compound of formula (I).

[0535] [ka]

[0536] Optionally, the intermediate compound (I-3) in Step 1C * ) is prepared by step 1C'. Step 1C' includes the following steps b3) and c3): b3) Compound 1b * and compound 13 * Coupling reaction with

[0537] [ka] compound 14 * to get

[0538] [ka] c3) Compound 14 * The carboxyl protecting group PG1 in * )

[0539] [ka]

[0540] , where A * is -NH(R N6 )-,

[0541] [ka] represents;

[0542] L * represents -CO2H, PG1 represents a carboxyl protecting group; and B, R 1 , R 3 , R 4 , R 5 , R 6 , R N6 , X 1 , X 2 , Z 13 , Z 14 has the same meaning as defined in formula (I).

[0543] Thus, the method of producing the compound of formula (I) may comprise Step 1C', Step 1C, and Step 2C. Intermediate compound (I-1 * ) or (I-2 *An activating reagent is typically used to activate the carboxylic acid in Step 2A to promote an intramolecular amide coupling reaction between the carboxylic acid group and the amino group of ), and in Step 2B. Activation may be introduced as a separate reaction or an in situ reaction.Preferably, any of the following coupling reagents can be used to activate the carboxylic acid group: BOP (benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), PyBOP (benzotriazol-1-yl-oxy-tris-pyrrolidino)-phosphonium hexafluorophosphate), AOP (7-(azabenzotriazol-1-yl)oxytris(dimethylamino)phosphonium hexafluorophosphate), ), PyAOP ((7-azabenzotriazol-1-yloxy)trispirrolizinophosphonium hexafluorophosphate), TBTU (2-(1H-benzotriazol-1)-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate), EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), polyphosphoric acid (PPA), DPPA (diphenylphosphoryl azide), HATU (N-[(dimethylamino)-1H-1,2,3-triazolo-[4 ,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide), HBTU (N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate), HOBt (1-hydroxybenzotriazole), HOAt (1-hydroxy-7-azabenzotriazole), DCC (N,N'-dicyclohexylcarbodiimide), EDCI (N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide), BOP-Cl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride), TFFH (tetramethylfluoroformamidinium hexafluorophosphate), Brop (bromotris(dimethylamino)phosphonium hexafluorophosphate), PyBrop (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) and CIP (2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate) or mixtures thereof.

[0544] Preferably, the intermediate compound (I-1 * ) or (I-2 *The intramolecular amide coupling reaction between the carboxylic acid group and the amino group in ) is carried out in the presence of HATU as a coupling reagent and DIPEA as a base.

[0545] Another aspect of the present invention is intermediate compound 7 * , 8 * , 11 * , 12 * , 13 * , 14 * , I-1 * , I-2 * , and I-3 * Targeting:

[0546] [ka]

[0547] where A * is -NH(R N6 )-,

[0548] [ka] represents;

[0549] L * represents -CO2H, PG1 represents a carboxyl protecting group; PG2 represents an amine protecting group; and B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R N6 , X 1 , X 2 , Z 13 , and Z 14 has the same meaning as defined in formula (I).

[0550] [Instructions] In a further aspect of the present invention, the novel compounds according to general formula (I) are used as pharmaceutically active agents.

[0551] Surprisingly, it has been revealed that the compounds of the above general formula (I) and pharmaceutical compositions thereof act as proteasome inhibitors, more specifically as inhibitors of the β5 type of proteasome subunit.

[0552] In the present application, the IC of the compound of general formula (I) for the proteasome subunit β5 type 50 Inhibitory activity assays were performed to determine the values. Table 2 shows activity data in biochemical assays (IC 50 The compounds of the present invention have been shown to highly effectively inhibit the β5 subunit of both the constitutive and immunoproteasomes. Furthermore, the compounds of the present invention have been shown to highly effectively inhibit the β5 subunit of both the constitutive and immunoproteasomes in a cell-based proteasome glo assay. Finally, the proteasome inhibition of these compounds has been shown to highly effectively inhibit tumor cell (HT29) proliferation.

[0553] Tables 3 to 5 show that the compounds of the present invention effectively inhibit the proliferation of other cancer cells, such as A549 (human lung cancer cell line), A2780 (human ovarian cancer cell line), MDA-MB-468 (breast cancer), Hs746T (human gastric cancer cell line), MM1S (B lymphoblast cell line), and RPMI8226 (B lymphocyte cell line, multiple myeloma).

[0554] Pharmaceutical compositions according to the present invention comprise as an active ingredient at least one compound according to the present invention, together with at least one pharmaceutically acceptable (i.e., non-toxic) carrier, excipient and / or diluent.

[0555] As used herein, the term proteasome "inhibitor," and in particular proteasome subunit beta5 "inhibitor," refers to any compound capable of downregulating, decreasing, suppressing, or otherwise modulating the amount and / or activity of the proteasome, which may be accomplished by any of a variety of mechanisms known in the art, including, but not limited to, directly binding to said proteasome subunit beta5.

[0556] As used herein, the term "inhibit" or "inhibition" refers to the ability of a compound to downregulate, decrease, reduce, suppress, inactivate, or at least partially inhibit the activity of an enzyme or the expression of an enzyme or protein.

[0557] Proteasome subunit beta5 is encoded by the PSMB5 gene in the constitutive proteasome and by LMP7 in the immunoproteasome in humans. Proteasome subunit beta5, together with other beta subunits, assembles two heptameric rings, which then construct the proteolytic chamber for substrate degradation. This protein possesses "chymotrypsin-like" activity, allowing it to cleave peptides after large hydrophobic residues. Eukaryotic proteasomes recognize damaged proteins for protein quality control or degradative proteins, including key regulatory protein components for dynamic biological processes. An essential function of the immunoproteasome, a modified proteasome, is the processing of class I MHC peptides.

[0558] A further aspect of the present invention relates to a compound of general formula (I) or a pharmaceutical composition as defined above for use in the prevention and / or treatment of a disease caused by or associated with the proteasome or immunoproteasome, particularly the proteasome subunit beta5, selected from cancer, infectious diseases, inflammatory diseases, autoimmune diseases, and transplant rejection.

[0559] A further aspect of the present invention relates to the use of a compound of general formula (I) for the preparation of a pharmaceutical composition useful for the prevention and / or treatment of a disease caused by or associated with the proteasome or immunoproteasome, particularly the proteasome subunit beta5, selected from cancer, infectious diseases, inflammatory diseases, autoimmune diseases, and transplant rejection.

[0560] In a further aspect of the present invention, there is provided a method for preventing and / or treating a disease caused by or associated with the proteasome or immunoproteasome, particularly the proteasome subunit β5, in a mammal, particularly a human, which method comprises administering to the mammal an effective amount of at least one compound according to general formula (I) and / or a pharmaceutically acceptable salt thereof to prevent and / or treat a disease caused by or associated with the proteasome or immunoproteasome, particularly the proteasome subunit β5, selected from cancer, neurodegenerative diseases, infectious diseases, inflammatory diseases, and autoimmune diseases, and to suppress allograft rejection during transplantation.

[0561] The term "effective amount" means the amount of a compound that, when administered to a patient in need of such treatment, is sufficient to: (i) treating or preventing certain diseases, conditions, or disorders that can be treated with proteasome inhibitors; (ii) alleviating, ameliorating, or eliminating one or more symptoms of a particular disease, condition, or disorder; or (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition, or disorder described herein;

[0562] The amount of the compound of general formula (I) corresponding to said amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity of the patient requiring treatment (e.g., body weight, etc.), etc., but can nevertheless be routinely determined by one skilled in the art.

[0563] [cancer] The compounds of the present application, or pharmaceutical compositions thereof, are useful for the treatment and / or prevention of cancer, wherein the cancer is: adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neuroma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial carcinoma, non-small cell lung cancer (NSCLC), breast cancer, Burkitt's lymphoma, corpus cancer, CUP syndrome (cancer of unknown primary), colon cancer, small intestine cancer, small intestine tumors, ovarian cancer, endometrial cancer, ependymoma, epithelial carcinoma type, Ewing's tumor, gastrointestinal tumors, stomach cancer, gallbladder cancer, gallbladder bladder) cancer, uterine cancer, cervical cancer, cervix, glioblastoma, gynecological tumors, tumors of the ear, nose, and throat, hematological tumors, hairy cell leukemia, urethral cancer, skin cancer, skin testicular cancer, brain tumors (gliomas), brain metastases, testicular cancer, pituitary tumors, carcinoid, Kaposi's sarcoma, laryngeal cancer, germ cell tumors, bone cancer, colorectal cancer, head and neck tumors (tumors of the ear, nose, and throat area), colon cancer, craniopharyngioma, oral cancer (cancer of the mouth area and lips), cancer of the central nervous system, liver cancer, liver metastases, leukemia, eyelid tumors, lung cancer, lymph node cancer (Hodgkin / non-Hodgkin), lymphoma, stomach cancer, malignant melanoma, malignant neoplasms, malignant tumors of the digestive tract, breast cancer, rectal cancer, medulloblastoma, melanoma, meningioma, Hodgkin's disease, Selected from the group consisting of mycosis fungoides, nasal cancer, schwannoma, neuroblastoma, kidney cancer, renal cell carcinoma, non-Hodgkin's lymphoma, oligodendroglioma, esophageal cancer, osteolytic and osteogenic carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, plasmacytoma, squamous cell carcinoma of the head and neck (SCCHN), prostate cancer, pharyngeal cancer, rectal cancer, retinoblastoma, vaginal cancer, thyroid cancer, Schneeberger's disease, esophageal cancer, spinal cord tumor, T-cell lymphoma (mycosis fungoides), thymoma, ductal carcinoma, eye tumor, urethral cancer, urinary tract tumor, urothelial carcinoma, vulvar cancer, wart appearance, soft tissue tumor, soft tissue sarcoma, Wilms' tumor, cervical cancer, tongue cancer, astrocytoma, bronchial carcinoma, laryngeal cancer, malignant melanoma, esophageal cancer, bile duct carcinoma, and renal cell carcinoma.

[0564] Preferably, the present application, or a pharmaceutical composition thereof, is useful for the treatment and / or prevention of cancer, wherein the cancer is leukemia, multiple myeloma, mantle cell lymphoma (MCL), breast cancer, colon cancer, non-small cell lung cancer, or ovarian cancer, more preferably, the cancer is multiple myeloma.

[0565] Optionally, the compounds of the present invention, or pharmaceutical compositions thereof, are used in combination with thalidomide or a derivative of thalidomide for the treatment / prevention of said cancers, in particular multiple myeloma.

[0566] The thalidomide derivative is selected from lenalidomide, pomalidomide, avadomide, iverdomide, and CC-885. CC-885 is a modulator of the E3 ligase protein cereblon, which has antiproliferative effects on human myeloid leukemia cell lines. CC-885 forms a complex with cereblon and GSPT1, a cell cycle regulator and translation termination factor. The antitumor activity of CC-885 depends on cereblon-dependent ubiquitination and degradation of GSPT1. Official name: N-(3-chloro-4-methylphenyl)-N'-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-5-yl]methyl]-urea (CAS number: 1010100-07-8).

[0567] [Infectious disease] The compounds of the present application, or pharmaceutical compositions thereof, are useful for the treatment and / or prevention of infectious diseases, wherein the infectious diseases include: HIV, echinococcosis, amebiasis (entamoeba histolytica infection), angiostrongylus infection, anisakiasis, anthrax, babesiosis (babesia infection), balantidium infection (balantidiosis), baylisascaris infection (raccoon roundworm), bilharziasis (schistosomiasis), blastocysts Hominis infection (blastomycosis), borreliosis, botulism, Brainerd's diarrhea, brucellosis, BSE (bovine spongiform encephalopathy), candidiasis, capillary worm infection, CFS (chronic fatigue syndrome), Chagas disease (American trypanosomiasis), chickenpox (varicella-zoster virus), chlamydia pneumonia, cholera, CJD (Creutzfeldt-Jakob disease), Clonorchiasis (liver fluke infection), CLM ( Cutaneous larva migrans, hookworm infection), coccidioid mycosis, conjunctivitis, Coxsackievirus A16 (hand, foot, and mouth disease), cryptococcosis, cryptosporidium infection, Culex pipiens mosquito (vector of West Nile virus), cyclosporiasis (Cyclospora infection), cysticercosis (neurocysticercosis), cytomegalovirus infection, dengue fever Fever), Dipyridium infection (dog and cat flea tapeworms), Ebola virus hemorrhagic fever, Echinococcosis (alveolar hydatid disease), Encephalitis, Entamoeba coli infection, Entamoeba dispar infection, Entamoeba hartmannii infection, Entamoeba histolytica infection (amebiasis), Entamoeba pollecki infection, Pinworm infection (pinworm infection), Enterovirus infection (non-polio), Epstein-Barr virus infection, E. coli infection, Foodborne infection, Foot and mouth disease, Fungal dermatitis, Gastroenteritis, Group A streptococcal infection, Group B streptococcal infection, Hansen's disease (leprosy), Hantavirus pulmonary syndrome, Head lice infestation (pediculosis), Helicobacter pylori infection, Blood disorders, Hendra virus infection, Hepatitis (HCV, HBV), Shingles (HerpesZoster (Shingles), human ehrlichiosis, human parainfluenza virus infection, influenza, isosporiasis (Isospora infection), Lassa fever, leishmaniasis, kala-azar (Kala-azar, Leishmania infection), leprosy, lice (body lice, head lice, pubic lice), Lyme disease, malaria, Marburg hemorrhagic fever, measles, meningitis, mosquito-borne diseases, Mycobacterium avium complex (MAC) infection, Naegleria infection, hospital-acquired infections, non-pathogenic intestinal ameba infections, onchocerciasis (river blindness), opisthorchiasis (opisthorchiasis infection), parvovirus infection, plague, PCP (Pneumocystis spp.) carinii pneumonia), polio, Q fever, rabies, respiratory syncytial virus (RSV) infection, rheumatic fever, Rift Valley fever, rotavirus infection, roundworm infection, salmonellosis, salmonellosis enteritidis, scabies, bacterial erythroderma, shingles, sleeping sickness, smallpox, streptococcal infection, tapeworm infection (taenia infection), tetanus, toxic shock syndrome, tuberculosis, ulcer (peptic ulcer disease), Valley fever, Vibrio parahaemolyticus infection, Vibrio vulnificus infection, viral hemorrhagic fever, warts, waterborne infections, West Nile virus infection (West Nile encephalitis), whooping cough, and yellow fever.

[0568] [Inflammatory disease] Inflammatory diseases are caused by cytokines, TNF-α, IL-1β, GM-CSF, IL-6 / IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin), and prostaglandins, and / or nitric oxide (NO).

[0569] [Autoimmune disease] Furthermore, the compounds of the present application, or pharmaceutical compositions thereof, are useful for the treatment and / or prevention of autoimmune diseases. Autoimmune diseases include: Achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Baro's disease, Behçet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman's disease (CD), Celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS), eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devics' disease (neuromyelitis optica), discoid lupus, Dressler syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia Myalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid of gestationis (PG), sweat gland tumor (HS) (acne inversa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear immunoglobulin A disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myelin oligodendrocyte glycoprotein antibody disorder, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR),PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome types I, II, and III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cholangitis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), thyroid eye disease (TED), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease.

[0570] Preferably, the autoimmune disease is selected from lupus nephritis, lupus, systemic lupus erythematosus, myasthenia gravis, multiple sclerosis, polyarthritis, rheumatoid arthritis, irritant sensitivity, psoriasis, asthma, and colitis, more preferably, the autoimmune disease is myasthenia gravis.

[0571] Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, resulting in the destruction of the transplanted tissue. Transplant rejection can be alleviated by determining the molecular similarity between the donor and the recipient and using immunosuppressants after transplantation. The compounds of the present invention may be used as immunosuppressants.

[0572] Compounds explicitly listed in Table 1 are preferably used within the methods or indications disclosed herein. The pharmaceutical composition of the present invention can be prepared in conventional solid or liquid carrier or diluent and conventional pharmaceutical adjuvants at suitable dosage levels by known methods.Preferred formulation is adapted for oral application.These dosage forms include, for example, pills, tablets, film tablets, coated tablets, capsules, powders and deposits.

[0573] Furthermore, the present invention also includes pharmaceutical formulations for parenteral application, including transdermal, intradermal, intragastric, intracutan, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, buccal, percutan, rectal, subcutaneous, sublingual, topical, or transdermal application, which formulations contain at least one compound according to the present invention and / or a pharmaceutically acceptable salt thereof as an active ingredient in addition to typical vehicles and / or diluents.

[0574] Pharmaceutical compositions according to the present invention, comprising at least one compound of the present invention and / or a pharmaceutically acceptable salt thereof as an active ingredient, will typically be administered in accordance with conventional pharmaceutical practice with suitable carrier materials selected for the intended dosage form, i.e., for oral administration in the form of tablets, capsules (either solid-filled, semisolid-filled, or liquid-filled), powders for constitution, gels, elixirs, dispersible granules, syrups, suspensions, and the like. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable carrier, preferably an inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid-fill capsules), and the like. Additionally, suitable binders, lubricants, disintegrants, and coloring agents may also be incorporated into the tablet or capsule. Powders and tablets may contain from about 5 to about 95% by weight of the compound of Formula (I) or its respective pharmaceutically active salt as the active ingredient.

[0575] Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol, and waxes. Suitable lubricants may be boric acid, sodium benzoate, sodium acetate, sodium chloride, etc. Suitable disintegrants may be starch, methylcellulose, guar gum, etc. Optionally, sweeteners and flavoring agents, as well as preservatives, may also be included. Disintegrants, diluents, lubricants, binders, etc. are described in more detail below.

[0576] Additionally, the pharmaceutical compositions of the present invention may be formulated in sustained release form to provide a rate-controlled release of any one or more components or active ingredients to optimize therapeutic efficacy, e.g., antihistamine activity, etc. Suitable dosage forms for sustained release include tablets with layers of different disintegration rates, or a controlled-release polymer matrix impregnated with the active ingredient and formed into a tablet form, or a capsule containing such an impregnated or encapsulated porous polymer matrix.

[0577] Liquid form preparations include solution, suspension and emulsion.For example, water or water / propylene glycol solution for parenteral injection, or the addition of sweeteners and opacifiers for oral solution, suspension and emulsion.Liquid form preparations can also include the solution for intranasal administration.

[0578] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.

[0579] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides, such as cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0580] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration, including solutions, suspensions, and emulsions.

[0581] The compounds of the present invention may also be administered transdermally. The transdermal compositions may take the form of creams, lotions, aerosols and / or emulsions and may be included in a transdermal patch of the matrix or reservoir type as are known in the art for this purpose.

[0582] The term "capsule" as used herein refers to a specific container or enclosure made of, for example, methylcellulose, polyvinyl alcohol, or modified gelatin or starch, for holding or containing a composition containing an active ingredient. Typically, hard-shell capsules are prepared from a mixture of relatively high gel strength gelatin from bone and pigskin. The capsule itself may contain small amounts of dyes, opacifiers, plasticizers, and / or preservatives.

[0583] Tablets are understood to be compressed or molded solid dosage forms containing the active ingredient together with suitable diluents. Tablets can be prepared by compressing mixtures or granulations obtained by wet granulation, dry granulation or compaction, which are well known to those skilled in the art.

[0584] Oral gels refer to active ingredients dispersed or solubilized in a hydrophilic semi-solid matrix. Powder for constitution refers to a powder mixture containing the active ingredient and a suitable diluent, which can be suspended in, for example, water or juice.

[0585] Suitable diluents are usually the substances that make up the majority of the composition or dosage form.Suitable diluents include sugars such as lactose, sucrose, mannitol, and sorbitol, as well as starches derived from wheat, corn, rice, and potato, and celluloses such as microcrystalline cellulose.The amount of bulking agent in the composition can be in the range of about 5% to about 95% by weight of the total composition, preferably in the range of about 25% to about 75% by weight, and more preferably in the range of about 30% to about 60% by weight.

[0586] The term disintegrant refers to a substance added to a composition to help break apart (disintegrate) and release the active pharmaceutical ingredient of the drug. Suitable disintegrants include starch, "cold water soluble" modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth, and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline cellulose and crosslinked microcrystalline cellulose such as croscarmellose sodium, alginates such as alginic acid and sodium alginate, clays such as bentonite, and effervescent mixtures. The amount of disintegrant in the composition may range from about 2% to about 20% by weight of the composition, more preferably from about 5% to about 10% by weight. Binders are substances that bind or "glue" powder particles together, clumping them together by forming granules and thus acting as the "adhesive" in the formulation. Binders add to the binding strength already available in the diluent or filler. Suitable binders include sugars such as sucrose, starches derived from wheat, corn, rice, and potato, natural gums such as acacia, gelatin, and tragacanth, seaweed derivatives such as alginic acid, sodium alginate, and ammonium calcium alginate, cellulose materials such as methylcellulose, sodium carboxymethylcellulose, and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate. The amount of binder in the composition may range from about 2% to about 20% by weight of the composition, preferably from about 3% to about 10% by weight, and more preferably from about 3% to about 6% by weight.

[0587] Lubricants are a class of substances added to dosage forms to reduce friction or wear after compression, thereby allowing tablets, granules, etc., to be released from the mold or die. Suitable lubricants include metal stearates, such as magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high-melting point waxes, and other water-soluble lubricants, such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol, and D,L-leucine. Because lubricants must be present on the surface of the granules, they are usually added at the last step before compression. The amount of lubricant in the composition may range from about 0.2% to about 5% by weight of the composition, preferably from about 0.5% to about 2% by weight, and more preferably from about 0.3% to about 1.5% by weight.

[0588] Glidant is a substance that prevents the solidification of compounds in pharmaceutical compositions and improves the flow properties of granules, thus making the flow smooth and uniform.Suitable glidant includes silicon dioxide and talc.The amount of glidant in the composition can be in the range of about 0.1% to about 5% by weight of the final composition, preferably in the range of about 0.5% to about 2% by weight.

[0589] A colorant is an excipient that provides color to a composition or dosage form. Such excipients can include, for example, food-quality colorants adsorbed onto a suitable adsorbent, such as clay or aluminum oxide. The amount of colorant can vary from about 0.1% to about 5% by weight of the composition, preferably from about 0.1% to about 1% by weight.

[0590] The following examples are included to demonstrate preferred embodiments of the invention. It should be understood by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventors to function well in the practice of the invention, and can therefore be considered to constitute preferred modes for such practice. However, those of skill in the art should, in light of the present disclosure, understand that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

[0591] Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this specification. Accordingly, this specification is to be construed as illustrative only, and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention. It should be understood that the forms of the invention shown and described herein are to be construed as exemplary embodiments. Elements and materials may be substituted for those shown and described herein, parts and steps may be reversed, and certain features of the invention may be utilized independently, all as will become apparent to those skilled in the art after having the benefit of this specification of the invention. Changes may be made in the elements described herein without departing from the spirit and scope of the invention, as set forth in the following claims.

[0592] [Example] Compound preparation: General information: All reactions involving air- or moisture-sensitive reagents or intermediates were performed in flame-dried glassware under an argon atmosphere. Dry solvents (THF, toluene, MeOH, DMF, DCM) were obtained commercially. 1 H-NMR and 13C-NMR was recorded on a Bruker DRX400 (400 MHz). Multiplicities are indicated as: brs (broad singlet), s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), m (multiplet); and coupling constants (J) are given in Hertz (Hz). HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using a Waters Acquity Performance Liquid Chromatography (UPLC) with an SQ3100 mass detector analyzer. Column: Acquity UPLC BEH C18 1.7 μm, 2.1 × 50 mm. Flow rate: 0.5 ml / min. Eluents: A: HO with 0.05% formic acid, and B: ACN with 0.05% TFA. All chemicals and solvents were purchased from commercial sources, including Sigma-Aldrich, Fluka, TCI, Acros Organics, ABCR, Alfa Aesar, Enamine, VWR, Combi-Blocks, Apollo Scientific, Aquilla Pharmatech, Ark Pharm, DL Chiral Chemicals, ChemBridge, Renno Tech, Accela, KeyOrganics, Pharmablock, and Chem Impex. Unless otherwise noted, all commercially available compounds were used as received without further purification.

[0593] Abbreviations used in the chemical descriptions and in the following examples are as follows: ACN or MeCN (acetonitrile); Asp (aspartic acid), br (broad); BOC (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), CDCl3 (deuterated chloroform); cHex (cyclohexane); CDI (1,1'-carbonyldiimidazole), DPCP (diphenyl chlorophosphate), DBU (1,8-diazabicyclo[5.4.0]diisopropyl ether), HCl (HCl ... ]undec-7-ene), DCE (1,2-dichloroethane), DCM (dichloromethane); DIAD (diisopropyl azodicarboxylate); DIEA (N,N-diisopropylethylamine), DIPEA (di-isopropylethylamine); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); DPPA (diphenylphosphoryl azide), EA (ethyl acetate), eq. (equivalent); EDCl (1-ethyl-3-(3-dimethylaminopropyl) chloramphenicol) Benzylimide), ES (electrospray); EtOAc (ethyl acetate); EtOH (ethanol); Glu (glutamic acid), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); HCl (hydrochloric acid); HOBt (hydroxybenzotriazole), hPhe (homophenylalanine), MeOH (methanol); MS (mass spectrometry); MTBE (methyl tert-butyl ether), Mwt (molecular weight); NMM (4-methylmorpholine), NMP (N-methyl-2-pyrrolidone), NMR (nuclear magnetic resonance); PE (petroleum ether), RP (reverse phase); RT / rt (room temperature); sat.aq. (saturated aqueous solution); SiO2 (silica gel); tBu (tert-butyl), T3P (propanephosphonic anhydride), TBME (tert-butyl methyl ether), TFA (trifluoroacetic acid); THF (tetrahydrofuran); TIS (triisopropylsilane).

[0594] [Preparation Example] General Procedure A

[0595] [ka]

[0596] 1.2 eq. HATU and 2 eq. DIPEA were dissolved in 1.5 ml / mmol DMF. A solution of 1 eq. amino acid in 2 ml / mmol DMF was added dropwise at room temperature or elevated temperature. One hour after the addition was complete, the reaction mixture was partitioned between ethyl acetate and 2N NaOH solution. The organic phase was separated, washed with brine, dried over sodium sulfate, and the solvent was evaporated. Depending on the scale, the crude product was purified by crystallization, flash chromatography, or HPLC.

[0597] General Procedure B

[0598] [ka]

[0599] The carboxylic acid (1.5 eq.), HATU (1.1 eq.), and DIPEA (6 eq.) are dissolved in DMF, and the amine is added. After the reaction is complete, the reaction mixture is diluted with ethyl acetate and then washed with sodium hydroxide solution and brine. The organic phase is dried over sodium sulfate, and the solvent is removed under reduced pressure. The crude product is then purified by crystallization, flash chromatography, or HPLC.

[0600] General Procedure C

[0601] [ka]

[0602] The Cbz-protected amine is dissolved in a solvent (e.g., EtOH, ethyl acetate) or solvent mixture at a concentration of, for example, 10 mg / ml, depending on solubility. Hydrogenation is carried out using an H-Cube® at 50°C using a Pd / C or Raney Ni catalyst cartridge. Typically, the hydrogen pressure can be set from atmospheric pressure to 50 bar and a flow rate of 1 ml / min. If necessary, the hydrogenation is repeated until completion. The solvent is removed under reduced pressure, usually to give a product sufficiently pure to be used in the next reaction. If necessary, the product can be purified by normal-phase or reverse-phase flash chromatography.

[0603] General Procedure D

[0604] [ka]

[0605] The Boc-protected amine or tert-butyl carboxylate is dissolved in, for example, 4N HCl in 1,4-dioxane, concentrated HCl in water, or TFA (e.g., 20%) in DCM at room temperature or elevated temperature (e.g., 60°C) and stirred at room temperature. After the reaction is determined to be complete, the volatiles are removed under reduced pressure. The remaining crude product is co-evaporated with, for example, acetonitrile or THF to remove excess HCl and provide the relevant ammonium salt or carboxylic acid sufficiently pure for use in the next reaction.

[0606] General Procedure E

[0607] [ka]

[0608] 1 eq. amine and triethylamine (3 eq.) were dissolved in DCM (10-15 ml / mmol) and cooled to 0°C. Sulfonyl chloride or carboxylic acid chloride (1.3 eq.) was added, and the mixture was stirred until the reaction was complete. For HPLC purification, the reaction mixture was diluted with some methanol. Otherwise, the reaction was diluted with ethyl acetate and washed with aqueous HCl or Na2CO3, and brine. After drying over Na2SO4 and removing the solvent under reduced pressure, the residue was purified by normal or reversed phase flash chromatography.

[0609] General Procedure F

[0610] [ka]

[0611] 1 eq. amine and triethylamine (3 eq.) were dissolved in THF (10-15 ml / mmol) at RT. The relevant isocyanate (1.3 eq.) was added and the mixture was stirred until completion. The reaction mixture was diluted with some methanol and directly purified by HPLC.

[0612] General Procedure G

[0613] [ka]

[0614] 1 eq. amine and triethylamine (3 eq.) were dissolved in THF (10-15 ml / mmol) at 0°C. The relevant chloroformate (1.5 eq.) was added and the reaction was allowed to warm to room temperature. After the reaction was complete, the reaction mixture was diluted with some methanol and directly purified by HPLC.

[0615] General Procedure H

[0616] [ka]

[0617] The aromatic nitrile was dissolved in ethanol, a solution of 2M NH3 in MeOH, or other solvents or mixtures, depending on solubility, at a concentration of, for example, 10 mg / ml. Hydrogenation was achieved using a Raney Ni catalyst cartridge at elevated temperatures, for example, 50°C to 80°C, in an H-Cube®. Typically, the hydrogen pressure can be set at 20 bar to 50 bar, with a flow rate of 1 ml / min. If necessary, the hydrogenation was repeated until completion. The solvent was removed under reduced pressure, usually to give a product sufficiently pure for use in the next reaction. If necessary, the product can be purified by normal-phase or reverse-phase flash chromatography.

[0618] Example A-1: ​​Preparation of Compound 8 (S)-tert-butyl 3-(((benzyloxy)carbonyl)amino)-4-(((S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl)amino)-4-oxobutanoate (1)

[0619] [ka]

[0620] To a solution of ZL-aspartic acid tert-butyl ester monohydrate (35 g, 102.5 mmol, 1.0 eq.) in DCM (1.2 L) and dry DMF (0.6 L) was added ethyl (S)-2-amino-4-phenylbutanoate hydrochloride (25 g, 102.5 mmol, 1.0 eq.) and HATU (57.3 g, 150.8 mmol, 1.5 eq.). After purging under N2, DIPEA (44.4 g, 56.8 mL, 343.8 mmol, 3.4 eq., previously filtered through a plug of Alox-basic) was added dropwise over 10 min. After 2 h at room temperature, LC-MS monitoring showed no starting material, so after evaporating the DCM under reduced pressure, the resulting residue was diluted with 1:1 EtOAc / TBME and then washed twice with saturated NaHCO solution, five times with water, and once with brine. The organic phase was dried over MgSO, filtered, and the solvent was evaporated under reduced pressure to give 60.7 g of crude product 1. This crude product was used in the next step without purification. Formula:C 28 H 36 N2O7, exact mass: 512.3, measured value: 513.4 [M+H] + Preparation of (S)-2-((S)-2-(((benzyloxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanamido)-4-phenylbutanoic acid (2)

[0621] [ka]

[0622] To a suspension of 1 (52 g, 101 mmol, 1.0 eq.) in THF (0.7 L) was added dropwise NaOH (0.5 M, 202 mL, 101 mmol, 1.0 eq.). The resulting mixture was stirred at room temperature for 12 h, after which THF was evaporated under reduced pressure. The resulting residue was diluted with water and TBME. After decantation, the aqueous phase was extracted twice more with TBME. The resulting basic aqueous phase (pH ∼8) was acidified to pH 2 by addition of 10% HCl and then extracted three times with DCM. The combined organic phases were dried over MgSO4, filtered, and evaporated to give 37 g of crude product. This crude product was purified by normal phase chromatography using Grace Reveleris and a solution of CHCl3 / 1% AcOH in MeOH as the solvent to give 34.6 g of the expected compound 2. Formula:C 26 H 32 N2O7, exact mass: 484.2, measured value: 485.3 [M+H] + tert-Butyl 3-(2-(3-cyano-4-methylphenoxy)ethyl)piperidine-1-carboxylate (3)

[0623] [ka]

[0624] To a solution of N-Boc-3-(2-hydroxyethyl)piperidine (21 g, 91.7 mmol, 1.0 eq.) in dry DMF (180 mL) was added NaH (3.7 g, 60%, 91.7 mmol, 1.0 eq.). The resulting mixture was stirred for 30 min, and then a solution of 5-fluoro-2-methylbenzonitrile (12.4 g, 91.7 mmol, 1.0 eq.) in dry DMF (40 mL) was added dropwise. After the addition, the mixture was heated at 60 °C. After heating for 20 h, LC-MS monitoring indicated 78% conversion, so after cooling to room temperature, additional NaH (3.7 g, 60%, 91.7 mmol, 1.0 eq.) was added. The mixture was again stirred at room temperature for 30 min and then heated at 60 °C for 7 h. After cooling, the reaction mixture was carefully quenched by the addition of saturated NH4Cl solution and extracted three times with TBME. The combined organic phase was washed once with saturated NH4Cl solution, once with saturated NaHCO3 solution, three times with water, and once with brine. After drying over MgSO4 and filtration, the solvent was evaporated under reduced pressure to give 33 g of crude product. This crude product was purified by normal phase chromatography using Grace Reveleris and DCM / CyH as solvent to give 26.9 g of the expected compound 3. Formula:C 20 H 28 N2O3, exact mass: 344.2, measured value: 345.1 [M+H] + tert-Butyl-3-(2-(3-(aminomethyl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (4)

[0625] [ka]

[0626] To a solution of 3 (22 g, 63.9 mmol, 1.0 eq.) in 7N ammonia in MeOH (1.2 L) was added Raney nickel (22 g, previously washed twice with MeOH). The resulting mixture was stirred at 70 °C under 50 bar H for 18 h. After cooling, TLC monitoring showed the absence of starting material, so the reaction mixture was filtered, and the solid was washed with MeOH. The combined filtrates were evaporated under reduced pressure to give 25 g of crude product 4 as a green oil, which was used in the next step without purification.

[0627] tert-Butyl 3-(2-(3-((5S,8S)-5-(2-(tert-butoxy)-2-oxoethyl)-3,6,9-trioxo-8-phenethyl-1-phenyl-2-oxa-4,7,10-triazaundecan-11-yl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (5)

[0628] [ka]

[0629] To a solution of 2 (34 g, 70.2 mmol, 1.0 eq.), 4 (24.5 g, 70.2 mmol, 1.0 eq.), and HATU (39.2 g, 103.2 mmol, 1.5 eq.) in a mixture of DCM (0.86 L) and dry DMF (0.4 L), DIPEA (30.4 g, 38.9 mL, 242 mmol, 3.4 eq.) was added dropwise over 20 min. The reaction mixture was stirred at room temperature for 24 h, and then the DCM was evaporated under reduced pressure. Water (1.2 L) was slowly added to the resulting solution, which was then stirred at room temperature. The resulting upper layer was decanted, and further water was added and stirred three times. After the final decantation, the slurry was dissolved with ACN and evaporated under reduced pressure. The resulting aqueous solid was dissolved with ACN and co-evaporated three more times to give 62 g of crude product. The crude product was purified by normal phase using Grace Reveleris and DCM / CyH as solvent to give 43 g of expected compound 5. Formula:C 46 H 62 N4O9, exact mass: 814.5, measured value: 815.6 [M+H] + (3S)-3-(((benzyloxy)carbonyl)amino)-4-(((2S)-1-((2-methyl-5-(2-(piperidin-3-yl)ethoxy)benzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-4-oxobutanoic acid (6)

[0630] [ka]

[0631] 39.84 g (48.9 mmol) of starting material 5 was dissolved in 40 mL of 4 M HCl in dioxane and stirred at room temperature for 90 min. The solution was concentrated, and 20 mL of 4 M HCl in dioxane was added and stirred at 60 °C for 1 h. The volatiles were removed under reduced pressure and coevaporated with acetonitrile. The crude product 6 was used in the next step without further purification. Formula:C 37 H 46 N4O7, exact mass: 658.3, measured value: 659.6 [M+H] + Benzyl ((9S,12S)-5 4 -Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)carbamate (7)

[0632] [ka]

[0633] 22.3 g (59 mmol) of HATU was dissolved in 80 ml of DMF. A solution of 48.9 mmol of amino acid 6 in a mixture of 114 ml of DMF and 51.2 ml of DIPEA was added dropwise at room temperature. The reaction mixture was partitioned between ethyl acetate and 2N NaOH solution. Some product precipitated, which was collected and washed with MeOH. The organic phase was dried and evaporated. The residue was triturated with methanol. The combined product 7 totaled 21.6 g. Formula:C 37 H 44 N4O6, exact mass: 640.3, measured value: 641.4 [M+H] + Similar to compound 7, the following diastereomers 289, 290, 291 and 292 were synthesized utilizing enantiomerically pure commercially available building blocks as shown in the relevant structures.

[0634] Benzyl ((13R,9R,12S)-5 4 -Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)carbamate (289)

[0635] [ka] Formula:C 37 H 44 N4O6, exact mass: 640.3, measured value: 641.5 [M+H] +

[0636] Benzyl ((13R,9R,12R)-5 4 -Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)carbamate (290)

[0637] [ka] Formula:C 37H 44 N4O6, exact mass: 640.3, measured value: 641.5 [M+H] +

[0638] Benzyl ((13R,9S,12R)-5 4 -Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)carbamate (291)

[0639] [ka] Formula:C 37 H 44 N4O6, exact mass: 640.3, measured value: 641.5 [M+H] +

[0640] Benzyl ((13R,9S,12S)-5 4 -Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)carbamate (292)

[0641] [ka] Formula:C 37 H 44 N4O6, exact mass: 640.3, measured value: 641.4 [M+H] +

[0642] (9S,12S)-12-amino-5 4 -Methyl-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (8)

[0643] [ka]

[0644] 6.8 g of benzyl carbamate 7 was dissolved in EtOH / DCM (5:1) and hydrogenated using an H-cube (ThalesNano) with 10% Pd / C at 50 °C under 50 bar H2 at a flow rate of 1 ml / min. Four cycles were required for complete removal of the protecting groups. After evaporation, the yield was quantitative. Formula: C 29 H 38 N4O4, exact mass: 506.3, measured value: 507.3 [M+H] + Example A-2: Preparation of macrocyclic compounds 13, 16, 19 and 22 tert-Butyl 3-(2-(3-(((S)-2-(((benzyloxy)carbonyl)amino)-4-phenylbutanamido)methyl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (9)

[0645] [ka]

[0646] Synthesis according to general procedure B using 473 mg of amine 4 and 350 mg of Cbz-hPhe. Purification was carried out by normal phase flash chromatography. Formula:C 38 H 49 N3O6, exact mass: 643.4, measured value: 644.4 [M+H] + tert-Butyl 3-(2-(3-(((S)-2-amino-4-phenylbutanamido)methyl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (10)

[0647] [ka]

[0648] General procedure C was followed using 260 mg of Cbz-protected amine dissolved in 100 ml of ethyl acetate / ethanol (1:1). H-Cube conditions: 1 ml / min, 50° C., full H mode. After removal of volatiles under reduced pressure, the product was used without further purification.

[0649] Amide derivative of amine 10

[0650] [ka]

[0651] Follow general procedure B using 75 mg of amine. Purification was achieved by normal phase flash chromatography. Table A-1

[0652] [Table 2-1]

[0653] [Table 2-2]

[0654] [Table 2-3]

[0655] Removal of protecting groups from compounds 11, 14, 17, and 20

[0656] [ka]

[0657] The protecting group was cleaved according to general procedure D by stirring the compound in 4N HCl / 1,4-dioxane at 60° C. for about 30 minutes. Table A-2

[0658] [Table 3-1]

[0659] [Table 3-2]

[0660] Macrocyclization of amino acids 12, 15, 18, and 21

[0661] [ka]

[0662] Macrocyclization according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Table A-3

[0663] [Table 4-1]

[0664] [Table 4-2]

[0665] Example A-3: Preparation of macrocyclic compounds 25, 26, 27, 28, 29, 30, 31, 32, 33, 40, 41, 42, 60, 61, 62, 63, 64, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 174, 175, 176, 177, 182, 219, 284, 285, 286, 287, 288, 323, 324, 327, 328, 329, 330, 331, 332, 333, 334, 335, 341, 369, 373 tert-Butyl 3-(2-(3-(((S)-2-((S)-4-ethoxy-2-(3-(3-fluorophenyl)propanamido)-4-oxobutanamido)-4-phenylbutanamido)methyl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (23)

[0666] [ka]

[0667] Amide coupling according to general procedure B using 113 mg of carboxylic acid (prepared similarly to compound 2) and 108 mg of benzylamine 4. Purification was achieved by normal phase flash chromatography applying a cyclohexane / ethyl acetate gradient. Formula:C 45 H 59 FN4O8, exact mass: 802.4, measured value: 703.6 [M+H-Boc] + (3S)-3-(3-(3-fluorophenyl)propanamido)-4-(((2S)-1-((2-methyl-5-(2-(piperidin-3-yl)ethoxy)benzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-4-oxobutanoic acid (24)

[0668] [ka]

[0669] Both protecting groups were cleaved according to general procedure D in concentrated aqueous HCl at 60° C. for 90 minutes. Formula:C 38 H 47 FN4O6, exact mass: 674.3, measured value: 675.2 [M+H] + 3-(3-fluorophenyl)-N-((9S,12S)-5 4 -Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)propanamide (25)

[0670] [ka]

[0671] 0.146 mmol amino acid 24 was cyclized according to general procedure A. Purification by RP18 flash chromatography. Formula:C 38 H 45 FN4O5, exact mass: 656.3, measured value: 657.3 [M+H] + Amide derivatization of compound 8 according to general procedure B

[0672] [ka]

[0673] Amine 8 (such as 20 mg) was coupled with a carboxylic acid according to general procedure B to give the amides disclosed in the table below. Purification was achieved by HPLC or reverse-phase flash chromatography. Table A-4

[0674] [Table 5-1]

[0675] [Table 5-2]

[0676] [Table 5-3]

[0677] [Table 5-4]

[0678] [Table 5-5]

[0679] [Table 5-6]

[0680]

Table 5-7

[0681]

Table 5-8

[0682]

Table 5-9

[0683]

Table 5-10

[0684]

Table 5-11

[0685]

Table 5-12

[0686]

Table 5-13

[0687]

Table 5-14

[0688]

Table 5-15

[0689]

Table 5-16

[0690] [Table 5-17]

[0691] [Table 5-18]

[0692] Example A-4: Preparation of macrocyclic compounds 34, 35, 36, 37, 38, 39, 43, 44, 45, and 364 (9S,12S)-5 4 -Methyl-9-phenethyl-12-(pyrimidin-2-ylamino)-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (34)

[0693] [ka]

[0694] A solution of 20 mg of amine 8, 9 mg of 2-chloropyrimidine, and 25 mg of KPO in 0.5 ml of DMF was heated to 100° C. overnight, diluted with some methanol, filtered, and purified by HPLC. Formula:C 33 H 40 N6O4, exact mass: 584.3, measured value: 585.3 [M+H] + (9S,12S)-5 4 -Methyl-12-(oxetan-3-ylamino)-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (35)

[0695] [ka]

[0696] A solution of 20 mg of amine 8 and 4 mg of 3-oxetanone in DCM was cooled in an ice bath. Sodium acetate (0.5 eq.) and 3 eq. of sodium triacetoxyborohydride were added, and the reaction mixture was allowed to warm to room temperature overnight. An additional 4.3 mg of ketone and 17 mg of borohydride were added, and stirring was continued for an additional 3 h, at which time some methanol was added, and the reaction mixture was purified by HPLC. Formula:C 32 H 42 N4O5, exact mass: 562.3, measured value: 563.5 [M+H] + (9S,12S)-5 4 -Methyl-9-phenethyl-12-(pyridin-2-ylamino)-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (36)

[0697] [ka]

[0698] A solution of 20 mg of amine 8, 6.4 mg of 2-iodopyridine, 5.2 mg of N-Me-proline, 3.8 mg of CuI, and 11.1 mg of KCO in 500 μl of DMSO was heated to 80° C. for 24 h. The mixture was diluted with some methanol, filtered, and purified by HPLC. Formula:C 34 H 41 N5O4, exact mass: 583.3, measured value: 584.3 [M+H] + N-((9S,12S)-5 4 -Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)methanesulfonamide (37)

[0699] [ka]

[0700] Compound 37 was synthesized according to general procedure E using 20 mg of amine 8. The product was purified by HPLC. Formula:C 30 H 40 N4O6S, exact mass: 584.3, measured value: 585.4 [M+H] + 1-Ethyl-3-((9S,12S)-5 4 -Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)urea (38)

[0701] [ka]

[0702] Compound 38 was synthesized according to general procedure F using a solution of 20 mg of amine 8 in 0.5 ml of THF. Formula:C 32 H 43 N5O5, exact mass: 577.3, measured value: 578.4 [M+H] + Ethyl ((9S,12S)-5 4 -Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)carbamate (39)

[0703] [ka]

[0704] Compound 39 was synthesized according to general procedure G using a solution of 20 mg of amine 8 in 0.5 ml of THF. Formula:C 32 H 42 N4O6, exact mass: 578.3, measured value: 579.4 [M+H] + (9S,12S)-12-(2,5-dioxopyrrolidin-1-yl)-5 4 -Methyl-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (43)

[0705] [ka]

[0706] A solution of 10 mg of amine 8 and 2.0 mg of succinic anhydride in 0.3 ml of THF was stirred overnight at 40 °C. Volatiles were removed under reduced pressure, and the residue was dissolved in 300 μl of DMF. A solution of 8.4 mg of HATU and 20.9 μl of DIPEA in 300 μl of DMF was added at room temperature. After the reaction was complete, some methanol was added, and purification was achieved by HPLC. Formula:C 33 H 40 N4O6, exact mass: 588.3, ​​measured value: 589.4 [M+H] + N-((9S,12S)-5 4 -Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)-3-phenylpropane-1-sulfonamide (44)

[0707] [ka]

[0708] Compound 44 was synthesized according to general procedure E using 20 mg of amine 8. The product was purified by HPLC. Formula:C 38 H 48 N4O6S, exact mass: 688.3, ​​measured value: 689.5 [M+H] + (9S,12S)-12-((1H-benzo[d]imidazol-2-yl)amino)-5 4 -Methyl-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (45)

[0709] [ka]

[0710] To a solution of 20 mg of amine 8 in 1 ml of DCM was added 30.5 μl of thiophosgene. 1 ml of saturated NaHCO solution was added, and the mixture was stirred until the starting material was consumed. The organic phase was separated, dried, and the volatiles were removed under reduced pressure. The residue and 5.2 mg of o-phenylenediamine were dissolved in 0.5 ml of THF and stirred overnight to give the intermediate thiourea. 5.6 mg of N,N'-diisopropylcarbodiimide was added, and the mixture was kept at 55 °C until the reaction was nearly complete. The mixture was diluted with some methanol and purified by HPLC. Formula:C 36 H 42 N6O4, exact mass: 622.3, measured value: 623.5 [M+H] + N-((9S,12S)-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)acetamide (364)

[0711] [ka]

[0712] Compound 580 was prepared similarly to compound 8, utilizing tert-butyl-3-(2-(3-aminomethyl(phenoxy)ethyl)piperidine-1-carboxylate 579 in place of amine 4.

[0713] [ka] Formula:C 30 H 38 N4O5, exact mass: 534.3, measured value: 535.5 [M+H] +

[0714] Example A-5: Preparation of macrocyclic compound 51 2-Methyl-5-(2-(piperidin-3-yl)ethoxy)benzonitrile (46)

[0715] [ka]

[0716] Compound 46 was prepared from 390 mg of Boc-protected amine 3 according to general procedure D using a solution of 4 N HCl in 1,4-dioxane at room temperature. The crude product was coevaporated twice with methanol and used without further purification. Formula:C 15 H 20 NO, exact mass: 244.2, measured value: 245.2 [M+H] + tert-Butyl 4-(3-(2-(3-cyano-4-methylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoate (47)

[0717] [ka]

[0718] Synthesis according to general procedure B using 1.13 mmol of amine 4 and 296 mg of mono-tert.-butylsuccinate. Purification was achieved by normal phase flash chromatography. Formula:C 23 H 32 N2O4, exact mass: 400.2, measured value: 401.4 [M+H] + tert-Butyl 4-(3-(2-(3-(aminomethyl)-4-methylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoate (48)

[0719] [ka]

[0720] 142 mg of nitrile 47 and 91 mg of NiCl2 were stirred in 7 ml of ethanol at 0 °C. 54 mg of NaBH4 was added, and the mixture was allowed to warm to room temperature. After 1 h, the same amounts of NaBH4 and NiCl2 as before were added, respectively. After 1 h, the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted several times with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was removed under reduced pressure. The crude product was used without further purification. Formula:C 23 H 36 N2O4, exact mass: 404.3, measured value: 405.1 [M+H] + tert-Butyl 4-(3-(2-(3-((2-((tert-butoxycarbonyl)amino)-4-(pyridin-3-yl)butanamido)methyl)-4-methylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoate (49)

[0721] [ka]

[0722] Synthesis according to general procedure B using 94 mg of amine 48 and 50 mg of 2-((tert-butoxycarbonyl)amino)-4-(pyridin-3-yl)butanoic acid. Purification was achieved by normal phase flash chromatography. Formula:C 37 H 54 N4O7, exact mass: 666.4, measured value: 667.4 [M+H] + 4-(3-(2-(3-((2-amino-4-(pyridin-3-yl)butanamido)methyl)-4-methylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoic acid (50)

[0723] [ka]

[0724] The compound was stirred in 4N HCl / 1,4-dioxane at room temperature to cleave the protecting group according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Formula:C 28 H 38 N4O5, exact mass: 510.3, measured value: 511.3 [M+H] + 5 4 -Methyl-9-(2-(pyridin-3-yl)ethyl)-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (51)

[0725] [ka]

[0726] Macrocyclization was achieved using 0.179 mmol of amino acid 50 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Formula:C 28 H 36 N4O4, exact mass: 492.3, measured value: 493.3 [M+H] + Example A-6: Preparation of macrocyclic compound 59 tert-Butyl 3-(2-(5-bromo-2,4-dimethylphenoxy)ethyl)piperidine-1-carboxylate (52)

[0727] [ka]

[0728] 855 mg of tert-butyl 3-(2-hydroxyethyl)piperidine-1-carboxylate, 500 mg of 5-bromo-2,4-dimethylphenol, and 978 mg of PPh3 were dissolved in 12 ml of THF. 734 μl of diisopropyl azodicarboxylate was added dropwise to 3 ml of THF, and the reaction was stirred at room temperature for 2 hours. The reaction was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine. The organic phase was dried over MgSO4, and the volatiles were removed under reduced pressure. The crude product was purified by normal-phase flash chromatography. Formula:C 20 H 30 BrNO3, exact mass: 411.1, measured value: 414.1 [M+H] + tert-Butyl 3-(2-(5-cyano-2,4-dimethylphenoxy)ethyl)piperidine-1-carboxylate (53)

[0729] [ka]

[0730] A solution of bromide 52 (780 mg) and 340 mg of CuCN in DMF was stirred at 120 °C for 4 days. The mixture was diluted with ethyl acetate, washed with saturated NaHCO solution and brine, and dried over MgSO. The solvent was removed under reduced pressure, and the residue was purified by normal-phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 21 H 30 N2O3, exact mass: 358.2, measured value: 358.3 [M+H] + tert-Butyl 3-(2-(5-(aminomethyl)-2,4-dimethylphenoxy)ethyl)piperidine-1-carboxylate (54)

[0731] [ka]

[0732] A solution of nitrile 53 (432 mg) in 40 ml of EtOH was reduced at 50 bar, 70° C. and 0.5 ml / min for four cycles according to general procedure H. After removal of volatiles, the residue was used without further purification. Formula:C 21 H 34 N2O3, exact mass: 362.3, measured value: 363.3 [M+H] + tert-Butyl 3-(2-(5-(((S)-2-(((benzyloxy)carbonyl)amino)-4-phenylbutanamido)methyl)-2,4-dimethylphenoxy)ethyl)piperidine-1-carboxylate (55)

[0733] [ka]

[0734] Synthesis according to general procedure B using 1.21 mmol of amine 54 and 493 mg of (S)-2-(((benzyloxy)carbonyl)amino)-4-phenylbutanoic acid. Purification was achieved by normal phase flash chromatography. Formula:C 39 H 51 N3O6, exact mass: 657.4, measured value: 658.3 [M+H] + tert-Butyl 3-(2-(5-(((S)-2-amino-4-phenylbutanamido)methyl)-2,4-dimethylphenoxy)ethyl)piperidine-1-carboxylate (56)

[0735] [ka]

[0736] Synthesis according to general procedure C using 695 mg of protected amine in 80 ml of ethanol / ethyl acetate (1:1) at 20 bar, 50° C., and 0.5 ml / min. After removal of volatiles, the crude product was used in the next step. Formula:C 31 H 45 N3O4, exact mass: 523.3, measured value: 524.4 [M+H] + tert-Butyl 3-(2-(5-(((S)-2-(4-(tert-butoxy)-4-oxobutanamido)-4-phenylbutanamido)methyl)-2,4-dimethylphenoxy)ethyl)piperidine-1-carboxylate (57)

[0737] [ka]

[0738] Synthesis according to general procedure B using 200 mg of amine 56 and 100 mg of mono-tert.-butylsuccinate. Purification was achieved by normal phase flash chromatography. Formula:C 39 H 57 N3O7, exact mass: 679.4, measured value: 680.4 [M+H] + 4-(((2S)-1-((2,4-dimethyl-5-(2-(piperidin-3-yl)ethoxy)benzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-4-oxobutanoic acid (58)

[0739] [ka]

[0740] Both protecting groups were cleaved in concentrated aqueous HCl at RT for 2 h according to general procedure D. The crude product was co-evaporated twice with acetonitrile and used without further purification. Formula:C 30 H 41 N3O5, exact mass: 523.3, measured value: -[M+H]+ (9R)-5 4 ,5 6 -Dimethyl-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (59)

[0741] [ka]

[0742] Macrocyclization was achieved according to general procedure A using 0.447 mmol of amino acid 58. The reaction mixture was diluted with some methanol and purified by HPLC. Formula:C 30 H 39 N3O4, exact mass: 505.3, measured value: 506.3 [M+H] + Example A-7: Preparation of macrocyclic compounds 77, 78, and 79 (S)-tert-Butyl 4-((1-(benzyloxy)-3-(1H-indol-3-yl)-1-oxopropan-2-yl)amino)-4-oxobutanoate (65)

[0743] [ka]

[0744] The amide bond was formed using 1.02 g of (S)-benzyl 2-amino-3-(1H-indol-3-yl)propanoate and 400 mg of mono-tert.-butylsuccinate according to general procedure B. Purification was achieved by RP18 reverse-phase flash chromatography. Formula:C 26 H 30 N2O5, exact mass: 450.2, measured value: 451.3 [M+H] + (S)-tert-Butyl 4-((1-(benzyloxy)-1-oxopropan-2-yl)amino)-4-oxobutanoate (66)

[0745] [ka]

[0746] The amide bond was formed using 744 g of (S)-benzyl 2-aminopropanoate and 400 mg of mono-tert.-butylsuccinate according to general procedure B. Purification was achieved by RP18 reversed-phase flash chromatography. Formula:C 18 H 25 NO5, exact mass: 360.2, actual value: 361.2 [M+H] + (S)-tert-Butyl 4-((1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl)amino)-4-oxobutanoate (67)

[0747] [ka]

[0748] The amide bond was formed using 1.01 g of (S)-benzyl 2-amino-3-phenylpropanoate and 400 mg of mono-tert.-butylsuccinate according to general procedure B. Purification was achieved by RP18 reversed-phase flash chromatography. Formula:C 24 H 29 NO5, exact mass: 411.2, actual value: 412.3 [M+H] + (S)-2-(4-(tert-butoxy)-4-oxobutanamido)-3-(1H-indol-3-yl)propanoic acid (68)

[0749] [ka]

[0750] The benzyl ester was cleaved according to general procedure C using a Raney Ni catalyst cartridge at 20 bar and 50° C. in a solvent mixture of ethanol / ethyl acetate (3:1). The product was purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula: C 19 H 24 N2O5, exact mass: 360.2, measured value: 361.2 [M+H] + (S)-2-(4-(tert-butoxy)-4-oxobutanamido)propanoic acid (69)

[0751] [ka]

[0752] The benzyl ester was cleaved according to general procedure C using a Raney Ni catalyst cartridge at 20 bar and 50° C. in a solvent mixture of ethanol / ethyl acetate (3:1). The product was purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula: C 11 H 19 NO5, exact mass: 245.1, measured value: 246.2 [M+H] + (S)-2-(4-(tert-butoxy)-4-oxobutanamido)-3-phenylpropanoic acid (70)

[0753] [ka]

[0754] The benzyl ester was cleaved according to general procedure C using a Raney Ni catalyst cartridge at 20 bar and 50° C. in a solvent mixture of ethanol / ethyl acetate (3:1). The product was purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula: C 17 H 23 NO5, exact mass: 321.2, actual value: 322.2 [M+H] + tert-Butyl 3-(2-(3-(((S)-2-(4-(tert-butoxy)-4-oxobutanamido)-3-(1H-indol-3-yl)propanamido)methyl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (71)

[0755] [ka]

[0756] The amide bond was formed using 100 mg of amine 4 and 134 mg of carboxylic acid 68 according to general procedure B. Purification was achieved by RP18 reverse phase flash chromatography. 39 H 54 N4O7, exact mass: 690.4, measured value: 691.6 [M+H] + tert-Butyl 3-(2-(3-(((S)-2-(4-(tert-butoxy)-4-oxobutanamido)propanamido)methyl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (72)

[0757] [ka]

[0758] The amide bond was formed using 100 mg of amine 4 and 91 mg of carboxylic acid 69 according to general procedure B. Purification was achieved by RP18 reverse phase flash chromatography. 31 H 49 N3O7, exact mass: 575.4, measured value: 576.4 [M+H] + tert-Butyl 3-(2-(3-(((S)-2-(4-(tert-butoxy)-4-oxobutanamido)-3-phenylpropanamido)methyl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (73)

[0759] [ka]

[0760] The amide bond was formed using 100 mg of amine 4 and 120 mg of carboxylic acid 70 according to general procedure B. Purification was achieved by RP18 reverse phase flash chromatography. 37 H 53 N3O7, exact mass: 651.4, measured value: 652.4 [M+H] + 4-(((2S)-3-(1H-indol-3-yl)-1-((2-methyl-5-(2-(piperidin-3-yl)ethoxy)benzyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid (74)

[0761] [ka]

[0762] The compound was stirred in 4N HCl / 1,4-dioxane at room temperature to cleave the protecting group according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Formula:C 30 H 38 N4O5, exact mass: 534.3, measured value: 536.3 [M+H] + 4-(((2S)-1-((2-methyl-5-(2-(piperidin-3-yl)ethoxy)benzyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid (75)

[0763] [ka]

[0764] The compound was stirred in 4N HCl / 1,4-dioxane at room temperature to cleave the protecting group according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Formula:C 22 H 33 N3O5, exact mass: 419.2, measured value: 420.1 [M+H] + 4-(((2S)-1-((2-methyl-5-(2-(piperidin-3-yl)ethoxy)benzyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-4-oxobutanoic acid (76)

[0765] [ka]

[0766] The compound was stirred in 4N HCl / 1,4-dioxane at room temperature to cleave the protecting group according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Formula:C 28 H 37 N3O5, exact mass: 495.3, measured value: 496.3 [M+H] + (9S)-9-((1H-indol-3-yl)methyl)-5 4 -Methyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (77)

[0767] [ka]

[0768] Macrocyclization was achieved using 0.287 mmol of amino acid 74 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Formula C 30 H36 N4O4, exact mass: 516.3, measured value: 517.3 [M+H] + (9S)-5 4 ,9-Dimethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (78)

[0769] [ka]

[0770] Macrocyclization was achieved using 0.224 mmol of amino acid 75 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Formula: C 22 H 31 N3O4, exact mass: 401.2, measured value: 402.3 [M+H] + (9S)-9-benzyl-5 4 -Methyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (79)

[0771] [ka]

[0772] Macrocyclization was achieved using 0.215 mmol of amino acid 76 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Formula C 28 H 35 N3O4, exact mass: 477.3, measured value: 478.3 [M+H] + Example A-8: Preparation of macrocycle 95 tert-Butyl 3-(2-(3-(((S)-2-(((benzyloxy)carbonyl)amino)-4-phenylbutanamido)methyl)-4,5-dimethylphenoxy)ethyl)piperidine-1-carboxylate (91)

[0773] [ka]

[0774] The amide bond was formed according to general procedure B. Purification was carried out by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). 39 H 51 N3O6, exact mass: 657.4, measured value: 658.6 [M+H] + tert-Butyl 3-(2-(3-(((S)-2-amino-4-phenylbutanamido)methyl)-4,5-dimethylphenoxy)ethyl)-piperidine-1-carboxylate (92)

[0775] [ka]

[0776] The benzyl carbamate was cleaved using a 10% Pd / C catalyst cartridge in a solvent mixture of ethanol / ethyl acetate (3:1) at 20 bar and 50° C. according to general procedure C. The dried product was used without further purification. Formula:C 31 H 45 N3O4, exact mass: 523.3, measured value: 524.6 [M+H] + tert-Butyl 3-(2-(3-(((S)-2-(4-(tert-butoxy)-4-oxobutanamido)-4-phenylbutanamido)methyl)-4,5-dimethylphenoxy)ethyl)piperidine-1-carboxylate (93)

[0777] [ka]

[0778] The amide bond was formed using approximately 0.181 mmol of amine 92 and 47 mg of the carboxylic acid according to general procedure B. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 39 H 57 N3O7, exact mass: 679.4, measured value: 680.7 [M+H] + 4-(((2S)-1-((2,3-dimethyl-5-(2-(piperidin-3-yl)ethoxy)benzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-4-oxobutanoic acid (94)

[0779] [ka]

[0780] The compound was stirred in 4N HCl / 1,4-dioxane at room temperature to cleave the protecting group according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Formula:C 30 H 41 N3O5, exact mass: 523.3, measured value: 524.5 [M+H] + (9S)-5 4 ,5 5 -Dimethyl-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (95)

[0781] [ka]

[0782] Macrocyclization was achieved using approximately 0.125 mmol of amino acid 94 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. 30 H 39N3O4, Calculated: 505.3, Found: 506.4 [M+H] + Example A-9: Preparation of macrocyclic compounds 105, 106, 107, 371, and 372 2-Vinylpyrazine (96)

[0783] [ka]

[0784] To a solution of 2-chloropyrazine (78 g, 681 mmol) in THF (800 mL) under an argon atmosphere was added potassium vinyltrifluoroborate (137 g, 1022 mmol), triethylamine (247 mL, 2020 mmol), and a solution of Pd(dppf)Cl2 in dichloromethane (5.6 g, 6.9 mmol). The reaction mass was refluxed for 24 h, cooled to room temperature, diluted with MTBE (800 mL), and filtered through a pad of Na2SO4. The filtrate was evaporated under reduced pressure to give crude 2-vinylpyrazine (60 g, 565.5 mmol), which was used in the next step without further purification.

[0785] Diethyl 2-acetamido-2-(pyrazin-2-ylmethyl)malonate (97)

[0786] [ka]

[0787] Diethyl acetamido malonate (184.6 g, 850 mmol) and DBU (127 mL, 850 mmol) were dissolved in DMF (800 mL) and stirred at room temperature for 15 minutes. 2-Vinylpyrazine (60 g, 565.5 mmol) was then slowly added dropwise to the reaction mixture, which was stirred at room temperature for 24 hours. It was then concentrated under reduced pressure, diluted with water (800 mL), and extracted with ethyl acetate (2 × 800 mL). The combined organic layers were washed with brine (3 × 800 mL), dried over NaSO, and concentrated to give 120 g of diethyl 2-acetamido-2-(pyrazin-2-ylmethyl)malonate (371 mmol, 65.6% yield), which was used in the next step without further purification.

[0788] Ethyl 2-amino-4-(pyrazin-2-yl)butanoate (98)

[0789] [ka]

[0790] Diethyl 2-acetamido-2-(pyrazin-2-ylmethyl)malonate (120 g, 371 mmol) was dissolved in 5 M hydrochloric acid (1000 mL) and refluxed for 14 hours. The solvent was then evaporated under reduced pressure to give 96 g of the crude intermediate (441 mmol, 19% yield), which was used in the next step without further purification.

[0791] To a cooled (5-10 °C) solution of the crude material from the previous step (441 mmol) in absolute ethanol (500 mL) was slowly added SOCl (14.5 mL, 199 mmol) dropwise and stirred for 30 min. The mixture was then refluxed for 12 h without air exposure. The reaction mixture was then concentrated under reduced pressure, and the resulting ethyl 2-amino-4-(pyrazin-2-yl)butanoate (100 g, 407 mmol) was used in the next step without further purification. Formula:C 10 H15 N3O2, exact mass: 209.1, measured value: 210.2 [M+H] + Ethyl 2-(((benzyloxy)carbonyl)amino)-4-(pyrazin-2-yl)butanoate (99)

[0792] [ka]

[0793] 5.0 g of aminoester 98 was dissolved in a mixture of 25 ml of water and 68 ml of THF and cooled to 0° C. 5.07 g of N-(benzyloxycarbonyloxy)succinimide and 8.24 g of trimethylamine were added, and the mixture was allowed to warm to room temperature. After complete consumption of the starting material, the mixture was partitioned between saturated NaHCO3 solution and ethyl acetate. The organic phase was dried over MgSO4, and the volatiles were removed under reduced pressure. The crude product was used without further purification.

[0794] 2-(((benzyloxy)carbonyl)amino)-4-(pyrazin-2-yl)butanoic acid (100)

[0795] [ka]

[0796] 6.45 g of ester 99 was dissolved in a mixture of 47 ml of 1,4-dioxane and 20 mL of 1 M aqueous NaOH at room temperature. After 3 hours, the mixture was adjusted to pH 3 with 1 M aqueous HCl. The mixture was extracted twice with ethyl acetate, and the combined organic phases were dried over MgSO. Volatiles were removed under reduced pressure. The crude product was sufficiently pure to be used in the next reaction. Formula:C 16 H 17 N3O4, exact mass: 315.1, measured value: 316.1 [M+H] + tert-Butyl 3-(2-(3-((2-(((benzyloxy)carbonyl)amino)-4-(pyrazin-2-yl)butanamido)methyl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (101)

[0797] [ka]

[0798] 600 mg of carboxylic acid 100 was coupled with 663 mg of amine 4 according to general procedure B. Purification was achieved by reverse-phase column chromatography (RP18, water / acetonitrile gradient).

[0799] tert-Butyl 3-(2-(3-((2-amino-4-(pyrazin-2-yl)butanamido)methyl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (102)

[0800] [ka]

[0801] A solution of 660 mg of compound 101 and 70 mg of 10% Pd / C in a mixture of 8 ml of methanol and 1.5 ml of THF was hydrogenated at room temperature under atmospheric pressure. After the reaction was complete, the mixture was filtered and the volatiles were removed. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 28 H 41 N5O4, exact mass: 511.3, measured value: 512.3 [M+H] + tert-Butyl 3-(2-(3-((5S)-5-(2-(tert-butoxy)-2-oxoethyl)-3,6,9-trioxo-1-phenyl-8-(2-(pyrazin-2-yl)ethyl)-2-oxa-4,7,10-triazaundecan-11-yl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (103)

[0802] [ka]

[0803] The amide bond was formed using 243 mg of amine 102 and 230 mg of Cbz-Asp(OtBu)-OH according to general procedure B. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 44 H 60 N6O9, exact mass: 816.4, measured value: 717.6 [M+H-Boc] + (3S)-3-(((benzyloxy)carbonyl)amino)-4-((1-((2-methyl-5-(2-(piperidin-3-yl)ethoxy)benzyl)amino)-1-oxo-4-(pyrazin-2-yl)butan-2-yl)amino)-4-oxobutanoic acid (104)

[0804] [ka]

[0805] The protecting group was cleaved from 280 mg of compound 103 by stirring the compound in 10 ml of 6N HCl / 1,4-dioxane at room temperature according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Formula:C 35 H 44 N6O7, exact mass: 660.3, measured value: 662.3 [M+H] + Benzyl ((12S)-5 4 -Methyl-8,11,14-trioxo-9-(2-(pyrazin-2-yl)ethyl)-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)carbamate (105)

[0806] [ka]

[0807] Macrocyclization was achieved using 0.343 mmol of amino acid 58 according to general procedure A. The reaction mixture was diluted with some methanol and purified by reverse phase column chromatography (RP18, water / methanol gradient). Formula:C 35 H 42 N6O6, exact mass: 642.3, measured value: 643.5 [M+H] + (12S)-amino-5 4 -Methyl-8,11,14-trioxo-9-(2-(pyrazin-2-yl)ethyl)-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane (106)

[0808] [ka]

[0809] The benzyl carbamate was cleaved using a 10% Pd / C catalyst cartridge in a solvent mixture of ethanol / ethyl acetate (3:1) at 20 bar and 50° C. according to general procedure C. After removal of volatiles, the residue was used directly in the next step. Formula:C 27 H 36 N6O4, exact mass: 508.3, measured value: -[M+H] + (2S)-N-((12S)-5 4 -Methyl-8,11,14-trioxo-9-(2-(pyrazin-2-yl)ethyl)-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)-2-phenylpropanamide (107)

[0810] [ka]

[0811] The amide bond was formed, for example, using 25 mg of amine 106 and 11 mg of carboxylic acid according to general procedure B. Purification was achieved by reverse phase HPLC. Formula:C 36 H 44 N6O5, exact mass: 640.3, measured value: 641.4 [M+H] + Further examples, exemplified by compound 107, are disclosed in the table below. In the case of compounds 371 and 372, the Boc group was cleaved from the relevant Boc-protected intermediate using a solution of 40% TFA in DCM before final purification by HPLC. Table A-5

[0812] [Table 6-1]

[0813] [Table 6-2]

[0814] Example A-10: Preparation of compound (116) Ethyl 4-(3-(2-(3-(aminomethyl)-4-methylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoate (112)

[0815] [ka]

[0816] 2.48 g of amine 46 and 5.64 ml of NEt were dissolved in 60 ml of DCM and cooled to 0 °C. 1.86 g of ethyl 4-chloro-4-oxobutanoate was added dropwise, and the mixture was allowed to warm to room temperature. After complete consumption of the starting amine, saturated NaHCO solution was added, and the mixture was extracted with DCM. The organic phase was dried and concentrated under reduced pressure. Purification of the residue was achieved by normal-phase column chromatography (silica, cyclohexane / ethyl acetate gradient).

[0817] 2.0 g of the intermediate ester was dissolved in 135 ml of methanol and hydrogenated with 7.0 Raney nickel at 50 bar and 70° C. The mixture was filtered and concentrated under reduced pressure. The residue was sufficiently pure to be used in the next reaction (mixture of methyl and ethyl esters). Formula:C 21 H 32 N2O4, exact mass: 376.2, measured value: 377.3 [M+H] + Ethyl 2-amino-2-(1-methyl-1H-pyrazol-4-yl)acetate (109)

[0818] [ka]

[0819] 3.75 g of 2-amino-2-(1-methyl-1H-pyrazol-4-yl)acetic acid was refluxed in 60 ml of 1.25 M HCl in ethanol until esterification was complete. Volatiles were removed under reduced pressure, and the residue was coevaporated twice with acetonitrile. The crude product was used without further purification. Formula:C8H 13 N3O2, exact mass: 183.1, measured value: 184.3 [M+H] + Ethyl 2-(((benzyloxy)carbonyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)acetate (110)

[0820] [ka]

[0821] 24 mmol of amino ester 109 was dissolved in THF / water (3:1) at 0 °C. 6.0 g of CbzOSu and 13.1 ml of NEt were added, and the mixture was allowed to warm to room temperature. The mixture was partitioned between ethyl acetate and saturated NaHCO solution. The organic phase was washed with 2 N HCl, dried over NaSO, and concentrated. The crude product was purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient) to give 3.54 g of ester 110. Formula:C 16 H 19 N3O4, exact mass: 317.1, measured value: 318.3 [M+H] + 2-(((benzyloxy)carbonyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)acetic acid (111)

[0822] [ka]

[0823] 3.4 g of ester 110 was dissolved in 12 ml of THF, and 4 ml of 2 M LiOH aq. was added. Some additional water was added to obtain only one phase. After completion of the reaction, the mixture was washed with ethyl acetate, and the aqueous phase was acidified to pH 2. Extraction with ethyl acetate and removal of the solvent under reduced pressure gave 2.1 g of Cbz-protected amino acid 111. Formula:C 14 H 15 N3O4, exact mass: 289.1, measured value: 290.3 [M+H] + Ethyl 4-(3-(2-(3-((2-(((benzyloxy)carbonyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)acetamido)methyl)-4-methylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoate (113)

[0824] [ka]

[0825] Peptide coupling was carried out using 468 mg of amine 112 and 300 mg of amino acid 111 according to general procedure B. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 35 H 45 N5O7, exact mass: 647.3, measured value: 648.3 [M+H] + Ethyl 4-(3-(2-(3-((2-amino-2-(1-methyl-1H-pyrazol-4-yl)acetamido)methyl)-4-methylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoate (114)

[0826] [ka]

[0827] The benzyl carbamate was cleaved from 647 mg of compound 113 using a 10% Pd / C catalyst cartridge in a solvent mixture of ethanol / ethyl acetate (1:1) at 30 bar and 60° C. according to general procedure C. The product was used without further purification after removal of volatiles. Formula:C 27 H 39 N5O5, exact mass: 513.3, measured value: 514.3 [M+H] + 4-(3-(2-(3-((2-amino-2-(1-methyl-1H-pyrazol-4-yl)acetamido)methyl)-4-methylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoic acid (115)

[0828] [ka]

[0829] 1.04 mmol of ester 114 was dissolved in 20 ml of concentrated aqueous HCl at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure and the crude product was used directly in the next step. Formula:C 22 H 35 N5O5, exact mass: 485.3, measured value: 486.2 [M+H] + 5 4 -Methyl-9-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (116)

[0830] [ka]

[0831] Macrocyclization was achieved using 1.04 mmol of amino acid 115 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Formula:C 25 H 33 N5O4, exact mass: 467.3, measured value: 468.3 [M+H] + Example A-11: Preparation of compound (120) 2,3-Dimethyl-5-(2-(piperidin-3-yl)ethoxy)benzonitrile (574)

[0832] [ka]

[0833] The Boc group was removed from 1.77 g of compound 573 using a solution of 2.8 g of TFA in 49 ml of DCM according to general procedure D. The volatiles were removed, the residue was dissolved in DCM, and washed with 5% aqueous NaOH. The organic phase was dried over MgSO, filtered, and the solvent was removed under reduced pressure. The crude product was used without further purification.

[0834] Ethyl 4-(3-(2-(3-cyano-4,5-dimethylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoate (575)

[0835] [ka]

[0836] The amide bond was formed using amine 574 according to general procedure B. Purification was achieved by normal phase flash chromatography. Ethyl 4-(3-(2-(3-(aminomethyl)-4,5-dimethylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoate (117)

[0837] [ka]

[0838] 536 mg of intermediate nitrile 575 was dissolved in 36 ml of methanol and hydrogenated with 1.9 g of Raney nickel at 70° C. and 50 bar. The mixture was filtered and concentrated under reduced pressure. The residue was sufficiently pure to be used in the next reaction (mixture of methyl and ethyl esters). Formula:C 22 H 34 N2O4, exact mass: 390.3, measured value: 391.3 [M+H] + tert-Butyl 3-((2S)-2-((tert-butoxycarbonyl)amino)-3-((5-(2-(1-(4-ethoxy-4-oxobutanoyl)piperidin-3-yl)ethoxy)-2,3-dimethylbenzyl)amino)-3-oxopropyl)-1H-indole-1-carboxylate (118)

[0839] [ka]

[0840] Condensation was achieved using 232 mg of amine 117 and 312 mg of Boc-protected amino acid according to general procedure B. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 43 H 60 N4O9, exact mass: 776.4, measured value: 777.5 [M+H] + 4-(3-(2-(3-(((S)-2-amino-3-(1H-indol-3-yl)propanamido)methyl)-4,5-dimethylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoic acid (119)

[0841] [ka]

[0842] The protecting group was cleaved from 240 mg of compound 118 by stirring the compound in 10 ml of concentrated aqueous HCl at room temperature according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Formula:C 31 H 40 N4O5, exact mass: 548.3, measured value: 549.4 [M+H] + (9S)-9-((1H-indol-3-yl)methyl)-5 4 ,5 5 -Dimethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (120)

[0843] [ka]

[0844] Macrocyclization was achieved using 0.309 mmol of amino acid 119 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Formula:C 31 H 38 N4O4, exact mass: 530.3, measured value: 531.4 [M+H] + Example A-12: Derivatization of Compound 8 with a Boc-protected amino acid

[0845] [ka]

[0846] Amine 8 (e.g., 20 mg to 100 mg) was coupled with carboxylic acids according to general procedure B to give the amides disclosed in the table below. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Table A-6

[0847] [Table 7-1]

[0848] [Table 7-2]

[0849] [Table 7-3]

[0850] [Table 7-4]

[0851] [Table 7-5]

[0852] [Table 7-6]

[0853]

Table 7-7

[0854]

Table 7-8

[0855]

Table 7-9

[0856]

Table 7-10

[0857]

Table 7-11

[0858]

Table 7-12

[0859]

Table 7-13

[0860]

Table 7-14

[0861]

Table 7-15

[0862]

Table 7-16

[0863] [Table 7-17] TIFF2024534613000510.tif94163

[0864] Example A-13: Removal of the Boc protecting group to give the basic macrocycle

[0865] [ka]

[0866] The Boc protecting group was cleaved from the compound by stirring the compound in 4 ml to 10 ml of 4N HCl / 1,4-dioxane at room temperature according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was purified by reverse-phase HPLC. Table A-7

[0867] [Table 8-1]

[0868] [Table 8-2]

[0869] [Table 8-3]

[0870] [Table 8-4]

[0871] [Table 8-5]

[0872] [Table 8-6]

[0873]

Table 8-7

[0874]

Table 8-8

[0875]

Table 8-9

[0876]

Table 8-10

[0877]

Table 8-11

[0878]

Table 8-12

[0879]

Table 8-13

[0880]

Table 8-14

[0881]

Table 8-15

[0882]

Table 8-16

[0883] [Table 8-17]

[0884] Example A-14: Preparation of intermediate compounds (S)-tert-Butyl 4-acetamido-5-(((S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl)amino)-5-oxopentanoate (137)

[0885] [ka]

[0886] The amide bond can be formed using Ac-Glu(OtBu)-OH and H-hPhe-OEt according to general procedure B. Purification can be achieved by normal phase flash chromatography. Formula:C 23 H 34 N2O6, exact mass: 434.2, measured value: 435.3 [M+H] + (S)-2-((S)-2-acetamido-5-(tert-butoxy)-5-oxopentanamido)-4-phenylbutanoic acid (138)

[0887] [ka]

[0888] Ester 137 was dissolved in 3 ml of THF. 0.5 ml of water and 0.5 ml of 2 M aqueous LiOH were added at room temperature. After complete saponification, the mixture was acidified to pH 2 and extracted with ethyl acetate. The organic phase was dried over MgSO4, and the solvent was removed under reduced pressure. The residue was used in the next step without further purification. Formula:C 21 H 30 N2O6, exact mass: 406.2, measured value: 407.5 [M+H] + tert-Butyl 2-(2-(3-cyano-4-methylphenoxy)ethyl)morpholine-4-carboxylate (140)

[0889] [ka]

[0890] 924 mg of the alcohol was deprotonated in DMF with 153 mg of NaH at room temperature. 450 mg of 5-fluoro-2-methylbenzonitrile was added, and the mixture was heated to 90 °C until the reaction was complete. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine. After drying over MgSO4 and removing the solvent under reduced pressure, the residue was purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 19 H 26 N2O4, exact mass: 346.2, measured value: 247.3 [M+H] + The building blocks in the table below were synthesized as exemplified by compound 140, utilizing appropriately substituted 3-fluorobenzonitriles and the related boc-protected amino alcohols. Table A-8

[0891] [Table 9-1]

[0892] [Table 9-2]

[0893] [Table 9-3]

[0894] [Table 9-4]

[0895] tert-Butyl 2-(2-(3-(aminomethyl)-4-methylphenoxy)ethyl)morpholine-4-carboxylate (141)

[0896] [ka]

[0897] 1.15 g of nitrile 140 was reduced and cleaved according to general procedure H in 70 ml of ethanol at 50 bar and 70 °C using a Raney Ni catalyst cartridge. Volatiles were removed under reduced pressure, and the residue was purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). The components in the following table were synthesized as exemplified by compound 141. Formula:C 19 H 30 N2O4, exact mass: 350.2, measured value: 351.3 [M+H] + Table A-9

[0898] [Table 10-1]

[0899] [Table 10-2]

[0900] [Table 10-3]

[0901] [Table 10-4]

[0902] [Table 10-5]

[0903] [Table 10-6]

[0904] [Table 10-7]

[0905] Example A-15: Preparation of macrocycles 143 and 148 tert-Butyl 2-(2-(3-(((S)-2-((S)-2-acetamido-5-(tert-butoxy)-5-oxopentanamido)-4-phenylbutanamido)methyl)-4-methylphenoxy)ethyl)morpholine-4-carboxylate (139)

[0906] [ka]

[0907] The amide bond was formed using 96 mg of amine 141 and 94 mg of protected amino acid 138 according to general procedure B. Purification was achieved by normal phase flash chromatography. The components in the following table were synthesized as exemplified by compound 139. Table A-10

[0908] [Table 11]

[0909] (4S)-4-Acetamido-5-(((2S)-1-((2-methyl-5-(2-(morpholin-2-yl)ethoxy)benzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-5-oxopentanoic acid (142)

[0910] [ka]

[0911] The protecting group was cleaved from compound 139 by stirring the compound in 10 ml of 4N HCl / 1,4-dioxane at room temperature according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification.

[0912] The components in the table below were synthesized as exemplified by compound 142. Table A-11

[0913] [Table 12]

[0914] N-((9S,12S)-5 4 -Methyl-8,11,15-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(2,4)-morpholina-5(1,3)-benzenacyclopentadecaphan-12-yl)acetamide (143)

[0915] [ka]

[0916] Macrocyclization was achieved using 0.20 mmol of amino acid 142 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. The compounds in the following table were synthesized as exemplified by compound 143. Table A-12

[0917] [Table 13]

[0918] Example A-16: Preparation of macrocycle 168 tert-Butyl (4-(3-cyano-4-methylphenoxy)butyl)carbamate (162)

[0919] [ka]

[0920] 978 mg of phenol, 2.5 g of bromide, and 6.46 g of CsCO were stirred in 10 ml of DMF at 60 °C until the phenol was consumed. The reaction mixture was diluted with DCM and washed with brine. The solvent was removed, and the residue was purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 17 H 24 N2O3, exact mass: 304.2, actual value: 304 (GC), 205.2 [M+H-Boc] + tert-Butyl (4-(3-(aminomethyl)-4-methylphenoxy)butyl)carbamate (163)

[0921] [ka]

[0922] A solution of 660 mg of NiCl in ethanol, 680 mg of NaBH was added in small portions to 1.55 g of nitrile 162 at room temperature. After the reaction was complete, the mixture was filtered through a pad of Celite. The crude product was purified by normal phase column chromatography (silica, DCM / methanol gradient). Formula:C 17 H 28 N2O3, exact mass: 308.2, measured value: 309.2 [M+H] + (S)-tert-Butyl-(4-(3-((2-(((benzyloxy)carbonyl)amino)-4-phenylbutanamido)methyl)-4-methylphenoxy)butyl)carbamate (164)

[0923] [ka]

[0924] The amide bond was formed using 346 mg of amine 163 and 421 mg of Cbz-hPhe-OH according to general procedure B. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 35 H 45 N3O6, exact mass: 603.3, measured value: 604.4 [M+H] + (S)-tert-butyl(4-(3-((2-amino-4-phenylbutanamido)methyl)-4-methylphenoxy)butyl)carbamate (165)

[0925] [ka]

[0926] The benzyl ester was cleaved in a solvent mixture of ethanol / ethyl acetate on a 10% Pd / C catalyst cartridge at 20 bar and 50° C. according to general procedure C. The product was used directly after removal of volatiles. Formula:C 27 H 39 N3O4, exact mass: 469.3, measured value: 470.4 [M+H] + (S)-tert-Butyl 3-acetamido-4-(((S)-1-((5-(4-((tert-butoxycarbonyl)amino)butoxy)-2-methylbenzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-4-oxobutanoate (166)

[0927] [ka]

[0928] The amide bond was formed with 190 mg of amine 165 and 112 mg of Ac-Asp(OtBu)-OH according to general procedure B. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C37 H 54 N4O8, exact mass: 682.4, measured value: 683.4 [M+H] + (S)-3-Acetamido-4-(((S)-1-((5-(4-aminobutoxy)-2-methylbenzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-4-oxobutanoic acid (167)

[0929] [ka]

[0930] The protecting group was cleaved from 276 mg of compound 166 by stirring the compound in 6 ml of 4 N HCl / 1,4-dioxane at room temperature according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Formula:C 28 H 38 N4O6, exact mass: 526.3, measured value: 527.3 [M+H] + N-((10S,13S)-1 4 -Methyl-8,11,14-trioxo-13-phenethyl-2-oxa-7,12,15-triaza-1(1,3)-benzenacyclohexadecaphan-10-yl)acetamide (168)

[0931] [ka]

[0932] Macrocyclization was achieved using 0.40 mmol of amino acid 167 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Formula:C 28 H 36 N4O5, exact mass: 508.3, measured value: 509.3 [M+H] + Example A-17: Preparation of macrocyclic compounds 171-173 (S)-tert-Butyl 4-acetamido-5-(((S)-1-((5-(4-((tert-butoxycarbonyl)amino)butoxy)-2-methylbenzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-5-oxopentanoate (169)

[0933] [ka]

[0934] The amide bond was formed with 190 mg of amine 165 and 119 mg of Ac-Glut(OtBu)-OH according to general procedure B. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 38 H 56 N4O8, exact mass: 696.4, measured value: 697.5 [M+H] + (S)-4-Acetamido-5-(((S)-1-((5-(4-aminobutoxy)-2-methylbenzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-5-oxopentanoic acid (170)

[0935] [ka]

[0936] The protecting group was cleaved from 282 mg of compound 169 by stirring the compound in 6 ml of 4 N HCl / 1,4-dioxane at room temperature according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Formula:C 29 H 40 N4O6, exact mass: 540.3, measured value: 541.3 [M+H] + N-((11S,14S)-1 4-Methyl-8,12,15-trioxo-14-phenethyl-2-oxa-7,13,16-triaza-1(1,3)-benzeneacycloheptadecaphan-11-yl)acetamide (171)

[0937] [ka]

[0938] Macrocyclization was achieved using 0.40 mmol of amino acid 170 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Formula:C 29 H 38 N4O6, exact mass: 522.3, measured value: 523.3 [M+H] + 2-(4-aminophenyl)-N-((13R,9S,12S)-5 4 -Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)acetamide (172)

[0939] [ka]

[0940] Compound 172 was prepared similarly to compound 128, except that (R)-tert-butyl 3-(2-hydroxyethyl)piperidine-1-carboxylate was used to synthesize the enantiomerically pure derivative of tert-butyl 3-(2-(3-cyano-4-methylphenoxy)ethyl)piperidine-1-carboxylate 3. Formula:C 37 H 45 N5O5, exact mass: 639.3, measured value: 640.4 [M+H] + 2-(4-aminophenyl)-N-((13S,9S,12S)-5 4-Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)acetamide (173)

[0941] [ka]

[0942] Compound 172 was prepared similarly to compound 128, except that (S)-tert-butyl 3-(2-hydroxyethyl)piperidine-1-carboxylate was used to synthesize the enantiomerically pure derivative of tert-butyl 3-(2-(3-cyano-4-methylphenoxy)ethyl)piperidine-1-carboxylate 3. Formula:C 37 H 45 N5O5, exact mass: 639.3, measured value: 640.4 [M+H] + Example A-18: Preparation of macrocyclic compounds 180, 181, 216, 217, and 294 Amide derivatization of compound 8 according to general procedure E

[0943] [ka]

[0944] Compounds were synthesized according to general procedure E, for example, using 20 mg to 100 mg of amine 8 and a carboxylic acid chloride or sulfonyl chloride, etc., to give the amides or sulfonamides disclosed in the table below. Purification was achieved by HPLC or reverse-phase flash chromatography. Table A-13

[0945] [Table 14-1]

[0946] [Table 14-2]

[0947] Example A-19: Preparation of macrocyclic compound 186 tert-Butyl 2-(2-(3-(((S)-2-((S)-2-acetamido-6-(tert-butoxy)-6-oxohexanamido)-4-phenylbutanamido)methyl)-4-methylphenoxy)ethyl)morpholine-4-carboxylate (184)

[0948] [ka]

[0949] The amide bond was formed using 140 mg of amine 141 and 268 mg of acid 183 according to general procedure B. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 41 H 60 N4O9, exact mass: 752.4, measured value: 753.7 [M+H] + (5S)-5-Acetamido-6-(((2S)-1-((2-methyl-5-(2-(morpholin-2-yl)ethoxy)benzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-6-oxohexanoic acid (185)

[0950] [ka]

[0951] The protecting group was cleaved from 99 mg of compound 184 by stirring the compound in 10 ml of 4 N HCl / 1,4-dioxane at room temperature according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Formula:C 32 H 44 N4O7, exact mass: 596.3, measured value: 597.3 [M+H]+ N-((9S,12S)-5 4 -Methyl-8,11,16-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(2,4)-morpholina-5(1,3)-benzenacyclohexadecaphan-12-yl)acetamide (186)

[0952] [ka]

[0953] Macrocyclization was achieved using 0.166 mmol of amino acid 185 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Formula:C 32 H 42 N4O6, exact mass: 578.3, measured value: 579.6 [M+H] + Example A-20: Preparation of macrocyclic compound 191 tert-Butyl 6-(3-(((S)-2-((S)-2-acetamido-6-(tert-butoxy)-6-oxohexanamido)-4-phenylbutanamido)methyl)-4-methylphenoxy)-3-azabicyclo[3.2.0]heptane-3-carboxylate (189)

[0954] [ka]

[0955] The amide bond was formed using 134 mg of amine 188 and 113 mg of acid 183 according to general procedure B. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 41 H 58 N4O8, exact mass: 734.4, measured value: 735.7 [M+H] + (5S)-6-(((2S)-1-((5-(3-azabicyclo[3.2.0]heptan-6-yloxy)-2-methylbenzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-5-acetamido-6-oxohexanoic acid (190)

[0956] [ka]

[0957] The protecting group was cleaved from 168 mg of compound 189 by stirring the compound in 10 ml of 4 N HCl / 1,4-dioxane at room temperature according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Formula:C 32 H 42 N4O6, exact mass: 578.3, measured value: 579.3 [M+H] + N-((11R,15S,7S,10S)-3 4 -Methyl-6,9,14-trioxo-7-phenethyl-2-oxa-13,5,8-triaza-1(7,3)-bicyclo[3.2.0]heptana-3(1,3)-benzenacyclotetradecaphan-10-yl)acetamide (191)

[0958] [ka]

[0959] Macrocyclization was achieved using 0.166 mmol of amino acid 190 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Formula:C 32 H 40 N4O5, exact mass: 560.3, measured value: 561.5 [M+H] + Example A-21: Preparation of macrocycles 347 and 353 (S)-tert-Butyl 6-(((benzyloxy)carbonyl)amino)-7-(((S)-1-((5-(3-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-7-oxoheptanoate (446)

[0960] [ka]

[0961] The amide bond was formed using 187 mg of amine 224 and 222 mg of acid 445 according to general procedure B. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Additional examples utilizing amines other than amine 4 are disclosed in the table below. Table A-14

[0962] [Table 15-1]

[0963] [Table 15-2]

[0964] (S)-7-(((S)-1-((5-(3-aminopropoxy)-2-methylbenzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-6-(((benzyloxy)carbonyl)amino)-7-oxoheptanoic acid (448)

[0965] [ka]

[0966] According to general procedure D, the protecting group was cleaved from 224 mg of compound 446 by stirring the compound in 5 ml of a solution of 40% TFA in DCM at room temperature. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Additional examples are disclosed in the following table. Table A-15

[0967] [Table 16-1]

[0968] [Table 16-2]

[0969] Benzyl ((13S,16S)-1 4 -Methyl-8,14,17-trioxo-16-phenethyl-2-oxa-7,15,18-triaza-1(1,3)-benzenacyclononadecaphan-13-yl)carbamate (347)

[0970] [ka]

[0971] Macrocyclization was achieved using 0.3 mmol of amino acid 449 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Additional examples are disclosed in the table below. Table A-16

[0972] [Table 17]

[0973] Example A-22: Preparation of macrocyclic compounds 195, 283, 322, 351, 352, 354, and 405 tert-Butyl 3-(2-(3-((5S,8S)-5-(4-(tert-butoxy)-4-oxobutyl)-3,6,9-trioxo-8-phenethyl-1-phenyl-2-oxa-4,7,10-triazaundecan-11-yl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (193)

[0974] [ka]

[0975] The amide bond was formed using 615 mg of amine 4 and 711 mg of acid 192 according to general procedure B. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Additional examples utilizing amines other than amine 4 are disclosed in the table below. Table A-17

[0976] [Table 18-1]

[0977] [Table 18-2]

[0978] [Table 18-3]

[0979] [Table 18-4]

[0980] [Table 18-5]

[0981] [Table 18-6]

[0982] [Table 18-7]

[0983] (5S)-5-(((benzyloxy)carbonyl)amino)-6-(((2S)-1-((2-methyl-5-(2-(piperidin-3-yl)ethoxy)benzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-6-oxohexanoic acid (194)

[0984] [ka]

[0985] Following general procedure D, the protecting group was cleaved from 900 mg of compound 193 by stirring the compound in 10 ml of 4N HCl / 1,4-dioxane at room temperature. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Additional examples are disclosed in the table below. Table A-18

[0986] [Table 19-1]

[0987] [Table 19-2]

[0988] [Table 19-3]

[0989] [Table 19-4]

[0990] Benzyl ((9S,12S)-5 4 -Methyl-8,11,16-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclohexadecaphan-12-yl)carbamate (195)

[0991] [ka]

[0992] Macrocyclization was achieved using 1.07 mmol of amino acid 194 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Additional examples are disclosed in the table below. Table A-19

[0993] [Table 20-1]

[0994] [Table 20-2]

[0995] [Table 20-3]

[0996] [Table 20-4]

[0997] Example A-23: Preparation of macrocyclic compounds 199, 301, 349, 350 and 402 tert-Butyl 3-(2-(3-((5S,8S)-5-(3-(tert-butoxy)-3-oxopropyl)-3,6,9-trioxo-8-phenethyl-1-phenyl-2-oxa-4,7,10-triazaundecan-11-yl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (197)

[0998] [ka]

[0999] The amide bond was formed using 615 mg of amine 4 and 808 mg of acid 196 according to general procedure B. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Additional examples utilizing amines other than amine 4 are disclosed in the table below. Table A-20

[1000] [Table 21-1]

[1001] [Table 21-2]

[1002] [Table 21-3]

[1003] [Table 21-4]

[1004] [Table 21-5]

[1005] (4S)-4-(((benzyloxy)carbonyl)amino)-5-(((2S)-1-((2-methyl-5-(2-(piperidin-3-yl)ethoxy)benzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-5-oxopentanoic acid (198)

[1006] [ka]

[1007] Following general procedure D, the protecting group was cleaved from 850 mg of compound 197 by stirring the compound in 10 ml of 4N HCl / 1,4-dioxane at room temperature. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Additional examples are disclosed in the table below. Table A-21

[1008] [Table 22-1]

[1009] [Table 22-2]

[1010] [Table 22-3]

[1011] Benzyl ((9S,12S)-5 4 -Methyl-8,11,15-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclopentadecaphan-12-yl)carbamate (199)

[1012] [ka]

[1013] Macrocyclization was achieved using 1.03 mmol of amino acid 198 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Additional examples are disclosed in the table below. Table A-22

[1014] [Table 23-1]

[1015] [Table 23-2]

[1016] Example A-24: Preparation of macrocyclic compounds 300, 312, 313, 314, 315, 325 and 337 tert-Butyl 2-(3-((5S,8S)-5-(2-(tert-butoxy)-2-oxopropyl)-3,6,9-trioxo-8-phenethyl-1-phenyl-2-oxa-4,7,10-triazaundecan-11-yl)-4-methylphenoxy)-6-azaspiro[3,5]nonane-6-carboxylate (383)

[1017] [ka]

[1018] The amide bond was formed using 271 mg of amine 271 and 336 mg of acid 382 according to general procedure B. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Additional examples utilizing amines other than amine 271 are disclosed in the table below. Table A-23

[1019] [Table 24-1]

[1020] [Table 24-2]

[1021] [Table 24-3]

[1022] [Table 24-4]

[1023] [Table 24-5]

[1024] [Table 24-6]

[1025] [Table 24-7]

[1026] (S)-4-(((S)-1-((5-(6-azaspiro[3.5]nonan-2-yloxy)-2-methylbenzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-3-(((benzyloxy)carbonyl)amino)-4-oxobutanoic acid (384)

[1027] [ka]

[1028] According to general procedure D, the protecting group was cleaved from 900 mg of compound 383 by stirring the compound in 10 ml of 4N HCl / 1,4-dioxane at room temperature. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Additional examples are disclosed in the following table. Table A-24

[1029] [Table 25-1]

[1030] [Table 25-2]

[1031] [Table 25-3]

[1032] [Table 25-4]

[1033] Benzyl ((7S,10S)-3 4 -Methyl-6,9,12-trioxo-7-phenethyl-2-oxa-5,8-diaza-13(3,1)-piperidina-3(1,3)-benzena-1(1,3)-cyclobutanatridecaphan-10-yl)carbamate (300)

[1034] [ka]

[1035] Macrocyclization was achieved using 93 mg of amino acid 384 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Additional examples are disclosed in the table below. Table A-25

[1036] [Table 26-1]

[1037] [Table 26-2]

[1038] [Table 26-3]

[1039] [Table 26-4]

[1040] Example A-25: Preparation of macrocyclic compound 211 tert-Butyl 3-(2-(3-cyano-4-fluorophenoxy)ethyl)piperidine-1-carboxylate (576)

[1041] [ka]

[1042] 1.03 g of tert-butyl 3-(2-hydroxyethyl)piperidine-1-carboxylate, 500 mg of 2-fluoro-5-hydroxybenzonitrile, and 1.17 g of PPh3 were dissolved in THF. 879 μl of DIAD was added to 5 ml of THF, and the mixture was stirred at room temperature for 2 hours. Saturated NaHCO3 solution was added, and the mixture was extracted with DCM. The organic phase was dried over MgSO4, and the volatiles were removed. Purification was achieved by normal-phase flash chromatography (silica, cyclohexane / ethyl acetate gradient).

[1043] tert-Butyl 3-(2-(3-(aminomethyl)-4-fluorophenoxy)ethyl)piperidine-1-carboxylate (200)

[1044] [ka]

[1045] 1.02 g of the nitrile was dissolved in 36 ml of acetic acid and 5 ml of water. Hydrogenation to amine 200 was achieved with 706 mg of 10% Pd / C under 50 bar of hydrogen at room temperature. The mixture was filtered through a pad of Celite and washed with MeOH. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with NaHCO3 solution (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was pure enough for the next reaction. Formula:C 19 H 29FN2O3, exact mass: 352.2.3, measured value: 353.0 [M+H] + tert-Butyl 3-(2-(3-(((S)-2-(((benzyloxy)carbonyl)amino)-4-phenylbutanamido)methyl)-4-fluorophenoxy)ethyl)piperidine-1-carboxylate (201)

[1046] [ka]

[1047] The amide bond was formed using 615 mg of amine 200 and 820 mg of Cbz-hPhe-OH according to general procedure B. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 37 H 46 FN3O6, exact mass: 647.3, measured value: 648.6 [M+H] + tert-Butyl 3-(2-(3-(((S)-2-amino-4-phenylbutanamido)methyl)-4-fluorophenoxy)ethyl)piperidine-1-carboxylate (202)

[1048] [ka]

[1049] The benzyl carbamate was cleaved in a solvent mixture of ethanol / ethyl acetate at 20 bar and 70° C. using a 10% Pd / C catalyst cartridge according to general procedure C. The product was purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 29 H 40 FN3O4, exact mass: 513.3, measured value: 514.3 [M+H] + tert-Butyl 3-(2-(3-(((S)-2-((S)-2-acetamido-4-(tert-butoxy)-4-oxobutanamido)-4-phenylbutanamido)methyl)-4-fluorophenoxy)ethyl)piperidine-1-carboxylate (203)

[1050] [ka]

[1051] The amide bond was formed using 150 mg of amine 202 and 88 mg of Ac-Asp(OtBu)-OH according to general procedure B. Purification was carried out by normal phase flash chromatography. Formula:C 39 H 55 FN4O8, exact mass: 726.4, measured value: 727.7 [M+H] + (3S)-3-Acetamido-4-(((2S)-1-((2-fluoro-5-(2-(piperidin-3-yl)ethoxy)benzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-4-oxobutanoic acid (204)

[1052] [ka]

[1053] The protecting group was cleaved from 101 mg of compound 203 by stirring the compound in 10 ml of 4N HCl / 1,4-dioxane at room temperature according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Formula:C 30 H 39 FN4O6, exact mass: 570.3, measured value: 571.4 [M+H] + N-((9S,12S)-5 4-Fluoro-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)acetamide (205)

[1054] [ka]

[1055] Macrocyclization was achieved using 1.03 mmol of amino acid 204 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Formula:C 30 H 37 FN4O5, exact mass: 552.3, measured value: 553.6 [M+H] + tert-Butyl 3-(2-(3-(((S)-2-(((benzyloxy)carbonyl)amino)-4-phenylbutanamido)methyl)-4-methoxyphenoxy)ethyl)piperidine-1-carboxylate (207)

[1056] [ka]

[1057] The amide bond was formed using 648 mg of amine 206 and 836 mg of Cbz-hPhe-OH according to general procedure B. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 38 H 49 N3O7, exact mass: 659.4, measured value: 660.7 [M+H] + tert-Butyl 3-(2-(3-(((S)-2-amino-4-phenylbutanamido)methyl)-4-methoxyphenoxy)ethyl)piperidine-1-carboxylate (208)

[1058] [ka]

[1059] The benzyl carbamate was cleaved in a solvent mixture of ethanol / ethyl acetate at 20 bar and 70° C. using a 10% Pd / C catalyst cartridge according to general procedure C. The product was purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 30 H 43 N3O5, exact mass: 525.3, measured value: 526.5 [M+H] + tert-Butyl 3-(2-(3-(((S)-2-((S)-2-acetamido-4-(tert-butoxy)-4-oxobutanamido)-4-phenylbutanamido)methyl)-4-methoxyphenoxy)ethyl)piperidine-1-carboxylate (209)

[1060] [ka]

[1061] The amide bond was formed with 150 mg of amine 208 and 86 mg of Ac-Asp(OtBu)-OH according to general procedure B. Purification was carried out by normal phase flash chromatography. Formula:C 40 H 58 N4O9, exact mass: 738.4, measured value: 739.7 [M+H] + (3S)-3-Acetamido-4-(((2S)-1-((2-methoxy-5-(2-(piperidin-3-yl)ethoxy)benzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-4-oxobutanoic acid (210)

[1062] [ka]

[1063] The protecting group was cleaved from 188 mg of compound 209 by stirring the compound in 10 ml of 4 N HCl / 1,4-dioxane at room temperature according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Formula:C 31 H 42 N4O7, exact mass: 582.3, measured value: 583.4 [M+H] + N-((9S,12S)-5 4 -Methoxy-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)acetamide (211)

[1064] [ka]

[1065] Macrocyclization was achieved using 0.289 mmol of amino acid 210 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Formula:C 31 H 40 N4O6, exact mass: 564.3, measured value: 565.5 [M+H] + Example A-26: Preparation of macrocyclic compounds 212, 213, 214 and 215 (9S,12S)-5 4 -Methyl-12-amino-8,11,16-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclohexadecaphane (212)

[1066] [ka]

[1067] The benzyl carbamate was cleaved in a solvent mixture of ethanol / ethyl acetate at 20 bar and 70° C. using a 10% Pd / C catalyst cartridge according to general procedure C. The product was purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 31 H 42 N4O4, exact mass: 534.3, measured value: 535.6 [M+H] + N-((9S,12S)-5 4 -Methyl-8,11,16-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclohexadecaphan-12-yl)acetamide (213)

[1068] [ka]

[1069] 50 mg of amine 212 and 54 μL of NEt were dissolved in DCM, and 14 μL of acetic anhydride was added. After the reaction was complete, the solvent was removed, and the residue was dissolved in some methanol. Purification by HPLC. Formula:C 33 H 44 N4O5, exact mass: 576.3, measured value: 577.6 [M+H] + (9S,12S)-12-amino-5 4 -methyl-8,11,15-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclopentadecaphane) (214)

[1070] [ka]

[1071] The benzyl carbamate was cleaved from compound 199 in a solvent mixture of ethanol / ethyl acetate at 20 bar and 70° C. using a 10% Pd / C catalyst cartridge according to general procedure C. The product was purified by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 30 H 40 N4O4, exact mass: 520.3, measured value: 521.5 [M+H] + N-((9S,12S)-5 4 -Methyl-8,11,15-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclopentadecaphan-12-yl)acetamide (215)

[1072] [ka]

[1073] 50 mg of amine 213 and 54 μL of NEt were dissolved in DCM, and 14 μL of acetic anhydride was added. After the reaction was complete, the solvent was removed and the residue was dissolved in some methanol. Purification by HPLC. Formula:C 32 H 42 N4O5, exact mass: 562.3, measured value: 563.5 [M+H] + Example A-27: Preparation of macrocyclic compounds 218, 220, and 293 2,5,8,11,14,17,20-heptaoxadocosan-22-yl ((9R,12R)-5 4 -Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)carbamate (218)

[1074] [ka]

[1075] A solution of 20 mg of 2,5,8,11,14,17,20-heptaoxadocosan-22-ol and 24.7 μl of trimethylamine in THF was cooled to 0 °C. 4-Nitrophenyl chloroformate (14.2 mg) was added, and the mixture was allowed to warm to room temperature. Volatiles were removed under reduced pressure, and the residue was dissolved in 1 ml of DMF. 30 mg of amine 8 was added at room temperature along with 62 μl of DIPEA. After consumption of compound 8, the reaction mixture was purified by reverse-phase HPLC. Formula:C 45 H 68 N4O 13 , Exact mass: 872.5, Measured value: 873.9 [M+H] + 2-(2-(2-methoxyethoxy)ethoxy)ethyl ((9R,12R)-5 4 -Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)carbamate (220)

[1076] [ka]

[1077] A solution of 50 mg of 2-(2-(2-methoxyethoxy)ethoxy)ethanol and 213 μl of trimethylamine in THF was cooled to 0° C. 4-Nitrophenyl chloroformate (92 mg) was added, and the mixture was allowed to warm to room temperature. The volatiles were removed under reduced pressure, and the residue was dissolved in 1 ml of DMF. 103 mg of amine 8 was added at room temperature along with 212 μl of DIPEA. After consumption of compound 8, the reaction mixture was purified by reverse-phase HPLC. Formula:C 37 H 52 N4O9, exact mass: 696.4, measured value: 697.5 [M+H] + (3-methyloxetan-3-yl)methyl((9S,12S)-5 4-Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)carbamate (293)

[1078] [ka]

[1079] A solution of 50(3-methyloxetan-3-yl)methanol and 341 μl of trimethylamine in THF was cooled to 0° C. 4-Nitrophenyl chloroformate (148 mg) was added, and the mixture was allowed to warm to room temperature. Volatiles were removed under reduced pressure, and the residue was dissolved in 1 ml of DMF. 124 mg of amine 8 was added at room temperature along with 742 μl of DIPEA. After consumption of compound 8, the reaction mixture was purified by reverse-phase HPLC. Formula:C 35 H 46 N4O7, exact mass: 634.3, measured value: 635.4 [M+H] + Example A-28: Preparation of macrocyclic compounds 252-261, 296 and 298 (S)-tert-Butyl 3-acetamido-4-(((S)-1-((5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylbenzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-4-oxobutanoate (223)

[1080] [ka]

[1081] Amide coupling of benzylamine derivatives with dipeptide 221 was achieved according to general procedure B, typically using 100 mg of dipeptide 221. As an example, compound 223 was synthesized from a solution of 100 mg of dipeptide 221, 93 mg of amine 222, 116 mg of HATU, and 266 μl of DIPEA in DMF at room temperature. Purification was achieved by normal-phase column chromatography (silica, cyclohexane / ethyl acetate gradient).

[1082] Additional examples are disclosed in the table below. Table A-26

[1083] [Table 27-1]

[1084] [Table 27-2]

[1085] [Table 27-3]

[1086] [Table 27-4]

[1087] [Table 27-5]

[1088] [Table 27-6]

[1089] (S)-3-Acetamido-4-(((S)-1-((5-(2-aminoethoxy)-2-methylbenzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-4-oxobutanoic acid (242)

[1090] [ka]

[1091] The protecting group was cleaved from 65 mg of compound 223 by stirring the compound in 10 ml of 4 N HCl / 1,4-dioxane at room temperature according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification.

[1092] Additional examples were prepared as disclosed in the table below, as exemplified by compound 242. Table A-27

[1093] [Table 28-1]

[1094] [Table 28-2]

[1095] [Table 28-3]

[1096] [Table 28-4]

[1097] [Table 28-5]

[1098] N-((8S,11S)-1 4 -Methyl-6,9,12-trioxo-11-phenethyl-2-oxa-5,10,13-triaza-1(1,3)-benzenacyclotetradecaphan-8-yl)acetamide (252)

[1099] [ka]

[1100] Macrocyclization was achieved using 0.248 mmol of amino acid 242 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Additional examples disclosed in the table below were prepared, as exemplified by compound 252. Table A-28

[1101] [Table 29-1]

[1102] [Table 29-2]

[1103] [Table 29-3]

[1104] [Table 29-4] TIFF2024534613000665.tif86162

[1105] Example A-29: Preparation of macrocyclic compounds 265, 282 and 299 tert-Butyl 2-((3-(((S)-2-((S)-2-acetamido-5-(tert-butoxy)-5-oxopentanamido)-4-phenylbutanamido)methyl)-4-methylphenoxy)methyl)-2-methylazetidine-1-carboxylate (263)

[1106] [ka]

[1107] Amide coupling of benzylamine derivatives with dipeptide 262 was achieved according to general procedure B, typically using 100 mg of dipeptide 262. As an example, compound 263 was synthesized from a solution of 112 mg of dipeptide 262, 115 mg of amine 231, 125 mg of HATU, and 214 μl of DIPEA in DMF at room temperature. Purification was achieved by normal-phase column chromatography (silica, cyclohexane / ethyl acetate gradient).

[1108] Additional examples are disclosed in the table below. Table A-29

[1109] [Table 30-1]

[1110] [Table 30-2]

[1111] (4S)-4-Acetamido-5-(((2S)-1-((2-methyl-5-((2-methylazetidin-2-yl)methoxy)benzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-5-oxopentanoic acid (264)

[1112] [ka]

[1113] The protecting group was cleaved from 117 mg of compound 263 by stirring the compound in 10 ml of 4 N HCl / 1,4-dioxane at room temperature according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification.

[1114] Additional examples disclosed in the table below were prepared, as exemplified by compound 264. Table A-30

[1115] [Table 31-1]

[1116] [Table 31-2]

[1117] N-((8S,11S)-1 2 ,4 4 -Dimethyl-7,10,14-trioxo-8-phenethyl-3-oxa-6,9-diaza-1(2,1)-azetidina-4(1,3)-benzenacyclotetradecaphan-11-yl)acetamide (265)

[1118] [ka]

[1119] Macrocyclization was achieved using 0.165 mmol of amino acid 264 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Additional examples disclosed in the table below were prepared, as exemplified by compound 265. Table A-31

[1120] [Table 32] TIFF2024534613000674.tif95162

[1121] Example A-30: Preparation of macrocyclic compounds 269, 280, 281 and 29 (S)-tert-Butyl 5-acetamido-6-(((S)-1-((5-(4-((tert-butoxycarbonyl)amino)butoxy)-2-methylbenzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-6-oxohexanoate (267)

[1122] [ka]

[1123] The amide bond between the benzylamine derivative and dipeptide 266 was achieved according to general procedure B, typically using 100 mg of dipeptide 262. As an example, compound 263 was synthesized from a solution of 113 mg of dipeptide 266, 107 mg of amine 163, 122 mg of HATU, and 280 μl of DIPEA in DMF at room temperature. Purification was achieved by normal-phase column chromatography (silica, cyclohexane / ethyl acetate gradient).

[1124] Additional examples are disclosed in the table below. Table A-32

[1125] [Table 33-1]

[1126] [Table 33-2]

[1127] (S)-5-Acetamido-6-(((S)-1-((5-(4-aminobutoxy)-2-methylbenzyl)amino)-1-oxo-4-phenylbutan-2-yl)amino)-6-oxohexanoic acid (268)

[1128] [ka]

[1129] The protecting group was cleaved from 78 mg of compound 267 by stirring the compound in 5 ml of 40% TFA / DCM at room temperature according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification.

[1130] As exemplified by compound 268, additional examples disclosed in the table below were prepared. Table A-33

[1131] [Table 34-1]

[1132] [Table 34-2]

[1133] N-((12S,15S)-1 4 -Methyl-8,13,16-trioxo-15-phenethyl-2-oxa-7,14,17-triaza-1(1,3)-benzenacyclooctadecaphan-12-yl)acetamide (269)

[1134] [ka]

[1135] Macrocyclization was achieved using 0.120 mmol of amino acid 268 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Additional examples disclosed in the table below were prepared, as exemplified by compound 269. Table A-34

[1136] [Table 35-1]

[1137] [Table 35-2]

[1138] Example A-31: Preparation of macrocyclic compounds 336, and 549-564 tert-Butyl 3-(2-(3-((5S)-5-(2-(tert-butoxy)-2-oxoethyl)-3,6,9-trioxo-1-phenyl-8-(2-(pyridin-4-yl)ethyl)-2-oxa-4,7,10-triazaundecan-11-yl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (435)

[1139] [ka]

[1140] For this Ugi reaction, 400 mg of 3-(pyridin-4-yl)propanal and 960 mg of Cbz-Asp(OtBu)-OH were dissolved in 3.5 ml of 2,2,2-trifluoroethanol. 700 μl of ammonia solution (30%, aqueous) and 715 mg of isonitrile 434 were added, and the mixture was stirred at room temperature overnight. Additional ammonia solution (350 μl) and a solution of 250 mg of aldehyde in 3.5 ml of 2,2,2-trifluoroethanol were added, and stirring at room temperature was continued for another day. Saturated NaHCO3 solution was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over MgSO4, and after removal of volatiles under reduced pressure, the product was obtained after normal-phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 45 H 61 N5O9, exact mass: 815.4, measured value: 716.4 [M+H] + The examples in the following table were prepared according to the procedure described for compound 435, except that Ac-Asp(OtBu)-OH was used in place of Cbz-Asp(OtBu)-OH, and the related aldehydes. Table A-35

[1141] [Table 36-1]

[1142] [Table 36-2]

[1143] [Table 36-3]

[1144] [Table 36-4]

[1145] [Table 36-5]

[1146] [Table 36-6]

[1147] (3S)-3-(((benzyloxy)carbonyl)amino)-4-((1-((2-methyl-5-(2-(piperidin-3-yl)ethoxy)benzyl)amino)-1-oxo-4-(pyridin-4-yl)butan-2-yl)amino)-4-oxobutanoic acid (436)

[1148] [ka]

[1149] The protecting group was cleaved from 750 mg of compound 435 by stirring the compound in 5 ml of 40% TFA / DCM at room temperature according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was dissolved in acetonitrile and concentrated twice. The product was used without further purification. Formula:C 35 H 45 N5O7, exact mass: 659.3, measured value: 660.3 [M+H] + The examples in the following table were prepared similarly to the procedure described for compound 436. Table A-36

[1150] [Table 37-1]

[1151] [Table 37-2]

[1152] [Table 37-3]

[1153] [Table 37-4]

[1154] [Table 37-5]

[1155] [Table 37-6]

[1156] [Table 37-7]

[1157] [Table 37-8]

[1158] Benzyl ((12S)-5 4 -Methyl-8,11,14-trioxo-9-(2-(pyridin-4-yl)ethyl)-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)carbamate (336)

[1159] [ka]

[1160] Macrocyclization was achieved using 606 mg of amino acid 436 according to general procedure A. The reaction mixture was diluted with some methanol and purified by reverse phase column chromatography (RP18, water / acetonitrile gradient) and HPLC. Formula:C 36 H 43 N5O6, exact mass: 641.3, measured value: 642.3 [M+H] + The examples in the following table were prepared similarly to the procedure described for compound 336. Table A-37

[1161] [Table 38-1]

[1162] [Table 38-2]

[1163] [Table 38-3]

[1164] [Table 38-4]

[1165] [Table 38-5]

[1166] [Table 38-6]

[1167] [Table 38-7]

[1168] [Table 38-8]

[1169] Example A-32: Preparation of macrocyclic compounds 338, 342-344, 437, 439, 443 and 444 ((12S)-12-amino-5 4 -methyl-8,11,14-trioxo-9-(2-(pyridin-4-yl)ethyl)-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl) (437)

[1170] [ka]

[1171] According to general procedure C, 190 mg of Cbz-protected amine 336 was dissolved in ethyl acetate / ethanol (1:1). H-cube conditions: 1 ml / min, 50 °C, 20 bar H. After removal of volatiles under reduced pressure, the product was used without further purification. Some piperidyl by-product 438 was removed after the next step. 437-Chemical formula:C 28 H 37 N5O 4、 Exact mass: 507.3, Measured value: 508.3 [M+H] + 438-Chemical formula:C 28 H 43 N5O4, exact mass: 513.3, measured value: 514.3 [M+H] + N-((12S)-9-(2-(1-acetylpiperidin-4-yl)ethyl)-5 4 -Methyl-8,11,14-trioxo-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)acetamide (338)

[1172] [ka]

[1173] Both free amines in compound 438 were acetylated by dissolving amine 438 in AcO / pyridine / DMF (20 / 10 / 70) at room temperature. Purification of the reaction mixture was achieved by HPLC to give compound 338. Formula:C 32 H 47 N5O6, exact mass: 597.4, measured value: 598.4 [M+H] + Amide derivatization of compound 437 according to general procedure B

[1174] [ka]

[1175] Amine 437 (32 mg) was coupled with a carboxylic acid according to general procedure B, as exemplified for derivative 439, to give the amides disclosed in the table below. Purification was achieved by HPLC or reverse-phase flash chromatography. Table A-38

[1176] [Table 39-1]

[1177] [Table 39-2]

[1178] Removal of the Boc-protecting group

[1179] [ka]

[1180] The Boc protecting group was cleaved from the compound by stirring the compound in 5 ml of 40% TFA in DCM at room temperature according to general procedure D. After deprotection was complete, the solvent was removed and the crude product was purified by reverse-phase HPLC. Table A-39

[1181] [Table 40-1]

[1182] [Table 40-2]

[1183] Example A-33: Preparation of macrocycle 348 2,2-Dimethyl-N-((9R,12R)-5 4 -Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)-3-(tritylthio)propanamide (450)

[1184] [ka]

[1185] Amine 8 (100 mg) was coupled with a carboxylic acid according to general procedure B to give the protected thiol 450. Purification was achieved by reverse-phase HPLC. Formula:C 32 H 47 N5O6, exact mass: 597.4, measured value: 598.4 [M+H] + 3-Mercapto-2,2-dimethyl-N-((9S,12S)-5 4 -Methyl-8,11,14-trioxo-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)propanamide (348)

[1186] [ka]

[1187] Compound 450 (140 mg) was dissolved in 1 ml of TIS / TFA / HO (10 / 2 / 2) at room temperature and stirred for 1 hour. Purification by reversed-phase column chromatography (RP18, water / acetonitrile gradient). Formula:C 34 H 46 N4O6, exact mass: 622.3, measured value: 623.5 [M+H] + Example A-34: Preparation of macrocyclic compound 355 Ethyl 4-(3-(2-(3-((2-(((benzyloxy)carbonyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)acetamido)methyl)-4,5-dimethylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoate (470)

[1188] [ka]

[1189] 162 mg of amine 117 and 100 mg of carboxylic acid 111 were coupled according to general procedure B to give compound 470. Purification was achieved by reverse-phase column chromatography (RP18, water / acetonitrile gradient). Formula:C 36 H 47 N5O7, exact mass: 661.3, measured value: 662.5 [M+H] + Ethyl 4-(3-(2-(3-((2-amino-2-(1-methyl-1H-pyrazol-4-yl)acetamido)methyl)-4,5-dimethylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoate (471)

[1190] [ka]

[1191] The Cbz-protecting group was removed in EtOH at 50° C. and 20 bar H pressure according to general procedure C. The solvent was removed under reduced pressure to give a product sufficiently pure to be used in the next reaction. Formula:C 28 H 41 N5O5, exact mass: 527.3, measured value: 528.4 [M+H] + 4-(3-(2-(3-((2-amino-2-(1-methyl-1H-pyrazol-4-yl)acetamido)methyl)-4,5-dimethylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoic acid (472)

[1192] [ka]

[1193] The crude ester 471 was dissolved in concentrated aqueous HCl at room temperature. The solution was stirred until the reaction was complete. The volatiles were removed and dissolved in acetonitrile. After drying, the crude product was used in the subsequent cyclization. Formula:C 26 H 37 N5O5, exact mass: 499.3, actual value: 500.2 [M+H] + 5 4 ,5 5 -Dimethyl-9-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (355)

[1194] [ka]

[1195] Macrocyclization was achieved using 75 mg of amino acid 472 according to general procedure A. The reaction mixture was diluted with some methanol and purified by reverse phase column chromatography (RP18, water / acetonitrile gradient) and HPLC. Formula:C 26 H 35 N5O4, exact mass: 481.3, measured value: 482.3 [M+H] + Example A-35: Preparation of macrocyclic compound 356 tert-Butyl 3-(2-(3-((2-(((benzyloxy)carbonyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)acetamido)methyl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (473)

[1196] [ka]

[1197] 452 mg of amine 4 and 341 mg of carboxylic acid 111 were coupled according to general procedure B to give compound 473. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 34 H 45 N5O6, exact mass: 619.3, measured value: 620.3 [M+H] + tert-Butyl 3-(2-(3-((2-amino-2-(1-methyl-1H-pyrazol-4-yl)acetamido)methyl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (474)

[1198] [ka]

[1199] The Cbz-protecting group was removed in EtOH at 50° C. and 20 bar H pressure according to general procedure C. The solvent was removed under reduced pressure to give a product sufficiently pure to be used in the next reaction. Formula:C 26 H 39 N5O4, exact mass: 485.3, measured value: 486.3 [M+H] + tert-Butyl 3-(2-(3-((2-(6-ethoxy-6-oxohexanamido)-2-(1-methyl-1H-pyrazol-4-yl)acetamido)methyl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (475)

[1200] [ka]

[1201] 100 mg of amine 474 and 43 mg of 6-ethoxy-6-oxohexanoic acid were coupled according to general procedure B to give compound 475. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 34 H 51 N5O7, exact mass: 641.4, measured value: 642.4 [M+H] + 6-((1-(1-methyl-1H-pyrazol-4-yl)-2-((2-methyl-5-(2-(piperidin-3-yl)ethoxy)benzyl)amino)-2-oxoethyl)amino)-6-oxohexanoic acid (476)

[1202] [ka]

[1203] Ester 475 was dissolved in concentrated aqueous HCl at room temperature. The solution was stirred until the reaction was complete. The volatiles were removed and dissolved in acetonitrile. After drying, the crude product was used in the subsequent cyclization. Formula:C 27 H 39 N5O5, exact mass: 513.3, measured value: 514.3 [M+H] + 5 4 -Methyl-9-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclohexadecaphane-8,11,16-trione (356)

[1204] [ka]

[1205] Macrocyclization was achieved using 0.11 amino acid 476 according to general procedure A. The reaction mixture was diluted with some methanol and purified by HPLC. Formula:C 27 H 37 N5O4, exact mass: 495.3, measured value: 496.3 [M+H] + Example A-36: Preparation of macrocyclic compounds 358-363, 479, 480, and 552 tert-Butyl 3-(2-(3-((5S)-5-(2-ethoxy-2-oxoethyl)-8-(1-methyl-1H-pyrazol-4-yl)-3,6,9-trioxo-1-phenyl-2-oxa-4,7,10-triazaundecan-11-yl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (477)

[1206] [ka]

[1207] 3 g of amine 474 and 3 g of Cbz-Asp(OtBu)-OH were coupled according to general procedure B to give compound 477. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 40 H 54 N6O9, exact mass: 762.4, measured value: 763.5 [M+H] + (3S)-3-(((benzyloxy)carbonyl)amino)-4-(((1-(1-methyl-1H-pyrazol-4-yl)-2-((2-methyl-5-(2-(piperidin-3-yl)ethoxy)benzyl)amino)-2-oxoethyl)amino)-4-oxobutanoic acid (478)

[1208] [ka]

[1209] 4.2 g of ester 477 was dissolved in 40 ml of 4 M HCl solution in 1,4-dioxane at room temperature. The solution was stirred until the reaction was complete. The volatiles were removed and dissolved in acetonitrile. After drying, the crude product was used in the subsequent cyclization. Formula:C 33 H 42 N6O7, exact mass: 634.3, measured value: 635.3 [M+H] + Benzyl ((12S)-5 4 -Methyl-9-(1-methyl-1H-pyrazol-4-yl)-8,11,14-trioxo-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)carbamate (479)

[1210] [ka]

[1211] Macrocyclization was achieved using 2.42 g of amino acid 478 according to general procedure A. Saturated NaHCO solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic phase was dried over MgSO and concentrated under reduced pressure. Purification was achieved by normal phase column chromatography (silica, cyclohexane / ethyl acetate gradient). Formula:C 33 H 40 N6O6, exact mass: 616.3, measured value: 617.3 [M+H] + (12S)-12-amino-5 4 -Methyl-9-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (480)

[1212] [ka]

[1213] The Cbz group was removed in EtOH at 50° C. and 20 bar H pressure according to general procedure C. The solvent was removed under reduced pressure to give a product sufficiently pure to be used in the next reaction. Formula:C 25 H 34 N6O4, exact mass: 482.3 Ethyl ((12S)-5 4 -Methyl-9-(1-methyl-1H-pyrazol-4-yl)-8,11,14-trioxo-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)carbamate (363)

[1214] [ka] Compound 363 was synthesized from 75 mg of amine 480 according to general procedure G. Final purification was achieved by HPLC. Formula:C 28 H 38 N6O6, exact mass: 554.3, measured value: 555.3 [M+H] +

[1215] N-((12S)-5 4 -Methyl-9-(1-methyl-1H-pyrazol-4-yl)-8,11,14-trioxo-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)acetamide (552)

[1216] [ka]

[1217] Compound 552 was synthesized from 75 mg of amine 480. Final purification was achieved by HPLC. Formula:C 27 H 36N6O5, exact mass: 524.3, measured value: 525.4 [M+H] + Amide derivatization of compound 480 according to general procedure B

[1218] [ka]

[1219] Amine 480 (e.g., 75 mg) was coupled with a carboxylic acid according to general procedure B to give the amides disclosed in the table below. Purification was achieved by HPLC. Table A-40

[1220] [Table 41-1]

[1221] [Table 41-2] TIFF2024534613000737.tif76161

[1222] Example A-37: Preparation of macrocycle 495 4-(3-(2-(3-(isocyanomethyl)-4-methylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoic acid (481)

[1223] [ka]

[1224] tert-Butyl 3-(2-(3-(isocyanomethyl)-4-methylphenoxy)ethyl)piperidine-1-carboxylate (307 mg, 0.86 mmol, 1.0 eq.) was dissolved in DCM (10 mL) and zinc bromide (385 mg, 1.7 mmol, 2 eq.) was added to the solution. The reaction mixture was stirred for 72 h to give the free piperidine derivative in situ. MS(ES)C 16 H22 N2O required value: 258, actual value: 259 (M+H) + .

[1225] To the reaction mixture, EtN (343 mg, 3.4 mmol, 4 eq.) and succinic anhydride (120 mg, 1.2 mmol, 1.4 eq.) were added, and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with DCM and HO. The aqueous layer was adjusted to pH 2-4 using 0.1 M HCl solution, and then extracted three times with DCM. The combined organic layers were dried over MgSO, and the solvent was removed under reduced pressure.

[1226] The crude product was purified by flash chromatography on silica gel (0-100% EtOAc / cHex, 0-100% MeOH / DCM) to give title compound 481 (50 mg, 0.14 mmol, 16%). Compound 481 is highly unstable and readily hydrolyzes to the corresponding formamide. MS(ES)C 20 H 26 Required N2O4 value: 358, Measured value: 359 (M+H) + .

[1227] 5 4 -Methyl-9-phenethyl-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphane-8,11,14-trione (495)

[1228] [ka]

[1229] 4-(3-(2-(3-(isocyanomethyl)-4-methylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoic acid (50 mg, 0.14 mmol, 1.0 eq.) was dissolved in 2,2,2-trifluoroethanol (1 mL), and a solution of 3-phenylpropanal (52 mg, 0.40 mmol, 2.8 eq.) in 2,2,2-trifluoroethanol (1 mL) and aq. NH3 (32%) (153 mg, 1.4 mmol, 10.0 eq.) were added to the solution. The reaction mixture was stirred for 10 min at room temperature.

[1230] The reaction mixture was diluted with DCM and NaHCO3 and the aqueous layer was extracted three times with DCM, then the combined organic layers were dried over MgSO4 and the solvent was removed in vacuo.

[1231] The crude product was purified by flash chromatography on silica gel (0-100% EtOAc / cHex, 0-100% MeOH / DCM) followed by reverse-phase RP-HPLC (column: C18) using HO (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to give compound 495 (30 mg, 0.06 mmol, 44%) as a white solid. MS(ES)C 29 H 37 Required N3O4 value: 491, Measured value: 492 (M+H) + . 1 HNMR(400MHz,d6-DMSO,300K)δ8.42-7.70(m,2H), 7.33-7.24(m,2H), 7.24-7.13(m,3H), 7.06-7.00(m,1H), 6.9 9-6.66(m,2H), 4.77-3.72(m,6H), 3.10-2.54(m,4H), 2.54-2.26(m,3H), 2.20-2.12(m,3H), 2.10-0.97(m,11H).

[1232] Example A-38: Preparation of macrocyclic compounds 503, 505, and 509-513 tert-Butyl (2S)-2-(((benzyloxy)carbonyl)amino)-4-(3-(2-(3-(isocyanomethyl)-4-methylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoate (515)

[1233] [ka] tert-Butyl (2S)-2-(((benzyloxy)carbonyl)amino)-4-(3-(2-(3-(formamidomethyl)-4-methylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoate (100 mg, 0.172 mmol, 1.0 eq.) was dissolved in DCM (10 mL) and EtN (104 mg, 1.0 mmol, 6 eq.) was added to the solution. A solution of POCl (53 mg, 0.34 mmol, 2 eq.) in DCM (1 mL) was added dropwise to the reaction mixture at 0 °C. Even after 1 h, 20% of the starting material was observed. An additional solution of POCl (26 mg, 0.172 mmol, 1 eq.) in DCM (0.5 mL) was added dropwise to the reaction mixture at 0 °C. The reaction was maintained for an additional 30 min.

[1234] The reaction mixture was diluted with DCM and NaHCO3, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over MgSO4, and the solvent was removed under reduced pressure.

[1235] The crude product was purified by flash chromatography on silica gel (0-100% EtOAc / cHex) to give the title compound 515 (95 mg, 0.168 mmol, 98%). 32 H 41 Required N3O6 value: 563, Measured value: 564 (M+H) + .

[1236] (2S)-2-(((benzyloxy)carbonyl)amino)-4-(3-(2-(3-(isocyanomethyl)-4-methylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoic acid (516)

[1237] [ka]

[1238] To a solution of tert-butyl (2S)-2-(((benzyloxy)carbonyl)amino)-4-(3-(2-(3-(isocyanomethyl)-4-methylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoate (1 g, 1.77 mmol, 1.0 eq.) in DCM (40 mL) was added EtN (358 mg, 3.54 mmol, 2 eq.) and zinc bromide (2 g, 8.9 mmol, 5 eq.). The reaction mixture was stirred for 16 h.

[1239] The reaction mixture was purified by reverse-phase chromatography (column: C18) using HO and ACN as eluents. The desired fractions were directly lyophilized to give the title compound 516 (672 mg, 1.32 mmol, 75%) as a white solid. MS(ES)C 28 H 33 Required N3O6 value: 507, Actual value: 508 (M+H) + .

[1240] Benzyl((12S)-9-(2-(1,5-naphthyridin-3-yl)ethyl)-5 4 -Methyl-8,11,14-trioxo-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)carbamate (511)

[1241] [ka]

[1242] (2S)-2-(((benzyloxy)carbonyl)amino)-4-(3-(2-(3-(isocyanomethyl)-4-methylphenoxy)ethyl)piperidin-1-yl)-4-oxobutanoic acid (77 mg, 0.15 mmol, 1.0 eq.) was dissolved in 2,2,2-trifluoroethanol (4 mL), and 3-(1,5-naphthyridin-3-yl)propanal (39 mg, 0.21 mmol, 1.4 eq.) and aq. NH3 (32%) (550 mg, 0.46 mmol, 3.0 eq.) were added to the solution. The reaction mixture was stirred for 12 hours at room temperature.

[1243] The reaction mixture was diluted with DCM and NaHCO3 and the aqueous layer was extracted three times with DCM, then the combined organic layers were dried over MgSO4 and the solvent was removed in vacuo.

[1244] The crude product was purified by flash chromatography on silica gel (0-100% EtOAc / cHex, 0-100% MeOH / DCM) followed by reverse-phase RP-HPLC (column: C18) using HO (0.1% TFA) and ACN (0.1% TFA) as eluents to afford the title compound 511 (35 mg, 0.04 mmol, 29%) as a yellowish solid (TFA salt). MS(ES)C 39 H 44 Required N6O6 value: 692, Measured value: 693 (M+H) + . 1 HNMR(400MHz,d6-DMSO,300K)δ9.14-8.71(m,2H), 8.63-7.56(m,5H), 7.52-6.96(m,7H), 6.98-6.54( m,2H), 5.22-4.87(m,2H), 4.68-3.62(8H), 3.13-2.58(m, 6H), 2.22-1.88(m, 4H), 1.81-1.02(m, 8H).

[1245] The examples in the following table were prepared according to the procedure described for compound 511. Table A-41

[1246] [Table 42-1]

[1247] [Table 42-2]

[1248] [Table 42-3]

[1249] [Table 42-4]

[1250] Example A-39: Preparation of macrocyclic compounds 565-568 N-((12S)-9-(1-benzyl-1H-pyrazol-4-yl)-5 4 -Methyl-8,11,14-trioxo-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)acetamide (565)

[1251] [ka]

[1252] N-((12S)-5 4 -Methyl-8,11,14-trioxo-9-(1H-pyrazol-4-yl)-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)acetamide 562 (50 mg, 0.098 mmol, 1.0 eq.) was dissolved in DMF (2 ml), potassium carbonate (41 mg, 0.29 mmol, 3.0 eq.), and benzyl bromide (21 mg, 0.12 mmol, 1.2 eq.) was added to the solution at room temperature, and the reaction mixture was stirred for 12 hours.

[1253] The reaction mixture was diluted with EtOAc and NaHCO3, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over MgSO4, and the solvent was removed in vacuo.

[1254] The crude product was purified by flash chromatography on silica gel (0-100% EtOAc / cHex, 0-100% MeOH / DCM) followed by reverse-phase RP-HPLC (column: C18) using HO (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to afford the title compound 565 (23.4 mg, 0.033 mmol, 34%) as a white solid (TFA salt). MS(ES)C 33 H 40 Required N6O5 value: 600, Actual value: 601 (M+H) + . 1 HNMR(400MHz,d6-DMSO,300K)δ8.69-8.34(m,1H),8.27-7.65(m,3H),7.54-7.20(m,6H),7.09-7.02(m,1H),6.9 7-6.66(m,2H),5.57-5.21(m,3H),4.77-4.04(m,6H),3.21-2.53(m,3H),2.22-2.02(m,4H),1.95-1.16(m,11H).

[1255] The examples in the table below were prepared similarly to the procedure described for 565. Table A-42

[1256] [Table 43-1]

[1257] [Table 43-2]

[1258] Standard acidic BOC (or tert-butyl)-deprotection followed according to general procedure D to give examples 566, 567 and 568. Example A-40: Preparation of macrocyclic compounds 570-572 N-((12S)-5 4 -Methyl-8,11,14-trioxo-9-(1-(3-(tritylthio)propyl)-1H-pyrazol-4-yl)-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)acetamide (569)

[1259] [ka]

[1260] N-((12S)-5 4 -Methyl-8,11,14-trioxo-9-(1H-pyrazol-4-yl)-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)acetamide 562 (100 mg, 0.20 mmol, 1.0 eq.) was dissolved in DMF (5 mL), potassium carbonate (81 mg, 0.59 mmol, 3.0 eq.) and (3-bromopropyl)(trityl)sulfane (187 mg, 0.47 mmol, 2.4 eq.) were added to the solution at room temperature, and the reaction mixture was heated to 80° C. and stirred for 18 hours.

[1261] The reaction mixture was diluted with DCM and NaHCO3, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over MgSO4, and the solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc / cHex, 0-100% MeOH / DCM) to give the desired title compound 569 (35.2 mg, 0.043 mmol, 22%). MS(ES)C 48 H 54 N6O5S Required value: 826, Measured value: 827 (M+H) + .

[1262] N-((12S)-9-(1-(3-mercaptopropyl)-1H-pyrazol-4-yl)-5 4-Methyl-8,11,14-trioxo-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)acetamide (570)

[1263] [ka]

[1264] N-((12S)-5 4 -Methyl-8,11,14-trioxo-9-(1-(3-(tritylthio)propyl)-1H-pyrazol-4-yl)-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)acetamide (35.2 mg, 0.043 mmol, 1.0 eq.) was dissolved in 25% TFA / DCM (3 mL) and stirred for 30 minutes at room temperature. The solvent was removed under reduced pressure to give the title compound 570 (30 mg, 0.043 mmol, quantitative) as the TFA salt. MS(ES)C 29 H 40 N6O5S Required value: 584, Measured value: 585 (M+H) + .

[1265] 3-(4-((12S)-12-acetamido-5 4 -Methyl-8,11,14-trioxo-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-9-yl)-1H-pyrazol-1-yl)propane-1-sulfonic acid (571)

[1266] [ka]

[1267] N-((12S)-9-(1-(3-mercaptopropyl)-1H-pyrazol-4-yl)-5 4

[0049] 3-Methyl-8,11,14-trioxo-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-12-yl)acetamide 570 (25 mg, 0.043 mmol, 1.0 eq.) was dissolved in DCM (5 mL), and 3-chlorobenzoperoxoic acid (45 mg, 0.26 mmol, 6.0 eq.) was added to the solution at 0 °C, and the reaction mixture was stirred for 12 h at room temperature. HO was added dropwise to the reaction, and the solvent was removed in vacuo.

[1268] The crude product was purified by reverse-phase RP-HPLC (column: C18) using HO (0.1% TFA) and ACN (0.1% TFA) as eluents. The desired fractions were lyophilized to afford the title compound 571 (7 mg, 0.009 mmol, 22%) as a yellowish solid (TFA salt). MS(ES)C 29 H 40 N6O8S Required value: 632, Measured value: 633 (M+H) + . N-(4-((12S)-12-acetamido-5 4 -Methyl-8,11,14-trioxo-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-9-yl)-1H-pyrazol-1-yl)ethane-1-sulfonic acid (572)

[1269] [ka]

[1270] Compound 2-(4-((12S)-12-acetamido-5 4 -Methyl-8,11,14-trioxo-4-oxa-7,10-diaza-1(3,1)-piperidina-5(1,3)-benzenacyclotetradecaphan-9-yl)-1H-pyrazol-1-yl)ethane-1-sulfonic acid 571 was prepared analogously to compound 570. MS(ES)C 29 H 40 N6O8S Required value: 618, Measured value: 619 (M+H) + .

[1271] Preparation of macrocyclic compounds 573-741 General method 1 1 H NMR spectra were recorded on a Bruker 400 MHz and TMS was used as the internal standard.

[1272] LCMS was measured on a Shimadzu LCMS 2010 (Shim-pack XR-ODS 3.0 × 30 mm 2.2 μm) quadrupole mass spectrometer operating in ES(+) ionization mode, flow rate: 0.8 mL / min, acquisition time: 3 min, wavelength: UV220, oven temperature: 50 °C.

[1273] Preparative HPLC was performed under the following conditions: Column: YMC Triart (30 × 150 mm × 7 μm); Wavelength: 220 nm; Mobile phase A: Water (NH3H2O ​​+ NH4HCO3); B: Acetonitrile; Flow rate: 25 mL / min; Injection volume: 2 mL; Run time: 10 min; Equilibration: 9.0 min.

[1274] General method 1 1 H NMR spectra were recorded on a Bruker 400 MHz and TMS was used as the internal standard.

[1275] LCMS was measured on a Shimadzu LCMS 2010 (Shim-pack XR-ODS 3.0 × 30 mm 2.2 μm) quadrupole mass spectrometer operating in ES(+) ionization mode, flow rate: 0.8 mL / min, acquisition time: 3 min, wavelength: UV220, oven temperature: 50 °C.

[1276] Preparative HPLC was performed under the following conditions: Column: YMC Triart (30 × 150 mm × 7 μm); Wavelength: 220 nm; Mobile phase A: Water (NH3H2O ​​+ NH4HCO3); B: Acetonitrile; Flow rate: 25 mL / min; Injection volume: 2 mL; Run time: 10 min; Equilibration: 9.0 min.

[1277] Example A-41: Preparation of macrocyclic compound 733 1. Preparation of Compound A41-2:

[1278] [ka]

[1279] To a solution of 8 (300 mg, 0.552 mmol, 1 eq. HCl) in DCM (18 mL) was added DIEA (142.78 mg, 1.10 mmol, 0.192 mL, 2 eq.), tert-butyl N-(1,1-dimethyl-2-oxo-ethyl)carbamate (310.28 mg, 1.66 mmol, 3 eq.), and AcOH (66.34 mg, 1.10 mmol, 0.063 mL, 2 eq.), and the reaction was stirred at 20 °C for 2 h to give a white solid. NaBH(OAc) (234.15 mg, 1.10 mmol, 2 eq.) was then added to the mixture, which was stirred at 20 °C for 17 h to give a white mixture. LCMS showed the desired mass. The reaction mixture was diluted with HO (50 mL) and extracted with EA (40 mL × 2). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue A41-2 (900 mg, crude) as a yellow oil, which was used in the next step without purification.

[1280] 2. Preparation of Compound A41-3:

[1281] [ka]

[1282] To a solution of A41-2 (900 mg, 1.33 mmol, 1 eq.) in dioxane (5 mL) was added HCl / dioxane (4 M, 3.32 mL, 10 eq.). The mixture was stirred at 20 °C for 1 h to give a pale yellow solution. LCMS showed that A41-2 remained. 3 mL of HCl / dioxane was added to the reaction, which was stirred for 1 h to give a pale yellow solution. LCMS showed that A41-2 was consumed. The reaction solution was concentrated under reduced pressure to give a residue. A41-3 (800 mg, 1.30 mmol, 98.10% yield, HCl) was used in the next step as a yellow gum without purification.

[1283] 3. Preparation of Compound 733:

[1284] [ka]

[1285] To a solution of A41-3 (700 mg, 1.14 mmol, 1 eq, HCl) in THF (15 mL) was added CDI (1.11 g, 6.84 mmol, 6 eq). The mixture was stirred at 70 °C for 6 h to give a yellow solution. LCMS showed that A41-3 was consumed. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (40 mL × 3). The combined organic layers were washed with brine (80 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (basic conditions, column: YMC Triart 30 × 150 mm × 7 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 43%-63%, 9 min) to give 733 (154.1 mg, 0.255 mmol, 22.40% yield) as a white solid. 1HNMR(DMSO-d6,400MHz): δ=7.59-8.55(m,2H),7.08-7.34(m,5H),6.83-7.06(m,2H ),6.55(brs,1H),6.42-6.77(m,1H),4.47-4.74(m,2H),3.60-4.44(m,7H),2.79-3. 31(m,4H),2.59-2.73(m,2H),2.29-2.47(m,1H),2.07-2.22(m,3H),1.88-2.02(m,1 H),1.27-1.81(m,7H),1.10-1.20(m,1H),1.10-1.20(m,1H),1.06-1.23ppm(m,6H). LCMS:100.00%、MS(ESI):m / z604.3[M+H] + .

[1286] Example A-42: Preparation of Macrocyclic Compound 717

[1287]

change

[1288] To a solution of 8 (0.15 g, 0.276 mmol, 1 eq, HCl), DIEA (71 mg, 0.552 mmol, 2 eq) in DCM (6 mL) was added cyclobutanone (39 mg, 0.552 mmol, 2 eq), and AcOH (33 mg, 0.552 mmol, 2 eq). The reaction was stirred at 20 °C for 1.5 h to give a yellow mixture. NaBH(OAc) (117 mg, 0.552 mmol, 2 eq) was added. The reaction was stirred at 20 °C for 17 h to give a yellow mixture. LCMS showed the reaction was complete. The mixture was partitioned between EA (60 mL) and H2O (40 mL). The organic layer was washed with H2O (40 mL), brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a white powder. The crude product was purified by preparative HPLC (column: 2_Phenomenex Gemini C18 75 × 40 mm × 3 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 46%–76%, 7.8 min). The eluate was lyophilized to give 717 (32.9 mg, 21% yield, 100% purity) as a white powder. 1 HNMR(400MHz,DMSO-d6)δppm 1.16-2.36(m,20H),2.58-3.00(m,4H),3.09-3.29(m,2H),3.49-4.76(m,8H),6.60-7.08(m,3H),7.12-7.36(m,5H),7.84-8.43(m,2H) LCMS:100%,MS(ESI):m / z 561.3[M+H] + .

[1289] Example A-43: Preparation of macrocyclic compound 711

[1290] [ka]

[1291] To a solution of 8 (0.15 g, 0.276 mmol, 1 eq, HCl), DIEA (71 mg, 0.552 mmol, 2 eq) in DCM (6 mL) was added bicyclo[2.2.1]hept-5-en-2-one (60 mg, 0.552 mmol, 2 eq), and AcOH (33 mg, 0.552 mmol, 2 eq). The reaction was stirred at 20 °C for 1.5 h to give a yellow mixture. NaBH(OAc) (117 mg, 0.552 mmol, 2 eq) was added. The reaction was stirred at 20 °C for 17 h to give a yellow mixture. LCMS showed that the starting material was not completely consumed. NaBH(OAc) (117 mg, 0.552 mmol, 2 eq) was added. The reaction was stirred at 20 °C for 8 h to give a yellow mixture. LCMS showed that the starting material was completely consumed. The mixture was partitioned between EA (60 mL) and HO (40 mL). The organic layer was washed with HO (40 mL), brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a white powder. The crude product was triturated with EtOH (2 mL). After filtration, the filter cake was dried under reduced pressure to give a white solid. MeCN (2 mL) and HO (2 mL) were added. The mixture was lyophilized to give 711 (78.1 mg, 47% yield) as a white powder. 1 HNMR(400MHz,DMSO-d6)δppm 0.96-2.37(m,18H),2.55-3.31(m,8H),3.59-4.81(m,8H),5.78-6.28(m,2H),6.54-7.38(m,8H),7.84-8.65(m,2H) LCMS:100%,MS(ESI):m / z599.3[M+H] + .

[1292] Example A-44: Preparation of macrocyclic compound 653 1. Preparation of A42-2:

[1293] [ka]

[1294] To a solution of A42-1 (0.3 g, 1.15 mmol, 1 eq) and DPPA (diphenylphosphoryl azide) (443 mg, 1.61 mmol, 1.4 eq) in toluene (11 mL) was added EtN (233 mg, 2.30 mmol, 2 eq). The reaction was stirred at 80 °C for 1 h to give a colorless solution. 1001-8e (578 mg, 1.38 mmol, 1.2 eq, HCl) and EtN (233 mg, 2.30 mmol, 2 eq) were added.

[1295] [ka]

[1296] The reaction was stirred at 20 °C for 17 hours to give a yellow mixture. LCMS showed that the desired MS was detected. The solution was partitioned between EA (60 mL) and H2O (20 mL). The organic layer was washed with saturated NaHCO3 (20 mL × 2), brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a yellow oil. The yellow oil was purified by combiflash (EA / PE = 0 / 1 to 1 / 1) to give A42-2 (0.41 g, 55% yield) as a yellow oil.

[1297] 2. Preparation of A42-3:

[1298] [ka]

[1299] To a solution of A42-2 (0.41 g, 0.640 mmol, 1 eq) in THF (5 mL) was added a solution of LiOH.HO (31 mg, 0.736 mmol, 1.15 eq) in HO (1 mL). The reaction was stirred at 20 °C for 1 h to give a yellow mixture. LCMS showed that the starting material was not completely consumed. A solution of LiOH HO (30 mg) in HO (1 mL) was added. The reaction was stirred at 20 °C for 1 h to give a yellow mixture. LCMS showed that the reaction was complete. HO (15 mL) was added. The aqueous layer was then acidified to pH = 4 by the addition of 1 M HCl. The aqueous layer was extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give A42-3 (0.352 g, 88% yield) as a yellow gum.

[1300] 3. Preparation of A42-4:

[1301] [ka]

[1302] To a solution of (2S)-2-amino-4-phenyl-butanoate (0.13 g, 0.533 mmol, 1 eq, HCl), A42-3 (351 mg, 0.560 mmol, 1.05 eq), and DIEA (276 mg, 2.13 mmol, 4 eq) in a mixture of DMF (1 mL) and DCM (4 mL) was added HATU (223 mg, 0.587 mmol, 1.1 eq) at 0 °C. The reaction was stirred at 0-10 °C for 1 h to give a yellow mixture. LCMS showed the reaction was complete. HO (10 mL) was added. The mixture was concentrated under reduced pressure to give a residue. The residue was partitioned between EA (60 mL) and HO (20 mL). The organic layer was washed with HO (20 mL × 2), brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a yellow oil. The crude product was purified by combi flash (EA / PE = 0 / 1 to 1 / 1) to give A42-4 (0.5 g, 100% yield, 87% purity) as a yellow oil.

[1303] 4. Preparation of A42-5:

[1304] [ka]

[1305] To a solution of A42-4 (0.5 g, 0.613 mmol, 1 eq) in THF (5 mL) was added a solution of LiOH.HO (30 mg, 0.705 mmol, 1.15 eq) in HO (1 mL). The reaction was stirred at 20 °C for 1 h, giving a yellow mixture. LCMS showed that the starting material was not completely consumed. A solution of LiOH HO (20 mg) in HO (1 mL) was added. The reaction was stirred at 20 °C for 0.5 h, giving a yellow mixture. LCMS showed that the reaction was complete. HO (15 mL) was added. The aqueous layer was then acidified to pH = 4 by the addition of 1 M HCl. The aqueous layer was extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give A42-5 (0.42 g, 87% yield) as a yellow oil.

[1306] 5. Preparation of A42-6:

[1307] [ka]

[1308] To a solution of A42-5 (0.42 g, 0.533 mmol, 1 eq) in a mixture of EtOH (6 mL) and DCM (6 mL) was added Pd / C (0.15 g, 10% purity). The reaction suspension was stirred at 20 °C under 15 psi of H for 17 h to give a black suspension. LCMS showed that the starting material was completely consumed. The reaction mixture was filtered through a pad of Celite cake. The filtrate was concentrated in vacuo to give A42-6 (0.28 g, 80% yield) as a white gum.

[1309] 6. Preparation of A42-7:

[1310] [ka]

[1311] To a solution of (2E)-2-cyano-2-hydroxyiminoacetate (122 mg, 0.856 mmol, 2 eq), 4-methylmorpholine (260 mg, 2.57 mmol, 6 eq), and [chloro(phenoxy)phosphoryl]oxybenzene (230 mg, 0.857 mmol, 2 eq) in a mixture of NMP (2 mL) and DCM (5 mL) was added A42-6 (0.28 g, 0.428 mmol, 1 eq), and the reaction was stirred at 20 °C for 1.5 h to give a yellow solution. LCMS showed complete consumption of the starting material. HO (15 mL) was added. The resulting solution was concentrated to remove DCM. The residue was partitioned between EA (80 mL) and HO (80 mL). The organic layer was washed with water (80 mL × 2), brine (80 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a yellow oil. The mother liquor was purified by combi-flash (EA / PE = 0 / 1 to 3 / 1) to give A42-7 (0.15 g, 44% yield, 80% purity) as a white solid.

[1312] 7.8 Preparation:

[1313] [ka]

[1314] To a solution of A42-7 (150 mg, 0.236 mmol, 1 eq) in dioxane (1 mL) was added HCl / dioxane (4 M, 1.18 mL, 20 eq). The reaction was stirred at 20° C. for 30 min to give a yellow solution. LCMS showed that the starting material was completely consumed. HCl / dioxane (4 M, 0.5 mL) was added. The reaction was stirred at 20° C. for 30 min to give a yellow solution. LCMS showed that the starting material was completely consumed. The solution was concentrated under reduced pressure to give 8 (141 mg, crude, HCl) as a white solid.

[1315] Preparation of 8.653:

[1316] [ka]

[1317] A solution of 8 (0.13 g, 0.227 mmol, 1 eq, HCl), 2-phenylacetic acid (40 mg, 0.295 mmol, 1.3 eq), 1-hydroxybenzotriazole (43 mg, 0.318 mmol, 1.4 eq), and DIEA (88 mg, 0.682 mmol, 3 eq) in a mixture of DCM (3 mL) and THF (3 mL) was stirred at 20 °C for 15 min to give a yellow mixture. 3-(Ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine; hydrochloride (61 mg, 0.318 mmol, 1.4 eq) was added. The reaction was stirred at 20 °C for 1 h to give a yellow mixture. LCMS showed complete consumption of the starting material. The solution was partitioned between EA (100 mL) and HO (20 mL). The organic layer was washed with 0.2 M HCl (40 mL), saturated NaHCO (30 mL), brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a yellow oil. The yellow oil was purified by preparative HPLC (column: 2_Phenomenex Gemini C18 75 × 40 mm × 3 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 50%-80%, 7.8 min). The eluate was lyophilized to give 653 (99.4 mg, 67% yield, 100% purity) as a white powder. 1 HNMR(400MHz,DMSO-d6)δppm 1.12-2.04(m,11H),2.15(s,3H),2.60-3.24(m,5H),3.52(s,2H),3.57-4.39(m,9 H),6.30-7.04(m,3H),7.00(d,J=8Hz,1H),7.09-7.35(m,10H),8.06-8.50(m,3H) LCMS:100%,MS(ESI):m / z654.3[M+H] + .

[1318] Example A-45: Preparation of macrocyclic compound 593

[1319] [ka]

[1320] To a solution of 8 (100 mg, 184.13 μmol, 1 equiv., HCl) in DCM (5 mL) was added DIEA (71.39 mg, 552.39 μmol, 96.22 μL, 3 eq) and A56-1 (34.57 mg, 276.19 μmol, 35.28 μL, 1.5 eq). The mixture was stirred at 20 °C for 16 h to give a yellow solution. The reaction mixture was filtered. The filter cake was washed with DCM (10 mL), dried, and concentrated. The crude product was triturated with DCM:EtOAc (5:1, 6 mL) to give 593 (66.13 mg, 104.67 μmol, 56.85% yield, 100% purity) as a white solid. 1 HNMR(400MHz,DMSO-d6)δ=8.34-7.88(m,2H),7.30-7.13(m,5H),7.03(dd,J=3.8,8.3Hz,1H),6.97-6.64 (m,2H),6.12-5.97(m,2H),4.64-3.70(m,8H),3.03-2.59(m,5H),2.34-2.11(m,4H),2.00-0.97(m,20H) LCMS:100%,MS(ESI):m / z632.3[M+H] + .

[1321] Example A-46: Preparation of macrocycle 624 1. Preparation of A44-1:

[1322] [ka]

[1323] To a solution of A43-2 (508 mg, 1.64 mmol, 1 eq) and bis(4-nitrophenyl)carbonate (0.5 g, 1.64 mmol, 1 eq) in DMF (8 mL) was added DIEA (637 mg, 4.93 mmol, 3 eq). The reaction was stirred at 20 °C for 17 h to give a yellow mixture. LCMS showed that the desired MS values ​​were detected. The mixture was partitioned between EA (60 mL) and HO (40 mL). The organic layer was washed with HO (40 mL), brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a yellow oil. The yellow oil was purified by combiflash (EA / PE = 0 / 1 to 1 / 9) to give A44-1 (0.72 g, 89% yield, 97% purity) as a yellow oil.

[1324] 2. Preparation of A44-2:

[1325] [ka]

[1326] To a solution of A44-1 (0.6 g, 1.26 mmol, 1 eq) and 1001-8e (657 mg, 1.39 mmol, 1.1 eq, oxalic acid) in DMF (12 mL) was added DIEA (490 mg, 3.79 mmol, 3 eq). The reaction was stirred at 20 °C for 17 h to give a yellow mixture. LCMS showed that the desired MS values ​​were detected. The mixture was partitioned between EA (100 mL) and HO (60 mL). The organic layer was washed with HO (60 mL), brine (60 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a yellow oil. The yellow oil was purified by combiflash (EA / PE = 0 / 1 to 1 / 3) to give A44-2 (0.88 g, 94% yield, 97% purity) as a colorless oil.

[1327] 3. Preparation of A44-3:

[1328] [ka]

[1329] To a solution of A44-2 (0.88 g, 1.23 mmol, 1 eq) in THF (10 mL) was added a solution of LiOH.HO (59 mg, 1.41 mmol, 1.15 eq) in HO (2 mL). The reaction was stirred at 20 °C for 2.5 h to give a yellow mixture. LCMS showed the reaction was complete. HO (15 mL) was added. The aqueous layer was then acidified to pH = 4 by the addition of 1 M HCl. The aqueous layer was extracted with EA (40 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give A44-3 (0.8 g, crude product) as a yellow oil.

[1330] 4. Preparation of A44-4:

[1331] [ka]

[1332] To a solution of ethyl (2S)-2-amino-4-phenylbutanoate (0.38 g, 1.56 mmol, 1 eq, HCl), A44-3 (1.03 g, 1.64 mmol, 1.05 eq), and DIEA (806 mg, 6.24 mmol, 4 eq) in a mixture of DMF (4 mL) and DCM (16 mL) was added HATU (652 mg, 1.72 mmol, 1.1 eq) at 0 °C. The reaction was stirred at 0 °C to 10 °C for 1 h to give a yellow mixture. LCMS showed the reaction was complete. H2O (10 mL) was added. The mixture was concentrated under reduced pressure to give a residue. The residue was partitioned between EA (60 mL) and H2O (20 mL). The organic layer was washed with HO (20 mL × 2), brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a yellow oil. The crude product was purified by combi flash (EA / PE = 0 / 1 to 2 / 5) to give A44-4 (1.16 g, 91% yield) as a colorless oil.

[1333] 5. Preparation of A44-5:

[1334] [ka]

[1335] To a solution of A44-4 (1.16 g, 1.42 mmol, 1 eq) in THF (12 mL) was added a solution of LiOH.H2O (68 mg, 1.63 mmol, 1.15 eq) in H2O (3 mL). The reaction was stirred at 20 °C for 3 h to give a yellow mixture. LCMS showed that the starting material was not completely consumed. A solution of LiOH H2O (30 mg) in H2O (1 mL) was added. The reaction was stirred at 20 °C for 1 h to give a yellow mixture. LCMS showed that the reaction was complete. H2O (15 mL) was added. The aqueous layer was then acidified to pH = 4 by the addition of 1 M HCl. The aqueous layer was extracted with EA (30 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give A44-5 (1.14 g, crude) as a yellow oil.

[1336] 6. Preparation of A42-6:

[1337] [ka]

[1338] To a solution of A44-5 (1.12 g, 1.42 mmol, 1 eq) in a mixture of EtOH (20 mL) and DCM (20 mL) was added Pd / C (0.4 g, 10% purity). The reaction suspension was stirred at 20 °C under 15 psi of H for 17 h to give a black suspension. LCMS showed that the starting material was completely consumed. The reaction mixture was filtered through a pad of Celite cake. The filtrate was concentrated in vacuo to give A42-6 (0.91 g, 97% yield) as a white gum.

[1339] 7. Preparation of A42-7:

[1340] [ka]

[1341] To a solution of ethyl (2E)-2-cyano-2-hydroxyiminoacetate (395 mg, 2.78 mmol, 2 eq), 4-methylmorpholine (843 mg, 8.34 mmol, 6 eq), and [chloro(phenoxy)phosphoryl]oxybenzene (747 mg, 2.78 mmol, 2 eq) in a mixture of NMP (4 mL) and DCM (12 mL) was added A42-6 (910 mg, 1.39 mmol, 1 eq), and the reaction was stirred at 20 °C for 1.5 h to give a yellow solution. LCMS showed complete consumption of the starting material. HO (15 mL) was added. The resulting solution was concentrated to remove DCM. The residue was partitioned between EA (80 mL) and HO (80 mL). The organic layer was washed with water (80 mL × 2), brine (80 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a yellow oil. The mother liquor was purified by combi-flash (EA / PE = 0 / 1 to 2 / 3) to give A42-7 (230 mg, 23% yield, 89% purity) as a white solid.

[1342] 8. Preparation of Compound 8:

[1343] [ka]

[1344] To a solution of A42-7 (230 mg, 0.361 mmol, 1 eq) in dioxane (1 mL) was added HCl / dioxane (4 M, 1.81 mL, 20 eq). The reaction was stirred at 20 °C for 1 h to give a yellow solution. LCMS showed that the starting material was completely consumed. The solution was concentrated under reduced pressure to give 8 (0.2 g, 96% yield, HCl) as a white solid.

[1345] 9. Preparation of Compound 624:

[1346] [ka]

[1347] A solution of 8 (100 mg, 0.174 mmol, 1 eq, HCl), 2-phenylacetic acid (31 mg, 0.227 mmol, 1.3 eq), 1-hydroxybenzotriazole (33 mg, 0.244 mmol, 1.4 eq), and DIEA (68 mg, 0.523 mmol, 3 eq) in a mixture of DCM (3 mL) and THF (3 mL) was stirred at 20 °C for 15 min to give a yellow mixture. 3-(Ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (47 mg, 0.244 mmol, 1.4 eq) was added. The reaction was stirred at 20 °C for 1 h to give a yellow mixture. LCMS showed complete consumption of the starting material. The solution was partitioned between EA (60 mL) and HO (20 mL). The organic layer was washed with 0.2 M HCl (40 mL), saturated NaHCO (30 mL), brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a yellow oil. The yellow oil was purified by preparative HPLC (column: 2_Phenomenex Gemini C18 75 × 40 mm × 3 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 52%-82%, 7.8 min). The eluate was lyophilized to give 624 (65.9 mg, 57% yield, 100% purity) as a white powder. 1 HNMR(400MHz,DMSO-d6)δppm 1.12-2.09(m,11H),2.16(s,3H),2.56-3.05(m,4H),3.49-4.44(m,12H),6.58-7.09(m,3H),7.09-7.39(m,10H),7.89-8.58(m,3H) LCMS:100%,MS(ESI):m / z655.3[M+H] + .

[1348] Example A-47: Preparation of macrocycle 740 1. Preparation of A149-2a:

[1349] [ka]

[1350] To a mixture of NaN3 (103.97 mg, 1.60 mmol, 1.05 eq) in a mixture of HO (4 mL) and MTBE (4 mL) was added a solution of A149-1a (500 mg, 1.52 mmol, 1 eq) in MeCN (0.5 mL) at 0 °C, and the resulting mixture was stirred at 0 °C to 5 °C for 30 min to obtain a colorless mixture. The mixture was partitioned between MTBE (4 mL) and water (4 mL). The organic layer was 19 F-NMR was used to monitor. A solution of A149-2a (180 mg, crude) in MTBE (4 mL) was obtained and used directly.

[1351] 2. Preparation of A149-1:

[1352] [ka]

[1353] To a mixture of 8 (15 mg, 0.296 mmol, 1 eq) and A149-2a in a mixture of MTBE (4 mL) and DMF (1 mL) was added a solution of KHCO (59.28 mg, 0.592 mmol, 2 eq) in HO (1 mL). The resulting mixture was stirred at 20-25 °C for 20 h to give a colorless mixture. TLC showed the reaction was complete. The mixture was diluted with HO (20 mL), extracted with EA (20 mL × 2), and washed with water (20 mL × 3). The combined organic layers were concentrated to dryness. The residue was purified by flash column chromatography (THF / PE = 40%-60%, SiO) to give A149-1 (50 mg, 0.093 mmol, 31.71% yield) as a white solid.

[1354] 3. Preparation of Compound 740:

[1355] [ka]

[1356] A mixture of A149-1 (50 mg, 0.65 mmol, 1 eq), propane-1-yne (1 M, 0.394 mL, 6 eq), CuSO (2.10 mg, 0.013 mmol, 0.002 mL, 0.2 eq), and sodium ascorbate (6.51 mg, 0.032 mmol, 0.5 eq) in a mixture of DMF (0.5 mL) and HO (0.3 mL) was stirred at 45 °C for 2 h under N to give a yellow mixture. TLC showed a new spot. To the mixture, 10 mL of EA was added and filtered through a pad of Celite. The mixture was then diluted with HO (10 mL), extracted with EA (10 mL × 2), and washed with water (10 mL × 2). The combined organic layers were concentrated to dryness. The residue was purified by flash column (EA = 40% to 100% in PE, SiO2) to give 740 (15.1 mg, 0.026 mmol, 40.12% yield) as a white powder. 1 HNMR(400MHz,DMSO-d6):δ=8.93-8.94(m,1H),7.89-8.45(m,2H),7.19-7.30(m,3H),6.98-7.13(m,1H),6.82-6.93(m,1H),6.65- 6.80(m,1H),5.50-5.80(m,1H),4.17-4.26(m,6H),3.50-3.90(m,2H),2.60-3.30(m,4H),1.76-2.20(m,12H),1.23-1.75(m,6H). HPLC:96.67%, MS(ESI):m / z573.3[M+H] + .

[1357] Example A-48: Preparation of macrocyclic compound 632 1. Preparation of A57-2a:

[1358] [ka]

[1359] To a solution of A57-1a (127 mg, 1.27 mmol, 132.29 μL, 1 eq) and A57-1b (1.16 g, 3.80 mmol, 3 eq) in DMF (3 mL) was added DIEA (491.64 mg, 3.80 mmol, 662.58 μL, 3 eq). The mixture was stirred at 25 °C for 3 h. The solution was partitioned between EA (20 mL) and HO (10 mL). The organic layer was washed with HO (10 mL × 3), brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO, PE / EA = 80 / 20) to give 306 mg (1.15 mmol, 90.98% yield) as a yellow solid.

[1360] 2. Preparation of Compound 632:

[1361] [ka]

[1362] To a solution of A57-2a (306 mg, 1.15 mmol, 1 eq) and 8 (584.44 mg, 1.15 mmol, 1 eq) in DMF (5 mL) was added DIEA (447.28 mg, 3.46 mmol, 602.80 μL, 3 eq). The mixture, as a colorless solution, was stirred at 25 °C for 3 h. The solution was partitioned between EA (20 mL) and HO (10 mL). The organic layer was washed with HO (10 mL × 3), brine (1 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: ACE 5 C18-AR 150 × 30 mm × 5 μm; mobile phase: [...

Claims

1. Compounds of general formula (I) 【Chemical 1】 During the ceremony, A is -CO-N (R) Ｎ６ )―、 【Chemistry 2】 , which represents; B is, -H, -NH (R) ２ ),-N(R ２ )(R Ｎ５ ) 【Chemistry 3】 represents; L is -CO-, -CO-NH-, -CO-N(R Ｎ３ )- or -CO-O-; R １ is -H, -(CH ２ ) ｐ -R ７ , -(CH ２ ) ｐ -NH-R ７ , -(CH ２ ) ｐ -R ９ , or -(CH ２ ) ｐ -NR Ｎ４ -R ９ represents; R ２ は、-H、-R ８ 、-R １１ 、-L １ -R １１ 、-L １ -(CH ２ ) ｒ -R ８ 、-L １ -R １０ 、-L １ -(C ２ H ４ O) ｓ -R １１ 、-L １ -(CH ２ ) ｔ -O-R １１ 、-L １ -(CH ２ ) ｔ -NH-(CH ２ ) ｒ -R ８ 、-L １ -(CH ２ ) ｔ -O-(CH ２ ) ｒ -R ８ 、-L １ -(CH ２ ) ｔ -NHR ８ 、-L １ -(CH ２ ) ｔ -NH-CO-R ８ 、-L １ -(CH ２ ) ｔ -NH-SO ２ -R ８ 、-L １ -(CH ２ ) ｔ -NR Ｎ６ R １０ 、-L １ -(CH ２ ) ｔ -O-(CH ２ ) ｕ -NR Ｎ６ R １０ 、-L １ -(CH ２ ) ｒ -R １４ 、-CO-C(R １２ )(R １３ )-R １０ , —CO—C(R １２ ) (R １３ )-R ８ , or —CO—C(R １２ ) (R １３ )-(CH ２ ) ｕ -R ８ represents; L １ is a bond, -CO-, -CO ２ -, -CONH-, or -SO ２ represents -; R ３ ~R ６ are each independently —H, —CH ３ , -OCH ３ , —F, or —Cl; Or, R ５ and R ６ teeth, 【Chemistry 4】 Forming; R ８ and R ９ are independent of each other. 【Chemistry 5】 【change】 represents; R ７ and R １０ are each independently —H, —CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ CN, -C(CH ３ ) ２ -CN, -CH ２ -C(CH ３ ) ２ -CN, -CH ２ -CF ３ , -CH ２ -C(CH ３ ) ２ -NH ２ , 【Chemistry 6】 , cyclo-C ３ H ５ , cyclo-C ４ H ７ , cyclo-C ５ H ９ , cyclo-C ６ H １１ , cyclo-C ７ H １３ , -C ４ H ９ , -CH ２ -CH(CH ３ ) ２ , -CH(CH ３ )-C ２ H ５ , -C(CH ３ ) ３ , -C ５ H １１ , -CH(CH ３ )-C ３ H ７ , -CH ２ -CH(CH ３ )-C ２ H ５ , -CH(CH ３ )-CH(CH ３ ) ２ , -C(CH ３ ) ２ -C ２ H ５ , -CH ２ -C(CH ３ ) ３ , —CH(C ２ H ５ ) ２ , -C ２ H ４ -CH(CH ３ ) ２ , -C ６ H １３ , -C ７ H １５ , -C ８ H １７ , -Ph, -CH ２ -Ph, -CH ２ -CH ２ -Ph, -C ２ H ４ -CH=CH ２ , -CH ２ -CH=CH-CH ３ , -CH ２ -C(CH ３ )=CH ２ 、-CH(CH ３ )-CH=CH ２ 、-C(CH ３ )=CH-CH ３ 、-CH ２ -CH=C(CH ３ ) ２ 、-CO-CH=C(CH ３ ) ２ 、-CH ２ -C≡CH、-C ２ H ４ -C≡CH、-CH ２ -C≡C-CH ３ 、-CH ２ -OCF ３ 、-C ２ H ４ -OCF ３ 、-C ３ H ６ -OCF ３ 、-CH ２ -OCHF ２ 、-C ２ H ４ -OCHF ２ 、-C ３ H ６ -OCHF ２ 、-CH ２ -OCH ３ 、-C ２ H ４ -OCH ３ 、-C ３ H ６ -OCH ３ 、-CH ２ -OC ２ H ５ 、-C ２ H ４ -OC ２ H ５ 、-C ３ H ６ -OC ２ H ５ 、-CH ２ -OH、-C ２ H ４ -OH、-C ３ H ６ -OH、-CH ２ -COOH、-C ２ H ４ -COOH, -C ３ H ６ -COOH, -C(CH ３ ) ２ -CN, -C(CH ３ ) ２ —OH, —C(CH ３ ) ２ -CH ２ -OH, -C(C ２ H ５ ) ２ -CH ２ —OH, —C(CH ２ -OH) ２ -CH ３ , -C(CH ２ -OH) ２ -C ２ H ５ , -C(CH ３ ) ２ -CH ２ -SH, -C(C ２ H ５ ) ２ -CH ２ -SH, -C(CH ２ -SH) ２ -CH ３ , -CO-OC(CH ３ ) ３ , or -C(CH ２ -SH) ２ -C ２ H ５ represents; R １１ は、-H、-CH ３ 、-C ２ H ５ 、-C ３ H ７ 、-CH(CH ３ ) ２ 、-CH ２ F、-CHF ２ 、-CF ３ 、-CH ２ CN、-C(CH ３ ) ２ -CN、-CH ２ -C(CH ３ ) ２ -CN、-CH ２ -CF ３ 、-CH ２ -C(CH ３ ) ２ -NH ２ 、 【Chemistry 7】 , cyclo-C ３ H ５ , cyclo-C ４ H ７ , cyclo-C ５ H ９ , cyclo-C ６ H １１ , cyclo-C ７ H １３ , -C ４ H ９ , -CH ２ -CH(CH ３ ) ２ , -CH(CH ３ )-C ２ H ５ , -C(CH ３ ) ３ , -C ５ H １１ , -CH(CH ３ )-C ３ H ７ , -CH ２ -CH(CH ３ )-C ２ H ５ , -CH(CH ３ )-CH(CH ３ ) ２ , -C(CH ３ ) ２ -C ２ H ５ , -CH ２ -C(CH ３ ) ３ , —CH(C ２ H ５ ) ２ , -C ２ H ４ -CH(CH ３ ) ２ , -C ６ H １３ , -C ７ H １５ , -C ８ H １７ , -Ph, -CH ２ -Ph, -CH ２ -CH ２ -Ph, -CH=CH ２ , -CH ２ -CH=CH ２ , -C(CH ３ ) = CH ２ 、-CH=CH-CH ３ 、-C(CH ３ )=CH-CH ３ 、-CH=C(CH ３ ) ２ 、-C(CH ３ )=C(CH ３ ) ２ 、-C ２ H ４ -CH=CH ２ 、-CH ２ -CH=CH-CH ３ 、-CH ２ -C(CH ３ )=CH ２ 、-CH(CH ３ )-CH=CH ２ 、-C(CH ３ )=CH-CH ３ 、-CH ２ -CH=C(CH ３ ) ２ 、-C≡CH、-CH ２ -C≡CH、-C ２ H ４ -C≡CH、-CH ２ -C≡C-CH ３ 、-C≡C-CH ３ 、-C≡C-C ２ H ５ 、-CH ２ -OCF ３ 、-C ２ H ４ -OCF ３ 、-C ３ H ６ -OCF ３ 、-CH ２ -OCHF ２ 、-C ２ H ４ -OCHF ２ 、-C ３ H ６ -OCHF ２ 、-CH ２ -OCH ３ 、-C ２ H ４ -OCH ３ 、-C ３ H ６ -OCH ３ 、-CH ２ -OC ２ H ５ , -C ２ H ４ -OC ２ H ５ , -C ３ H ６ -OC ２ H ５ , -CH ２ —OH, —C ２ H ４ —OH, —C ３ H ６ —OH, —C(CH ３ ) ２ -CH ２ -OH, -C(C ２ H ５ ) ２ -CH ２ —OH, —C(CH ２ -OH) ２ -CH ３ , -C(CH ２ -OH) ２ -C ２ H ５ , -C(CH ３ ) ２ -CH ２ -SH, -C(C ２ H ５ ) ２ -CH ２ -SH, -C(CH ２ -SH) ２ -CH ３ , or -C(CH ２ -SH) ２ -C ２ H ５ represents; R １２ and R １３ are each independently —H, —CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -Ph, -CH ２ -Ph, -COOH, -NH ２ , -NHCO ２ (CCH ３ ) ３ , -CH ２ -NH ２ , -CHF ２ , -CF ３ , -F, -OCF ３ , -OCHF ２ , —OH, —OCH ３ , -OC ２ H ５ , -OC ３ H ７ , or -OCH(CH ３ ) ２ represents; or R １２ and R １３ together 【Chemistry 8】 Forming; R １４ teeth, 【Chemistry 9】 represents; R １５ and R １６ are, independently of each other, -X ３ -L ２ -R １７ , or -(OCH ２ CH ２ ) ｗ -R １７ represents; L ２ is -(CH ２ ) ｖ -, -(CH ２ CH ２ -O) ｗ -CH ２ - or -(CH ２ CH ２ -O) ｗ -CH ２ CH ２ represents -; R １７ -OH, -SH, -SO ３ H, —NH ２ , or -CO ２ represents H; R Ｎ１ , R Ｎ２ , R Ｎ３ , and R Ｎ４ are, independently of each other, -R １５ , -H, -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CHF ２ , -CF ３ , 【Chemistry 10】 , cyclo-C ３ H ５ , cyclo-C ４ H ７ , cyclo-C ５ H ９ , cyclo-C ６ H １１ , cyclo-C ７ H １３ , -C ４ H ９ , -CH ２ -CH(CH ３ ) ２ , -CH(CH ３ )-C ２ H ５ , -C(CH ３ ) ３ , -C ５ H １１ , -CH(CH ３ )-C ３ H ７ , -CH ２ -CH(CH ３ )-C ２ H ５ , -CH(CH ３ )-CH(CH ３ ) ２ , -C(CH ３ ) ２ -C ２ H ５ , -CH ２ -C(CH ３ ) ３ , —CH(C ２ H ５ ) ２ , -C ２ H ４ -CH(CH ３ ) ２ , -C ６ H １３ , -C ７ H １５ , -C ８ H １７ , -Ph, -CH ２ -Ph, -CH ２ -CH ２ -Ph, -C ２ H ４ -CH=CH ２ , -CH ２ -CH=CH-CH ３ , -CH ２ -C(CH ３ )=CH ２ 、-CH(CH ３ )-CH=CH ２ 、-CH ２ -CH=C(CH ３ ) ２ 、-CH ２ -C≡CH、-C ２ H ４ -C≡CH、-CH ２ -C≡C-CH ３ 、-COCH ３ 、-COC ２ H ５ 、-COC ３ H ７ 、-CO-シクロ-C ３ H ５ 、-COCH(CH ３ ) ２ 、-COC(CH ３ ) ３ 、-COOH、-COOCH ３ 、-COOC ２ H ５ 、-COOC ３ H ７ 、-COO-シクロ-C ３ H ５ 、-COOCH(CH ３ ) ２ 、-COOC(CH ３ ) ３ 、-COOCH ２ Ph、-CONH ２ 、-CONHCH ３ 、-CONHC ２ H ５ 、-CONHC ３ H ７ 、-CONH-シクロ-C ３ H ５ 、-CONH[CH(CH ３ ) ２ ]、-CONH[C(CH ３ ) ３ ]、-CON(CH ３ ) ２ 、-CON(C ２ H ５ ) ２ 、-CON(C ３ H ７ ) ２ , -CON(cyclo-C ３ H ５ ) ２ , -CON[CH(CH ３ ) ２ ] ２ , -CON[C(CH ３ ) ３ ] ２ , or -SO ３ represents H; R Ｎ５ and R Ｎ６ are each independently —H, —CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , cyclo-C ３ H ５ , -COOC(CH ３ ) ３ , or -COOCH ２ represents Ph; X １ is -(CH ２ ) ｍ represents -; X ２ is -(CH ２ ) ｎ represents -; X ３ represents a bond, —O—, —NH—, or —S—; Z １ ~Z １４ are independent of each other, 【Chemistry 11】 , cyclo-C ３ H ５ , cyclo-C ４ H ７ , cyclo-C ５ H ９ , cyclo-C ６ H １１ , cyclo-C ７ H １３ , -R １６ , -H, -OH, -OCH ３ , -OC ２ H ５ , -OC ３ H ７ , —O-cyclo-C ３ H ５ , -OCH(CH ３ ) ２ , -OC(CH ３ ) ３ , -OC ４ H ９ , —O-cyclo-C ４ H ７ , —O-cyclo-C ５ H ９ , —O-cyclo-C ６ H １１ , -OCH ２ CH (CH ３ ) ２ , -OCH ２ -cyclo-C ３ H ５ , -OCH ２ -cyclo-C ４ H ７ , -OCH ２ -cyclo-C ５ H ９ , -OCH ２ -cyclo-C ６ H １１ , -OPh, -OCH ２ -Ph, -OCPh ３ , -CH ２ -OCH ３ , -C ２ H ４ -OCH ３ , -C ３ H ６ -OCH ３ , -CH ２ -OC ２ H ５ , -C ２ H ４ -OC ２ H ５ 、-C ３ H ６ -OC ２ H ５ 、-CH ２ -OC ３ H ７ 、-C ２ H ４ -OC ３ H ７ 、-C ３ H ６ -OC ３ H ７ 、-CH ２ -O-シクロ-C ３ H ５ 、-C ２ H ４ -O-シクロ-C ３ H ５ 、-C ３ H ６ -O-シクロ-C ３ H ５ 、-CH ２ -OCH(CH) ３ ) ２ 、-C ２ H ４ -OCH(CH ３ ) ２ 、-C ３ H ６ -OCH(CH ３ ) ２ 、-CH ２ -OC(EH ３ ) ３ 、-C ２ H ４ -OC(EH ３ ) ３ 、-C ３ H ６ -OC(EH ３ ) ３ 、-CH ２ -OC ４ H ９ 、-C ２ H ４ -OC ４ H ９ 、-C ３ H ６ -OC ４ H ９ 、-CH ２ -OPh, -C ２ H ４ -OPh, -C ３ H ６ -OPh, -CH ２ -OCH ２ -Ph, -C ２ H ４ -OCH ２ -Ph, -C ３ H ６ -OCH ２ -H--HH、-SCH ３ ,-SC ２ H ５ ,-SC ３ H ７ 、-S-シクロ-C ３ H ５ , -SCH (CH ３ ) ２ , -SC (CH) ３ ) ３ 、-F、-C-、-Br、-I、-&N、-COCH ３ ,-COC ２ H ５ ,-COC ３ H ７ 、-CO-シクロ-C ３ H ５ , -COCH (CH ３ ) ２ , -COC (CH) ３ ) ３ 、-COOOH、-COOCH ３ ,-COOC ２ H ５ ,-COOC ３ H ７ 、-COOO-シクロ-C ３ H ５ 、-COOOCH (CH ３ ) ２ , -COOC (CH ３ ) ３ ,-OO--CH ３ ,---- ２ H ５ ,---- ３ H ７ 、OOC-シクロ-C ３ H ５ 、-OOC-CH (CH ３ ) ２ 、-OOC-C (CH ３ ) ３ 、-CONH ２ 、-CONHCH ３ 、-CONHC ２ H ５ 、-CONHC ３ H ７ 、-CONH-シクロ-C ３ H ５ 、-CONH[CH(CH ３ ) ２ ]、-CONH[C(CH ３ ) ３ ]、-CON(CH ３ ) ２ 、-CON(C ２ H ５ ) ２ 、-CON(C ３ H ７ ) ２ 、-CON(シクロ-C ３ H ５ ) ２ 、-CON[CH(CH ３ ) ２ ] ２ 、-CON[C(CH ３ ) ３ ] ２ 、-NHCOCH ３ 、-NHCOC ２ H ５ 、-NHCOC ３ H ７ 、-NHCO-シクロ-C ３ H ５ 、-NHCO-CH(CH ３ ) ２ 、-NHCO-C(CH ３ ) ３ 、-NHCO-CH(NH ２ )CH ２ -COOH、-NHCO-CH(NH ２ )CH ２ CH ２ -COOH、-NHCO-OCH ３ 、-NHCO-OC ２ H ５ 、-NHCO-OC ３ H ７ 、-NHCO-O-シクロ-C ３ H ５ 、-NHCO-OCH(CH ３ ) ２ 、-NHCO-OC(CH ３ ) ３ ,-NH ２ ,-NHCH ３ ,-NHC ２ H ５ ,-NHC ３ H ７ 、-NH-シクロ-C ３ H ５ , -NHCH (CH ３ ) ２ , -NHC (CH) ３ ) ３ , -N (CH) ３ ) ２ , -N (C) ２ H ５ ) ２ , -N (C) ３ H ７ ) ２ 、-N (シクロ-C ３ H ５ ) ２ , -N[CH(CH ３ ) ２ ] ２ , -N[C(CH ３ ) ３ ] ２ ,-SOC ３ ,-SOC ２ H ５ ,-SOC ３ H ７ 、-SO-シクロ-C ３ H ５ , - SOC (CH) ３ ) ２ , - SOC (CH) ３ ) ３ ,-E ２ CH ３ ,-E ２ C ２ H ５ ,-E ２ C ３ H ７ ,-E ２ -シクロ-C ３ H ５ ,-E ２ CH (CH) ３ ) ２ ,-E ２ C (CH) ３ ) ３ ,-E ３ H, -SO ３ CH ３ ,-E ３ C ２ H ５ ,-E ３ C ３ H ７ ,-E ３ -シクロ-C ３ H ５ ,-E ３ CH (CH) ３ ) ２ ,-E ３ C (CH) ３ ) ３ ,-E ２ NH ２ ,-E ２ NHCHH ３ ,-E ２ NH ２ H ５ ,-E ２ NH ３ H ７ ,-E ２ NH-シクロ-C ３ H ５ ,-E ２ NHCH (CH) ３ ) ２ ,-E ２ NH (CH) ３ ) ３ ,-E ２ N (CH) ３ ) ２ ,-E ２ N (C) ２ H ５ ) ２ ,-E ２ N (C) ３ H ７ ) ２ ,-E ２ N (シロロ-C ３ H ５ ) ２ ,-E ２ N[CH(CH ３ ) ２ ] ２ ,-E ２ N[C(CH) ３ ) ３ ] ２ 、-O-S(=O)CH ３ 、-O-S(=O)C ２ H ５ 、-O-S(=O)C ３ H ７ 、-O-S(=O)-シクロ-C ３ H ５ 、-O-S(=O)CH(CH ３ ) ２ 、-O-S(=O)C(CH ３ ) ３ 、-S(=O)(=NH)CH ３ 、-S(=O)(=NH)C ２ H ５ 、-S(=O)(=NH)C ３ H ７ 、-S(=O)(=NH)-シクロ-C ３ H ５ 、-S(=O)(=NH)CH(CH ３ ) ２ 、-S(=O)(=NH)C(CH ３ ) ３ 、-NH-SO ２ -CH ３ 、-NH-SO ２ -C ２ H ５ 、-NH-SO ２ -C ３ H ７ 、-NH-SO ２ -シクロ-C ３ H ５ 、-NH-SO ２ -CH(CH ３ ) ２ 、-NH-SO ２ -C(CH ３ ) ３ 、-O-SO ２ -CH ３ 、-O-SO ２ -C ２ H ５ 、-O-SO ２ -C ３ H ７ 、-O-SO ２ -シクロ-C ３ H ５ 、-O-SO ２ -CH(CH ３ ) ２ 、-O-SO ２ -C(CH ３ ) ３ 、-OCH ２ F、-OCHF ２ 、-OCF ３ 、-CH ２ -OCF ３ 、-C ２ H ４ -OCF ３ 、-C ３ H ６ -OCF ３ 、-CH ２ -OCHF ２ 、-C ２ H ４ -OCHF ２ 、-C ３ H ６ -OCHF ２ 、-OC ２ F ５ 、-CH ２ -OC ２ F ５ 、-C ２ H ４ -OC ２ F ５ 、-C ３ H ６ -OC ２ F ５ 、-O-COOCH ３ 、-O-COOC ２ H ５ 、-O-COOC ３ H ７ 、-O-COO-シクロ-C ３ H ５ 、-O-COOCH(CH ３ ) ２ 、-O-COOC(CH ３ ) ３ 、-NH-CO-NH ２ 、-NH-CO-NHCH ３ 、-NH-CO-NHC ２ H ５ 、-NH-CO-NHC ３ H ７ 、-NH-C(=NH)-NH ２ 、-NH-CO-N(C ３ H ７ ) ２ 、-NH-CO-NH[CH(CH ３ ) ２ ]、-NH-CO-NH[C(CH ３ ) ３ ]、-NH-CO-N(CH ３ ) ２ 、-NH-CO-N(C ２ H ５ ) ２ 、-NH-CO-NH-シクロ-C ３ H ５ 、-NH-CO-N(シクロ-C ３ H ５ ) ２ 、-NH-C O-N[CH(CH ３ ) ２ ] ２ 、-NH-C(=NH)-NHCH ３ 、-NH-C(=NH)-NHC ２ H ５ 、-NH-C(=NH)-NHC ３ H ７ 、-O-CO-NH-シクロ-C ３ H ５ 、-NH-C(=NH)-NH-シクロ-C ３ H ５ 、-NH-C(=NH)-NH[CH(CH ３ ) ２ ]、-O-CO-NH[CH(CH ３ ) ２ ]、-NH-C(=NH)-NH[C(CH ３ ) ３ ]、-NH-C(=NH)-N(CH ３ ) ２ 、-NH-C(=NH)-N(C ２ H ５ ) ２ 、-NH-C(=NH)-N(C ３ H ７ ) ２ 、-NH-C(=NH)-N(シクロ-C ３ H ５ ) ２ 、-O-CO-NHC ３ H ７ 、-NH-C(=NH)-N[CH(CH ３ ) ２ ] ２ 、-NH-C(=NH)-N[C(CH ３ ) ３ ] ２ 、-O-CO-NH ２ 、-O-CO-NHCH ３ 、-O-CO-NHC ２ H ５ 、-O-CO-NH[C(CH ３ ) ３ ]、-O-CO-N(CH ３ ) ２ 、-O-CO-N(C ２ H ５ ) ２ 、-O-CO-N(C ３ H ７ ) ２ 、-O-CO-N(シクロ-C ３ H ５ ) ２ 、-O-CO-N[CH(CH ３ ) ２ ] ２ 、-O-CO-N[C(CH ３ ) ３ ] ２ 、-O-CO-OCH ３ 、-O-CO-OC ２ H ５ 、-O-CO-OC ３ H ７ 、-O-CO-O-シクロ-C ３ H ５ 、-O-CO-OCH(CH ３ ) ２ 、-O-CO-OC(CH ３ ) ３ 、-CH ２ F、-CHF ２ 、-CF ３ 、-CH ２ -CH ２ F、-CH ２ -CHF ２ 、-CH ２ -CF ３ 、シクロ-C ８ H １５ 、-Ph、-CH ２ -Ph、-CH ２ -CH ２ -Ph、-CH=CH-Ph、-CPh ３ 、-CH ３ 、-C ２ H ５ 、-C ３ H ７ 、-CH(CH ３ ) ２ 、-C ４ H ９ 、-CH ２ -CH(CH ３ ) ２ 、-CH(CH ３ )-C ２ H ５ 、-C(CH ３ ) ３ 、-C ５ H １１ 、-CH(CH ３ )-C ３ H ７ 、-CH ２ -CH(CH ３ )-C ２ H ５ 、-CH(CH ３ )-CH(CH ３ ) ２ 、-C(CH ３ ) ２ -C ２ H ５ 、-CH ２ -C(CH ３ ) ３ 、-CH(C ２ H ５ ) ２ 、-C ２ H ４ -CH(CH ３ ) ２ 、-C ６ H １３ 、-C ７ H １５ 、-C ８ H １７ 、-C ３ H ６ -CH(CH ３ ) ２ 、-C ２ H ４ -CH(CH ３ )-C ２ H ５ 、-CH(CH ３ )-C ４ H ９ 、-CH ２ -CH(CH ３ )-C ３ H ７ 、-CH(CH ３ )-CH ２ -CH(CH ３ ) ２ 、-CH(CH ３ )-CH(CH ３ )-C ２ H ５ 、-CH ２ -CH(CH ３ )-CH(CH ３ ) ２ 、-CH ２ -C(CH ３ ) ２ -C ２ H ５ 、-C(CH ３ ) ２ -C ３ H ７ 、-C(CH ３ ) ２ -CH(CH ３ ) ２ 、-C ２ H ４ -C(CH ３ ) ３ 、-CH(CH ３ )-C(CH ３ ) ３ 、-CH=CH ２ 、-CH ２ -CH=CH ２ 、-C(CH ３ )=CH ２ 、-CH=CH-CH ３ 、-C ２ H ４ -CH=CH ２ 、-CH ２ -CH=CH-CH ３ 、-CH=CH-C ２ H ５ 、-CH ２ -C(CH ３ )=CH ２ 、-CH(CH ３ )-CH=CH、-CH=C(CH ３ ) ２ 、-C(CH ３ )=CH-CH ３ 、-CH=CH-CH=CH ２ 、-C ３ H ６ -CH=CH ２ 、-C ２ H ４ -CH=CH-CH ３ 、-CH ２ -CH=CH-C ２ H ５ 、-CH=CH-C ３ H ７ 、-CH=CH-CH=CH-CH ３ 、-C ２ H ４ -C(CH ３ )=CH ２ 、-CH ２ -CH(CH ３ )-CH=CH ２ 、-CH(CH ３ )-CH ２ -CH=CH ２ 、-CH ２ -CH=C(CH ３ ) ２ 、-CH ２ -C(CH ３ )=CH-CH ３ 、-CH(CH ３ )-CH=CH-CH ３ 、-CH=CH-CH(CH ３ ) ２ 、-CH=C(CH ３ )-C ２ H ５ 、-C(CH ３ )=CH-C ２ H ５ 、-C(CH ３ )=C(CH ３ ) ２ 、-C(CH ３ ) ２ -CH=CH ２ 、-CH(CH ３ )-C(CH ３ )=CH ２ 、-C ４ H ８ -CH=CH ２ 、-C ３ H ６ -CH=CH-CH ３ 、-C ２ H ４ -CH=CH-C ２ H ５ 、-CH ２ -CH=CH-C ３ H ７ 、-CH=CH-C ４ H ９ 、-C ３ H ６ -C(CH ３ )=CH ２ 、-C ２ H ４ -CH(CH ３ )-CH=CH ２ 、-CH ２ -CH(CH ３ )-CH ２ -CH=CH ２ 、-C ２ H ４ -CH=C(CH ３ ) ２ 、-CH(CH ３ )-C ２ H ４ -CH=CH ２ 、-C ２ H ４ -C(CH ３ )=CH-CH ３ 、-CH ２ -CH(CH ３ )-CH=CH-CH ３ 、-CH(CH ３ )-CH ２ -CH=CH-CH ３ 、-CH ２ -CH=CH-CH(CH ３ ) ２ 、-CH ２ -CH=C(CH ３ )-C ２ H ５ 、-CH ２ -C(CH ３ )=CH-C ２ H ５ 、-CH(CH ３ )-CH=CH-C ２ H ５ 、-CH=CH-CH ２ -CH(CH ３ ) ２ 、-CH=CH-CH(CH ３ )-C ２ H ５ 、-CH=C(CH ３ )-C ３ H ７ 、-C(CH ３ )=CH-C ３ H ７ 、-CH ２ -CH(CH ３ )-C(CH ３ )=CH ２ 、-C[C(CH ３ ) ３ ]=CH ２ 、-CH(CH ３ )-CH ２ -C(CH ３ )=CH ２ 、-CH(CH ３ )-CH(CH ３ )-CH=CH ２ 、-CH=CH-C ２ H ４ -CH=CH ２ 、-C(CH ３ ) ２ -CH ２ -CH=CH ２ 、-CH ２ -C(CH ３ )=C(CH ３ ) ２ 、-CH(CH ３ )-CH=C(CH ３ ) ２ 、-C(CH ３ ) ２ -CH=CH-CH ３ 、-CH=CH-CH ２ -CH=CH-CH ３ 、-CH(CH ３ )-C(CH ３ )=CH-CH ３ 、-CH=C(CH ３ )-CH(CH ３ ) ２ 、-C(CH ３ )=CH-CH(CH ３ ) ２ 、-C(CH ３ )=C(CH ３ )-C ２ H ５ 、-CH=CH-C(CH ３ ) ３ 、-C(CH ３ ) ２ -C(CH ３ )=CH ２ 、-CH(C ２ H ５ )-C(CH ３ )=CH ２ 、-C(CH ３ )(C ２ H ５ )-CH=CH ２ 、-CH(CH ３ )-C(C ２ H ５ )=CH ２ 、-CH ２ -C(C ３ H ７ )=CH ２ 、-CH ２ -C(C ２ H ５ )=CH-CH ３ 、-CH(C ２ H ５ )-CH=CH-CH ３ 、-C(C ４ H ９ )=CH ２ 、-C(C ３ H ７ )=CH-CH ３ 、-C(C ２ H ５ )=CH-C ２ H ５ 、-C(C ２ H ５ )=C(CH ３ ) ２ 、-C[CH(CH ３ )(C ２ H ５ )]=CH ２ 、-C[CH ２ -CH(CH ３ ) ２ ]=CH ２ 、-C ２ H ４ -CH=CH-CH=CH ２ 、-CH ２ -CH=CH-CH ２ -CH=CH ２ 、-C ３ H ６ -C≡C-CH ３ 、-CH ２ -CH=CH-CH=CH-CH ３ 、-CH=CH-CH=CH-C ２ H ５ 、-CH(CH ３ )-CH ２ -C≡CH、-CH(CH ３ )-C≡C-CH ３ 、-C ２ H ４ -CH(CH ３ )-C≡CH、-CH=CH-CH=C(CH ３ ) ２ 、-CH ２ -CH(CH ３ )-CH ２ -C≡CH、-CH=CH-C(CH ３ )=CH-CH ３ 、-CH=C( CH ３ )-CH=CH-CH ３ 、-CH ２ -CH(CH ３ )-C≡CH、-C(CH ３ )=CH-CH=CH-CH ３ 、-C≡CH、-C≡C-CH ３ 、-CH ２ -C≡CH、-C ２ H ４ -C≡CH、-CH ２ -C≡C-CH ３ 、-C≡C-C ２ H ５ 、-C ３ H ６ -C≡CH、-C ２ H ４ -C≡C-CH ３ 、-CH ２ -C≡C-C ２ H ５ 、-C≡C-C ３ H ７ 、-CH(CH ３ )-C≡CH、-C ４ H ８ -C≡CH、-C ２ H ４ -C≡C-C ２ H ５ 、-CH ２ -C≡C-C ３ H ７ 、-C≡C-C ４ H ９ 、-C≡C-CH ２ -CH(CH ３ ) ２ 、-CH(CH ３ )-C ２ H ４ -C≡CH、-CH ２ -CH(CH ３ )-C≡C-CH ３ 、-C(CH ３ )(C ２ H ５ )-C≡CH、-CH(CH ３ )-CH ２ -C≡C-CH ３ 、-CH(CH ３ )-C≡C-C ２ H ５ 、-CH ２ -C≡C-CH(CH ３ ) ２ 、-C≡C-CH(CH ３ )-C ２ H ５ 、-CH ２ -C≡C-C≡C-CH ３ 、-CH(C ２ H ５ )-C≡C-CH ３ 、-C(CH ３ ) ２ -C≡C-CH ３ 、-CH(C ２ H ５ )-CH ２ -C≡CH、-CH ２ -CH(C ２ H ５ )-C≡CH、-C(CH ３ ) ２ -CH ２ -C≡CH、-CH ２ -C(CH ３ ) ２ -C≡CH、-CH(CH ３ )-CH(CH ３ )-C≡CH、-CH(C ３ H ７ )-C≡CH、-CH ２ -CH(C≡CH) ２ 、-C≡C-C≡CH、-CH ２ -C≡C-C≡CH、-C≡C-C≡C-CH ３ 、-CH(C≡CH) ２ 、-C ２ H ４ -C≡C-C≡CH、-CH ２ -C≡C-CH ２ -C≡CH、-C≡C-C ２ H ４ -C≡CH、-C≡C-C(CH ３ ) ３ 、-C≡C-CH ２ -C≡C-CH ３ 、-C≡C-C≡C-C ２ H ５ 、 【Chemistry 12】 represents; Z ３ and Z ４ together 【Chemistry 13】 may form Z １３ and Z １４ together 【Chemistry 14】 may form m is an integer selected from 0, 1, 2, 3, 4, 5, or 6; n is an integer selected from 0, 1, 2, 3, 4, 5, or 6; p is an integer selected from 0, 1, 2, 3, 4, 5, or 6; r is an integer selected from 0, 1, 2, 3, or 4; s is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; t is an integer selected from 1, 2, 3, or 4; u is an integer selected from 1, 2, 3, or 4; v is an integer selected from 0, 1, 2, 3, 4, 5, or 6; w is an integer selected from 0, 1, 2, 3, 4, 5, or 6; A compound of general formula (I) or an enantiomer, stereoisomer, mixture of enantiomers, diastereomer, mixture of diastereomers, hydrate, solvate, acid salt form, tautomer, racemate of said compound, or a pharmaceutically acceptable salt thereof.

2. 2. The compound of claim 1, wherein R ８ teeth 【Chemistry 15-1】 【change】 【Chemistry 15-2】 represents; In the formula, R Ｎ１ , Z １ , Z ２ , Z ６ , Z ７ , Z ８ , Z ９ , and Z １０ has the same meaning as defined in claim 1, compound.

3. 2. The compound of claim 1, wherein R ９ teeth 【Chemistry 16】 represents In the formula, R Ｎ１ , Z １ , Z ２ , Z ６ , Z ７ , Z ８ , Z ９ , and Z １０ has the same meaning as defined in claim 1, compound.

4. 2. The compound according to claim 1, wherein A is -CO-NH-, -CO-N(CH ３ ) -, 【Chemistry 17】 and / or In the formula, -X 2 -AX 1 - is 【Chemistry 18】 Represents, compound.

5. 2. The compound of claim 1, wherein R １ is -CH ３ , -CH ２ CH ２ -CH(CH ３ ) ２ , -CH ２ CH ２ -C≡CH, 【Chemistry 19】 and / or In the formula, B is -H, -NH 2 , -NHCOCH 3 , -NHCOC(CH 3 ) 3 , -NHCOC(CN)(CH 3 ) 2 , -NHCOCH=CH 2 , -NHCOCH 2 C(CH 3 ) 3 , -NHCOPh, -NHCOCH 2 Ph, -NHCOCH 2 -NH(CH 3 ), -NHCOCH 2 -N(CH 3 )CO 2 tBu, -NHCOC(CH 3 ) 2 CH 2 OH, -NHCOC(CH 3 ) 2 CH 2 SH, -NHCOC(CH 3 ) 2 CH 2 NH 2 , -NHCOC(CH 3 ) 2 CH 2 F, -NHCOC(CH 3 ) 2 CF 3 , -NHCOCF 2 CH 2 OH, -NHCOCF 2 CH 2 NH 2 , -NHCOC(CH 2 CH 3 ) 2 CH 2 OH, -NHCOC(CH 3 )(CH 2 OH) 2 , -NHCOCH 2 OCH 2 CH 2 -NH(CH 3 ), -NHCOCH 2 OCH 2 CH 2 -N(CH 3 )CO 2 tBu, -NHCO(CH 2 CH 2 O) 2 CH 3 , -NHCO 2 CH 2 CH 3 , -NHCO 2 (CH 2 CH 2 O) 3 CH 3 , -NHCO 2 (CH 2 CH 2 O) 5 CH 3 , -NHCO 2 (CH 2 CH 2 O) 7 CH 3 , -NHCO 2 CH 2 Ph -NHCONHCH 2 CH 3 , -NHSO 2 CH 3 , -NHSO 2 CH=CH 2 , -NHSO 2 CH 2 Ph, -NHSO 2 CH 2 CH 2 Ph, -NHSO2CH2CH2CH2Ph, -NHSO2CH2CF3, -NHCH2CF3, -NHCH2(CH3)2NH2, -NHCH2(CH3)2CH2OH, 【Chemistry 20-1】 【Chemistry 20-2】 【Chemistry 20-3】 【Chemistry 20-4】 【Chemistry 20-5】 【Chemistry 20-6】 Represents, compound.

6. 2. The compound according to claim 1, wherein the compound is represented by formulas (II-1) to (II-16), (III-1) to (III-10), (IV-1) to (IV-10), and (V-1) to (V-9): 【Chemistry 21-1】 【Chemistry 21-2】 【Chemistry 21-3】 【Chemistry 21-4】 【Chemistry 21-5】 【Chemistry 21-6】 and In the formula, A, B, R １ , R ２ , R ４ , R ８ , R ９ , R １２ , R １３ , R Ｎ１ , R Ｎ４ , X １ , X ２ , Z １ , Z ２ , Z ３ , Z ４ , Z ５ , and Z ８ has the same meaning as defined in claim 1, compound. 【Request 7】 【Chemical 22-1】 【Chemistry 22-2】 【Chemistry 22-3】 【Chemistry 22-4】 【Chemistry 22-5】 【Chemistry 22-6】 【Chemistry 22-7】 【Chemistry 22-8】 【Chemistry 22-9】 【Hua 22-10】 【Chemistry 22-11】 【Hua 22-12】 【Chemistry 22-13】 【Chemistry 22-14】 【Hua 22-15】 【Chemistry 22-16】 【Hua 22-17】 【Hua 22-18】 【Chemistry 22-19】 【Hua 22-20】 【Chemistry 22-21】 【Hua 22-22】 【Chemistry 22-23】 【Chemistry 22-24】 【Hua 22-25】 【Chemistry 22-26】 【Hua 22-27】 【Hua 22-28】 【Chemistry 22-29】 【22-30】 【Chemistry 22-31】 【Hua 22-32】 【Chemistry 22-33】 【Chemistry 22-34】 【Hua 22-35】 【Hua 22-36】 【Hua 22-37】 【Hua 22-38】 【Hua 22-39】 【Chemistry 22-40】 【Chemistry 22-41】 【Hua 22-42】 【Chemistry 22-43】 【22-44】 【Chemistry 22-45】 【Hua 22-46】 【Hua 22-47】 【22-48】 【Chemistry 22-49】 【Chemistry 22-50】 【Hua 22-51】 【Hua 22-52】 【Hua 22-53】 【Hua 22-54】 【Hua 22-55】 【Hua 22-56】 【Hua 22-57】 【Hua 22-58】 【Hua 22-59】 【Hua 22-60】 【Hua 22-61】 【Hua 22-62】 【Hua 22-63】 【Hua 22-64】 【Hua 22-65】 【Hua 22-66】 【Hua 22-67】 【Hua 22-68】 【Hua 22-69】 【Hua 22-70】 【Hua 22-71】 【Hua 22-72】 【Hua 22-73】 【Hua 22-74】 【Hua 22-75】 【Hua 22-76】 【Hua 22-77】 2. The compound of claim 1 selected from the group consisting of: or an enantiomer, stereoisomer, mixture of enantiomers, diastereomer, mixture of diastereomers, hydrate, solvate, acid salt form, tautomer, racemate, or pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising as an active ingredient at least one compound according to any one of claims 1 to 7, together with at least one pharmaceutically acceptable carrier, excipient and / or diluent.

9. A compound according to any one of claims 1 to 7 for use as a medicament.

10. A compound according to any one of claims 1 to 7 for use in the prevention and / or treatment of a disease associated with and / or caused by the proteasome or immunoproteasome selected from cancer, infectious diseases, inflammatory diseases, autoimmune diseases and transplant rejection.

11. The pharmaceutical composition of claim 8 for use in the prevention and / or treatment of a disease associated with and / or caused by the proteasome or immunoproteasome selected from cancer, infectious diseases, inflammatory diseases, autoimmune diseases, and transplant rejection.

12. The cancers include adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neuroma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial cancer, non-small cell lung cancer (NSCLC), breast cancer, Burkitt's lymphoma, endometrial cancer, corpus cancer, CUP syndrome (cancer of unknown primary origin), colon cancer, small intestine cancer, small intestine tumor, ovarian cancer, endometrial cancer, ependymoma, epithelial carcinoma type, Ewing's tumor, gastrointestinal tumor, stomach cancer, gallbladder ... bladder cancer, uterine cancer, cervical cancer, glioblastoma, gynecological tumors, ear, nose, and throat tumors, hematological tumors, hairy cell leukemia, urethral cancer, skin cancer, skin testicular cancer, brain tumors (gliomas), brain metastases, testicular cancer, pituitary tumors, carcinoid, Kaposi's sarcoma, laryngeal cancer, germ cell tumors, bone cancer, colorectal cancer, head and neck tumors (tumors of the ear, nose, and throat area), colon cancer, Craniopharyngioma, oral cancer (cancer of the mouth area and lips), cancer of the central nervous system, liver cancer, liver metastases, leukemia, eyelid tumors, lung cancer, lymph node cancer (Hodgkin's / non-Hodgkin's), lymphoma, stomach cancer, malignant melanoma, malignant neoplasms, malignant tumors of the digestive tract, breast cancer, rectal cancer, medulloblastoma, melanoma, meningioma, Hodgkin's disease, mycosis fungoides, nasal cancer, schwannoma, neuroblastoma, kidney cancer, renal cell carcinoma, non-Hodgkin's lymphoma, oligodendroglioma, esophageal cancer, osteolytic and osteogenic carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, plasmacytoma, squamous cell carcinoma of the head and neck (SCCHN), prostate cancer, pharyngeal cancer, rectal cancer, retinoblastoma, vaginal cancer, thyroid cancer, Schneeberger's disease, esophageal cancer, spinal cord tumor, T-cell lymphoma (mycosis fungoides), thymoma, ductal carcinoma, eye tumor, urethral cancer, urinary tract tumor, urothelial carcinoma, vulvar cancer, wart appearance, soft tissue tumor, soft tissue sarcoma, Wilms' tumor, cervical cancer, tongue cancer, astrocytoma, bronchial carcinoma, laryngeal cancer, malignant melanoma, esophageal cancer, bile duct carcinoma, and renal cell carcinoma, preferably, said cancer is leukemia, multiple myeloma, mantle cell lymphoma (MCL), breast cancer, colorectal cancer, non-small cell lung cancer, or ovarian cancer. A pharmaceutical composition for use according to claim 11.

13. The infectious diseases include HIV, echinococcosis, amebiasis (entamoeba histolytica infection), angiostrongylus infection, anisakiasis, anthrax, babesiosis (babesia infection), balantidium infection (balantidiosis), baylisascaris infection (raccoon roundworm), bilharziasis (schistosomiasis), Blastocystis hominis infection (blastomycosis), borreliosis, botulism, Brainard's diarrhea, brucellosis, BSE (bovine spongiform encephalopathy), candidiasis, capillary worm infection, CFS (chronic fatigue syndrome), Chagas disease (American trypanosomiasis), chickenpox (varicella-zoster virus), chlamydia pneumonia infection, cholera, CJD (Creutzfeldt-Jakob disease), clonorchiasis (liver fluke infection), CLM ( Cutaneous larva migrans, hookworm infection), coccidioid mycosis, conjunctivitis, Coxsackievirus A16 (hand, foot, and mouth disease), cryptococcosis, cryptosporidium infection, Culex pipiens mosquito (vector of West Nile virus), cyclosporiasis (Cyclospora infection), cysticercosis (neurocysticercosis), cytomegalovirus infection, dengue fever Fever), Dipyridium infection (dog and cat flea tapeworms), Ebola virus hemorrhagic fever, Echinococcosis (alveolar hydatid disease), Encephalitis, Entamoeba coli infection, Entamoeba dispar infection, Entamoeba hartmannii infection, Entamoeba histolytica infection (amebiasis), Entamoeba pollecki infection, Pinworm infection (pinworm infection), Enterovirus infection (non-polio), Epstein-Barr virus infection, E. coli infection, Foodborne infection, Foot and mouth disease, Fungal dermatitis, Gastroenteritis, Group A streptococcal infection, Group B streptococcal infection, Hansen's disease (leprosy), Hantavirus pulmonary syndrome, Head lice infestation (pediculosis), Helicobacter pylori infection, Blood disorders, Hendra virus infection, Hepatitis (HCV, HBV), Shingles (Herpes zoster)Zoster (Shingles), human ehrlichiosis, human parainfluenza virus infection, influenza, isosporiasis (Isospora infection), Lassa fever, leishmaniasis, kala-azar (Kala-azar, Leishmania infection), leprosy, lice (body lice, head lice, pubic lice), Lyme disease, malaria, Marburg hemorrhagic fever, measles, meningitis, mosquito-borne diseases, Mycobacterium avium complex (MAC) infection, Naegleria infection, hospital-acquired infections, non-pathogenic intestinal ameba infections, onchocerciasis (river blindness), opisthorchiasis (opisthorchiasis infection), parvovirus infection, plague, PCP (Pneumocystis typhimurium) 12. The pharmaceutical composition for use according to claim 11, wherein the antiviral agent is selected from the group consisting of: pneumonia (carinii pneumonia), polio, Q fever, rabies, respiratory syncytial virus (RSV) infection, rheumatic fever, Rift Valley fever, rotavirus infection, roundworm infection, salmonellosis, salmonellosis enteritidis, scabies, bacterial erythroderma, shingles, sleeping sickness, smallpox, streptococcal infection, tapeworm infection (taenia infection), tetanus, toxic shock syndrome, tuberculosis, ulcers (peptic ulcer disease), Valley fever, Vibrio parahaemolyticus infection, Vibrio vulnificus infection, viral hemorrhagic fever, warts, waterborne infections, West Nile virus infection (West Nile encephalitis), whooping cough, and yellow fever.

14. The autoimmune diseases include achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Baro's disease, Behcet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, catarrh, and the like. Suleman's disease (CD), celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS), eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devics' disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia , Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid of gestationis (PG), sweat gland tumor (HS) (inverse acne), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus ( Type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear immunoglobulin A disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myelin oligodendrocyte glycoprotein antibody disorder, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis,Relapsing rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Paroxysmal Romberg's syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, II, III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cholangitis, primary sclerosing cholangitis, progestational dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, spermatozoa and 12. The pharmaceutical composition for use according to claim 11, wherein the autoimmune disease is selected from the group consisting of testicular autoimmunity, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), thyroid eye disease (TED), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, and Vogt-Koyanagi-Harada disease, and preferably, the autoimmune disease is selected from lupus nephritis, lupus, systemic lupus erythematosus, myasthenia gravis, multiple sclerosis, polyarthritis, rheumatoid arthritis, irritant hypersensitivity, psoriasis, asthma, and colitis.

15. A process for producing a compound of formula (I) comprising: Step 1A: Intermediate Compound (I-1 ＊ ) to provide: 【Chemical 23】 In the formula, A, B, R １ , R ３ , R ４ , R ５ , R ６ , X １ , and X ２ has the same meaning as defined in formula (I) of claim 1; Step 2A: Intermediate Compound (I-1 ＊ ) to carry out an intramolecular amide coupling reaction between the carboxylic acid group and the amine group of the compound of formula (I): 【Chemistry 24】 or A process for producing a compound of formula (I) comprising: Step 1B: Intermediate Compound (I-2 ＊ ) to provide: 【Chemistry 25】 During the ceremony, A ＊ は、-NH(R Ｎ６ )-、 【Chemical 26】 represents L ＊ is -CO ２ represents H, and B., R. １ , R ３ , R ４ , R ５ , R ６ , R Ｎ６ , X １ , X ２ , Z １３ , and Z １４ has the same meaning as defined in formula (I) of claim 1; Step 2B: Intermediate Compound (I-2 ＊ ) L ＊ and A ＊ carrying out an intramolecular amide coupling reaction with the amino group of the moiety to obtain a compound of formula (I); or A process for producing a compound of formula (I) comprising: Step 1C: Intermediate Compound (I-3 ＊ ) to provide: 【Chemical 27】 During the ceremony, A, B, R １ , R ３ , R ４ , R ５ , R ６ , X １ , and X ２ has the same meaning as defined in formula (I) of claim 1; Step 2C: R １ Intermediate compound (I-3) having —CHO ＊ ) and aqueous ammonia (NH ３ ) to obtain a compound of formula (I): method.

16. Compound I-1 ＊ , I-2 ＊ , and I-3 ＊ an intermediate compound selected from: 【Chemical 28】 During the ceremony, A ＊ は、-NH(R Ｎ６ )-、 【Chemical 29】 represents; L ＊ is -CO ２ represents H; and A, B, R １ , R ３ , R ４ , R ５ , R ６ , R Ｎ６ , X １ , X ２ , Z １３ , and Z １４ has the same meaning as defined in formula (I) of claim 1, Intermediate compounds.

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