Novel compounds and composition for targeted therapy of kidney-associated cancers

A compound of the following formula I

• or a pharmaceutically acceptable salt, solvate, or hydrate thereof wherein:
• R1 and R2 are optional groups, with at least one of the groups R1 and R2 being present in the formula I;
• and
• R1 and R2 are independently selected from alkyl, aryl, biaryl, heteroaryl, heteroarylaryl, and arylheteroaryl;
• or
• R1 and R2 are groups independently attached to X and Z, respectively, by subtracting a single or multiple H atom(s) from respective parent (precursor) structure(s) (H)nR and (H)oR2 at any one of the following optional H-containing group(s) independently selected from NH, OH, SH, C(═O)OH, CONH, SO2NH, and S(═O)NH when present in (H)nR and (H)oR2;
• and wherein
• a) (H)nR and (H)oR2 are independently compound(s) possessing biological or therapeutic activity;
• or
• b) (H)nR and (H)oR2 are independently a cytotoxic compound(s), an antibody(ies), or an immunomodulating compound(s) possessing an activity or capable of inducing an activity against one or more cancer cells;
• or
• c) (H)nR1 and (H)oR2 are independently mono- or multi-valent antibody(ies) with activity against one or more cancer cells;
• or
• d) (H)nR1 and (H)oR2 are independently afatinib ((E)-N-[4-(3-chloro-4-fluoroanilino)-7-[(3S)-oxolan-3-yl]oxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide), ARS-1630 ((R)-1-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one), axitinib (N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide), BGB-324 (1-(6,7-dihydro-5H-benzo[2,3]cyclohepta[2,4-d]pyridazin-3-yl)-3-N-[(7S)-7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl]-1,2,4-triazole-3,5-diamine), BLU-554 (N-[(3S,4S)-3-[[6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl]amino]oxan-4-yl]prop-2-enamide), brivanib ((S)—(R)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propan-2-yl 2-aminopropanoate), (R)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propan-2-ol, cabozantinib, cediranib, ceritinib, ciforadenant, derazantinib, dovitinib (4-amino-5-fluoro-3-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)quinolin-2(1H)-one), E-7046 (4-[(1S)-1-[[3-(difluoromethyl)-1-methyl-5-[3-(trifluoromethyl)phenoxy]pyrazole-4-carbonyl]amino]ethyl]benzoic acid), emtansine, englerin ((1R,3aR,4S,5R,7R,8S,8aR)-5-(glycoloyloxy)-7-isopropyl-1,4-dimethyldecahydro-4,7-epoxyazulen-8-yl (2E)-3-phenylacrylate), foretinib, lenvatinib (4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide), monomethyl auristatin E ((S)—N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide), irinotecan, maytansinoid, neratinib, nilotinib, nintedanib, ozogamicin, paclitaxel, pazopanib (5-[[4-[(2,3-dimethylindazol-6-yl)-methylamino]pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide), regorafenib, sacituzumab, selpercatinib, semaxanib ((Z)-3-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)indolin-2-one), sorafenib (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide), sunitinib ((Z)—N-(2-(diethylamino)ethyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide), SN38 (same 7-ethyl-10-hydroxy-camptothecin), trastuzumab, tesirine ([4-[[(2S)-2-[[(2S)-2-[3-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]-3-methylbutanoyl]amino]propanoyl]amino]phenyl]methyl (6S,6aS)-3-[5-[[(6aS)-2-methoxy-8-methyl-11-oxo-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]pentoxy]-6-hydroxy-2-methoxy-8-methyl-11-oxo-6a,7-dihydro-6H-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate), temsirolimus ([(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl]3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate), tivantinib, tivozanib (1-{2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-(5-methylisoxazol-3-yl)urea), vatalanib, veliparib, or vinblastine;
• or variants of aforementioned structures derived from these by modification(s) of said structure(s);
• or
• e) (H)nR1 and (H)oR2 are independently compound(s) active against a kidney cancer disease;
• or
• f) (H)nR1 is a heterocyclic structure(s) connected to X at one of heterocyclic nitrogen atom(s) present within the structure (H)nR1;
• wherein said nitrogen atom becomes a nitrogen atom with a single positive charge, such as imidazolium, pyrazolium, pyridinium, or indazolium group;
• and
• when an optional group R1 is absent, then the fragment R1X is replaced with R11a, wherein R11a is selected from H, Alk, C3-7cycloalkyl, 5- to 6-membered heterocyclyl, aryl, biaryl, heteroaryl, AlkC(═O), AlkOC(═O), AlkNHC(═O), AlkN(C1-12alkyl)C(═O), AlkSO2, AlkNHSO2, C3-7cycloalkylC(═O), C3-7cycloalkylOC(═O), C3-7cycloalkylNHC(═O), C3-7cycloalkylN(C1-12alkyl)C(═O), arylC(═O), arylOC(═O), arylNHC(═O), arylN(C1-12alkyl)C(═O), arylSO2, arylNHSO2, heteroarylC(═O), heteroarylOC(═O), heteroarylNHC(═O), heteroaryl N(C1-12alkyl)C(═O), heteroarylSO2, and heteroarylNHSO2;
• or wherein
• when an optional group R2 is absent, then the fragment R2Z is replaced with R12a, wherein R12a is selected from H, Alk, C3-7cycloalkyl, 5- to 6-membered heterocyclyl, aryl, biaryl, heteroaryl, AlkC(═O), AlkOC(═O), AlkNHC(═O), AlkN(C1-12alkyl)C(═O), AlkSO2, AlkNHSO2, C3-7cycloalkylC(═O), C3-7cycloalkylOC(═O), C3-7cycloalkylNHC(═O), C3-7cycloalkylN(C1-12alkyl)C(═O), arylC(═O), arylOC(═O), arylNHC(═O), arylN(C1-12alkyl)C(═O), arylSO2, arylNHSO2, heteroarylC(═O), heteroarylOC(═O), heteroarylNHC(═O), heteroaryl N(C1-12alkyl)C(═O), heteroarylSO2, and heteroarylNHSO2;
• or wherein
• integers n and o are independently selected from 0, 1, 2, 3, 4, 5, 6, and 7, such that [n+o]≥1;
• and
• A1 through A11 are optional amino acid residues independently selected from unsubstituted or substituted at any N atom alpha-, beta-, or gamma-amino acids, Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, L-homoserine, Thr, Trp, Tyr, Val, D-Ala, D-Arg, D-Asn, D-Asp, D-Cys, D-Glu, D-Gln, D-His, D-Ile, D-Leu, D-Lys, D-Met, D-Phe, D-Pro, D-Ser, D-homoserine, D-Thr, D-Trp, D-Tyr, D-Val, 3-aminoproline, 4-aminoproline, biphenylalanine (Bip), D-Bip, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), 2,5-diaminopentanoic acid, azetidine-2-carboxylic acid, azetidine-3-carboxylic acid, piperidine-2-carboxylic acid, 6-aminopiperidine-2-carboxylic acid, 5-aminopiperidine-2-carboxylic acid, 4-aminopiperidine-2-carboxylic acid, 3-aminopiperidine-2-carboxylic acid, piperidine-3-carboxylic acid, 6-aminopiperidine-3-carboxylic acid, 5-aminopiperidine-3-carboxylic acid, 4-aminopiperidine-3-carboxylic acid, piperazine-2-carboxylic acid, 6-aminopiperazine-2-carboxylic acid, 8-azabicyclo[3.2.1]octane-2-carboxylic acid, 4-amino-8-azabicyclo[3.2.1]octane-2-carboxylic acid, 3-amino-8-azabicyclo[3.2.1]octane-2-carboxylic acid, 6-azabicyclo[3.1.1]heptane-2-carboxylic acid, 3-amino-6-azabicyclo[3.1.1]heptane-2-carboxylic acid, and 4-amino-6-azabicyclo[3.1.1]heptane-2-carboxylic acid, 4-amino-3-arylbutanoic acid, 4-amino-3-(3-chlorophenyl)butanoic acid;
• and 5-amino-4-arylpentanoic acid;
• A12, A13, A14, and A15 are independently unsubstituted or substituted at any N atom alpha-, beta-, or gamma-amino acids, Ala, Arm, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, L-homoserine, Thr, Trp, Tyr, Val, D-Ala, D-Arm, D-Asn, D-Asp, D-Cys, D-Glu, D-Gln, D-His, D-Ile, D-Leu, D-Lys, D-Met, D-Phe, D-Pro, D-Ser, D-homoserine, D-Thr, D-Trp, D-Tyr, D-Val, 3-aminoproline, 4-aminoproline, biphenylalanine (Bip), D-Bip, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), 2,5-diaminopentanoic acid, azetidine-2-carboxylic acid, azetidine-3-carboxylic acid, piperidine-2-carboxylic acid, 6-aminopiperidine-2-carboxylic acid, 5-aminopiperidine-2-carboxylic acid, 4-aminopiperidine-2-carboxylic acid, 3-aminopiperidine-2-carboxylic acid, piperidine-3-carboxylic acid, 6-aminopiperidine-3-carboxylic acid, 5-aminopiperidine-3-carboxylic acid, 4-aminopiperidine-3-carboxylic acid, piperazine-2-carboxylic acid, 6-aminopiperazine-2-carboxylic acid, 8-azabicyclo[3.2.1]octane-2-carboxylic acid, 4-amino-8-azabicyclo[3.2.1]octane-2-carboxylic acid, 3-amino-8-azabicyclo[3.2.1]octane-2-carboxylic acid, 6-azabicyclo[3.1.1]heptane-2-carboxylic acid, 3-amino-6-azabicyclo[3.1.1]heptane-2-carboxylic acid, and 4-amino-6-azabicyclo[3.1.1]heptane-2-carboxylic acid, 4-amino-3-arylbutanoic acid, 4-amino-3-(3-chlorophenyl)butanoic acid, or 5-amino-4-arylpentanoic acid, or similar natural or unnatural amino acid residues;
• integers a through m are independently selected from 0, 1, and 2, and wherein
• [m+l]≥1, wherein the symbol “l” in [m+l] and at the group [R1—X]l represents a letter “l”;
• and wherein
• when any of integers a through k is 0, then any of the two groups adjacent to a respective absent group (according to the integer 0 at said absent group) are connected to each other directly;
• and wherein
• when the integers a through g are all 0, then the groups A1-A7 are absent, and the group A8 terminates with either COOH, CH2OH, or C(═O)NR3R4, wherein R3 and R4 are independently selected from H, alkyl, aryl, heteroaryl, and heterocyclyl;
• or the group A8 is directly connected to the group Y;
• and
• each optional divalent group X is independently selected from O, NH, N(C1-6alkyl), S, S—S, S—N, S(═O), SO2, C(═O), OC(═O), C(═O)O, NHC(═O)NH, N(C1-6alkyl)C(═O)NH, N(C1-6alkyl)C(═O)NC1-6alkyl), NHC(═O)NC1-6alkyl), C1-12alkylene, arylene, biarylene, (heteroaryl)arylene, (aryl)heteroarylene, heterocyclylene,
• (C1-12alkylene)C(═O)O, OC(═O)(C1-12alkylene),
• (C1-12alkylene)OC(═O), C(═O)O(C1-12alkylene),
• (C1-12alkylene)C(═O)N(R5a), N(R5a)C(═O)(C1-12alkylene),
• (C1-12alkylene)N(R5a)C(═O), C(═O)N(R5a)(C1-12alkylene),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)O(CR5R6)O(CR7R8)r(CR9R10)sC(═O),
• P(═O)(OCR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR7R8)p(CR9R10)rP(═O)(OCR5R6)m,
• P(═O)(NHCR5R6)p(CR7R8)r(CR9R10)sC(═O),
• P(═O)(OCR5R6)CF2, P(═O)(OCR5R6)CF2(CR7R8)rC(═O),
• P(═O)(OH)CF2, P(═O)(OH)CF2(CR7R8)rC(═O),
• C(═O)(CR7R8)r(CR9R10)sP(═O)(NHCR5R6)p,
• C(═O)O(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)N(R5a)(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sOC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sN(R5a)C(═O), C(═O)CR5═CR7—(CR9R10)sC(═O),
• C(═O)OCR5═CR7—(CR9R10)sC(═O),
• C(═O)N(R5a)CR5═CR7—(CR9R10)sC(═O),
• C(═O)CR5═CR7—(CR9R10)sOC(═O),
• C(═O)CR5═CR7—(CR9R10)sN(R5a)C(═O),
• C(═O)N(R5a)SO2(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sN(R5a)SO2C(═O),
• C(═O)(CR5R6)pS—S(CR7R8)r(CR9R10)sC(═O),
• C(═O)O(CR5R6)pS—S(CR7R8)r(CR9R10)sC(═O),
• C(═O)N(R5a)(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR5R6)pS—S(CR7R8)r(CR9R10)sOC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sN(R5a)C(═O),
• C(═O)(CR5R6)p(CR7R8)rS—S(CR9R10)sC(═O),
• C(═O)O(CR5R6)p(CR7R8)rS—S(CR9R10)sC(═O),
• C(═O)N(R5a)(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR5R6)pS—S(CR7R8)rS—S(CR9R10)sOC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sN(R5a)C(═O),
• C(═O)CR5═CR7—S—S—(CR9R10)sC(═O),
• C(═O)OCR5═CR7—(CR9R10)sC(═O),
• C(═O)N(R5a)CR5═CR7—(CR9R10)sC(═O),
• C(═O)CR5═CR7—(CR9R10)sOC(═O),
• C(═O)CR5═CR7—(CR9R10)sN(R5a)C(═O),
• C(═O)N[(CR5R6)p(CR7R8)rNHC(═O)A14](CR9R10)sC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rNHC(═O)A14](CR9R10)sNHC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rNHC(═O)A14](CR9R10)sOC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rN(C1-6alkyl)C(═O)A14](CR9R10)sNHC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rN(C1-6alkyl)C(═O)A14](CR9R10)sC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rN(C1-6alkyl)C(═O)A14](CR9R10)sNHC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rN(C1-6alkyl)C(═O)A14](CR9R10)sOC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rOC(═O)A14](CR9R10)sC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rOC(═O)A14](CR9R10)sN(C═O),
• C(═O)N[(CR5R6)p(CR7R8)rOC(═O)A14](CR9R10)sO(C═O),
• C(═O)N[(CR5R6)p(CR7R8)rNHC(═O)A14A15](CR9R10)sC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rNHC(═O)A14A15](CR9R10)sN(C═O),
• C(═O)N[(CR5R6)p(CR7R8)rNHC(═O)A14A15](CR9R10)sO(C═O),
• C(═O)N[(CR5R6)p(CR7R8)rOC(═O)A14A15](CR9R10)sC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rOC(═O)A14A15](CR9R10)sN(C═O),
• C(═O)N[(CR5R6)p(CR7R8)rOC(═O)A14A15](CR9R10)sO(C═O),
• C(═O)N[(CR5R6)p(CR7R8)rNHC(═O)(CR9R10)sNCH(NH2)COOH]CH2CH2C(═O),
• C(═O)N[(CR5R6)p(CR7R8)rN(C1-6alkyl)C(═O)—(CR9R10)sNCH(NH2)COOH]CH2CH2C(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH]CH2CH2C(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOC1-6alkyl]CH2CH2C(═O)
• C(═O)N[CH2CH2OC(═O)CH2CH2CH(NH2)COOH]CH2CH2C(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH](CR5R6)p(CR7R8)rC(═O)O(CR9R10)sC(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH](CR5R6)p(CR7R8)r OC(═O)
• (CR9R10)sC(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH](CR5R6)pC(═O)O(CR7R8)r
• (CR9R10)sC(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH](CR5R6)p OC(═O)(CR7R8)r
• (CR9R10)sC(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH]CH2CH2C(═O)OCH2CH2C(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH]CH2CH2OC(═O)CH2CH2C(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH]CH2CMe2C(═O)OCH2CH2C(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH]CH2CH2OC(═O)CH(Me)-CH2C(═O),
• C(═O)N[CH2CH2N(C1-6alkyl)C(═O)CH2CH2CH(NH2)COOH]CH2CH2C(═O),
• (S)—C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH]CH2CH2C(═O),
• (R)—C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH]CH2CH2C(═O),
• (S)—C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH(C═O)R7)COOH]CH2CH2C(═O),
• (R)—C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH(C═O)R7)COOH]CH2CH2C(═O),
• (S)—C(═O)N[CH2CH2NHC(═O)CHNH(Me)]CH2CH2C(═O),
• (R)—C(═O)N[CH2CH2NHC(═O)CHNH(Me)]CH2CH2C(═O),
• (S)—C(═O)N[CH2CH2NHC(═O)CHNH(CH2CH2CH2CH2NH2)]CH2CH2C(═O),
• (R)—C(═O)N[CH2CH2NHC(═O)CHNH(CH2CH2CH2CH2NH2)]CH2CH2C(═O),
• (S)—C(═O)N[CH2CH2NHC(═O)CHNH(CH2CH2NH2)]CH2CH2C(═O), and
• (R)—C(═O)N[CH2CH2NHC(═O)CHNH(CH2CH2NH2)]CH2CH2C(═O),
• or any variant of above groups formed by repositioning(s), addition(s), or deletion(s) of the fragments C(═O), OC(═O), N(R5a)C(═O), P(═O)(OCR5R6)CF2, P(═O)(OH)CF2, or C(═O)N(R5a)SO2 therein;
• R6, R7, R8, R9, and R10 are independently H, NH, halo, NH(C1-6alkyl), NH(OC1-6alkyl), C1-14alkyl, C3-6cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl, or heteroarylalkyl;
• R5 is H, NH2, NH(C1-6alkyl), NH(OC1-6alkyl), C1-14alkyl, C3-6cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl, or heteroarylalkyl;
• R5a is H, C1-14alkyl, C3-6cycloalkyl, aryl, arylalkyl, biaryl, biarylalkyl, or heteroarylalkyl;
• or wherein
• any two of R5 through R10, together with the atom(s) to which they are attached form a 4 to 7-member saturated or unsaturated heterocycle containing at least one O atom, or containing one O atom and an additional heteroatom independently selected from N and S and wherein remaining atoms are carbon;
• or wherein
• any two of R5 through R10, together with the carbon atom(s) to which they are attached form a 4 to 7-member saturated or unsaturated C3-6cycloalkylene;
• or any of i) ii) R6 and R7, ii) R5 and R6, and iii) R9 and R10, together with the atom to which they are attached form a saturated or unsaturated C3-6cycloalkylene;
• or wherein
• any two of R5 through R10 together with the atom(s) to which they are attached form a 5 to 7-member saturated or unsaturated heterocycle wherein the ring optionally comprises an additional heteroatom selected from N, O, and S, and wherein the remaining atoms are carbon;
• or the resulting ring comprises 1,3-dioxol-2-one heterocycle;
• or wherein
• R6 and R8 together with the atom to which they are attached form a 4 to 6-member saturated heterocycle containing at least one O atom wherein the heterocycle optionally comprises an additional heteroatom selected from N, O, and S, and wherein the remaining atoms are carbon;
• or the resulting ring comprises 1,3-dioxol-2-one heterocycle;
• and wherein
• integers p, r, and s are independently selected from 0, 1, and 2;
• and wherein when fragments (CR5R6)p(CR7R8)r(CR9R10)s or (OCR5R6)p(CR7R8)r(CR9R10)s are present, then [p+r+s]≥1;
• and wherein
• when fragments (CR5R6)p(CR7R8)r or (OCR5R6)p(CR7R8)r are present, then [p+r]≥1;
• and wherein
• when fragments (CR7R8)r(CR9R10)s or (OCR7R8)r(CR9R10)s are present, then [r+s]≥1;
• or
• alternatively, each optional divalent group X is independently comprised of the following structures, optionally connected to one to two amino acid residue(s) A12 or A13:
• (C1-12alkylene)OC(═O), OC(═O)(C1-2alkylene),
• (C1-12alkylene)OC(═O), C(═O)O(C1-12alkylene),
• (C1-12alkylene)C(═O),
• N(R5a)C(═O)(C1-12alkylene),
• (C1-12alkylene)N(R5a)C(═O), C(═O)N(R5a)(C1-12alkylene),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)O(CR5R6)O(CR7R8)r(CR9R10)sC(═O),
• P(═O)(OCR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR7R8)p(CR9R10)rP(═O)(OCR5R6)m,
• P(═O)(NHCR5R6)p(CR7R8)r(CR9R10)sC(═O),
• P(═O)(OCR5R6)CF2, P(═O)(OCR5R6)CF2(CR7R8)rC(═O),
• P(═O)(OH)CF2, P(═O)(OH)CF2(CR7R8)rC(═O),
• C(═O)(CR7R8)r(CR9R10)sP(═O)(NHCR5R6)p,
• C(═O)O(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)N(R5a)(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sOC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)rN(R5a)C(═O),
• C(═O)CR5═CR7—(CR9R10)pC(═O),
• C(═O)OCR5═CR7—(CR9R10)pC(═O),
• C(═O)N(R5a)CR5═CR7—(CR9R10)rC(═O),
• C(═O)CR5═CR7—(CR9R10)sOC(═O),
• C(═O)CR5═CR7—(CR9R10)sN(R5a)C(═O),
• C(═O)N(R5a)SO2(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sN(R5a)SO2C(═O),
• C(═O)(CR5R6)pS—S(CR7R8)r(CR9R10)sC(═O),
• C(═O)O(CR5R6)pS—S(CR7R8)r(CR9R10)sC(═O),
• C(═O)N(R5a)(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR5R6)pS—S(CR7R8)r(CR9R10)sOC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sN(R5a)C(═O),
• C(═O)(CR5R6)p(CR7R8)rS—S(CR9R10)sC(═O),
• C(═O)O(CR5R6)p(CR7R8)rS—S(CR9R10)sC(═O),
• C(═O)N(R5a)(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR5R6)pS—S(CR7R8)rS—S(CR9R10)sOC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sN(R5a)C(═O),
• C(═O)CR5═CR7—S—S—(CR9R10)sC(═O),
• C(═O)OCR5═CR7—(CR9R10)pC(═O),
• C(═O)N(R5a)CR5═CR7—(CR9R10)rC(═O),
• C(═O)CR5═CR7—(CR9R10)pOC(═O),
• C(═O)CR5═CR7—(CR9R10)rN(R5a)C(═O),
• or any variant of the above X groups formed by repositioning(s), addition(s), or deletion(s) of the fragments C(═O), OC(═O), N(R5a)C(═O), P(═O)(OCR5R6)CF2, P(═O)(OH)CF2, or C(═O)N(R5s)SO2 therein;
• and wherein when both amino acid residues A12 and A13 are incorporated at the right side of above groups to comprise the group X, then residues A12 or A13 are interconnected with a peptide bond A12-A13;
• and wherein
• when an optional group X is absent, then group R1 is directly connected to one of groups A8, A9, A10, or A11;
• or
• additionally, each optional divalent group X independently incorporates additional divalent groups selected from C1-12alkylene, C2-12alkenylene, C2-12alkynylene, (CH2)pO(CH2)rO(CH2)sC(═O), (CH2)pO(CH2)rO(CH2)sOC(═O), (CH2)pO(CH2)rO(CH2)sNHC(═O), (CH2)pO(CH2)rO(CH2)sN(C1-14alkyl)C(═O), O(CH2)pO(CH2)rO(CH2)sC(═O), O(CH2)pO(CH2)rO(CH2)sOC(═O), O(CH2)pO(CH2)rO(CH2)sNHC(O), O(CH2)pO(CH2)rO(CH2)sN(C1-14alkyl)C(═O), NH(CH2)pO(CH2)rO(CH2)sC(═O), NH(CH2)pO(CH2)rO(CH2)sOC(═O), NH(CH2)pO(CH2)rO(CH2)sNHC(═O), NH(CH2)pO(CH2)rO(CH2)sN(C1-14alkyl)C(═O), N(C1-14alkyl)(CH2)nO(CH2)rO(CH2)sC(═O), N(C1-14alkyl)(CH2)pO(CH2)rO(CH2)sOC(═O), N(C1-14alkyl)(CH2)pO(CH2)rO(CH2)sNHC(═O), and N(C1-14alkyl)(CH2)pO(CH2)rO(CH2)sN(C1-14alkyl)C(═O);
• optional divalent groups Y and Z are independently selected from O, NH, N(C1-6alkyl), S, S—S, S—N, S(═O), SO2, C(═O), OC(═O), C(═O)O, NHC(═O)NH, N(C1-6alkyl)C(═O)NH, N(C1-6 alkyl)C(═O)NC1-6alkyl), NHC(═O)NC1-6alkyl), C1-12alkylene, arylene, biarylene, (heteroaryl)arylene, (aryl)heteroarylene, heterocyclylene,
• (C1-12alkylene)C(═O)O, OC(═O)(C1-12alkylene),
• (C1-12alkylene)OC(═O), C(═O)O(C1-12alkylene),
• (C1-12alkylene)C(═O)N(R5a), N(R5a)C(═O)(C1-12alkylene),
• (C1-12alkylene)N(R5a)C(═O), C(═O)N(R5a)(C1-12alkylene),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)O(CR5R6)O(CR7R8)r(CR9R10)sC(═O),
• P(═O)(OCR5R6)p(CR7R8)r(CR9R10)sC═O),
• C(═O)(CR7R8)p(CR9R10)rP(═O)(OCR5R6)m,
• P(═O)(NHCR5R6)p(CR7R8)r(CR9R10)sC═O),
• P(═O)(OCR5R6)CF2, P(═O)(OCR5R6)CF2(CR7R8)rC(═O),
• P(═O)(OH)CF2, P(═O)(OH)CF2(CR7R8)rC(═O),
• C(═O)(CR7R8)r(CR9R10)sP(═O)(NHCR5R6)p,
• C(═O)O(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)N(R5a)(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sOC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sN(R5a)C(═O),
• C(═O)CR5═CR7—(CR9R10)sC(═O),
• C(═O)OCR5═CR7—(CR9R10)sC(═O),
• C(═O)N(R5a)CR5═CR7—(CR9R10)sC(═O),
• C(═O)CR5═CR7—(CR9R10)sOC(═O),
• C(═O)CR5═CR7—(CR9R10)sN(R5a)C(═O),
• C(═O)N(R5a)SO2(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sN(R5a)SO2C═O),
• C(═O)(CR5R6)pS—S(CR7R8)r(CR9R10)sC(═O),
• C(═O)O(CR5R6)pS—S(CR7R8)r(CR9R10)sC(═O),
• C(═O)N(R5a)(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR5R6)pS—S(CR7R8)r(CR9R10)sOC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sN(R5a)C(═O),
• C(═O)(CR5R6)p(CR7R8)rS—S(CR9R10)sC(═O),
• C(═O)O(CR5R6)p(CR7R8)rS—S(CR9R10)sC(═O),
• C(═O)N(R5a)(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR5R6)pS—S(CR7R8)rS—S(CR9R10)sOC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sN(R5a)C(═O),
• C(═O)CR5═CR7—S—S—(CR9R10)sC(═O),
• C(═O)OCR5═CR7—(CR9R10)sC(═O),
• C(═O)N(R5a)CR5═CR7—(CR9R10)sC(═O),
• C(═O)CR5═CR7—(CR9R10)sOC(═O),
• C(═O)CR5═CR7—(CR9R10)sN(R5a)C(═O),
• C(═O)N[(CR5R6)p(CR7R8)rNHC(═O)A14](CR9R10)sC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rNHC(═O)A14](CR9R10)sNHC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rNHC(═O)A14](CR9R10)sOC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rN(C1-6alkyl)C(═O)A14](CR9R10)sNHC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rN(C1-6alkyl)C(═O)A14](CR9R10)sC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rN(C1-6alkyl)C(═O)A14](CR9R10)sNHC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rN(C1-6alkyl)C(═O)A14](CR9R10)sOC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rOC(═O)A14](CR9R10)sC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rOC(═O)A14](CR9R10)sN(C═O),
• C(═O)N[(CR5R6)p(CR7R8)rOC(═O)A14](CR9R10)sO(C═O),
• C(═O)N[(CR5R6)p(CR7R8)rNHC(═O)A14A15](CR9R10)sC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rNHC(═O)A14A15](CR9R10)sN(C═O),
• C(═O)N[(CR5R6)p(CR7R8)rNHC(═O)A14A15](CR9R10)sO(C═O),
• C(═O)N[(CR5R6)p(CR7R8)rOC(═O)A14A15](CR9R10)sC(═O),
• C(═O)N[(CR5R6)p(CR7R8)rOC(═O)A14A15](CR9R10)sN(C═O),
• C(═O)N[(CR5R6)p(CR7R8)rOC(═O)A14A15](CR9R10)sO(C═O),
• C(═O)N[(CR5R6)p(CR7R8)rNHC(═O)(CR9R10)sNCH(NH2)COOH]CH2CH2C(═O),
• C(═O)N[(CR5R6)p(CR7R8)rN(C1-6alkyl)C(═O)—(CR9R10)sNCH(NH2)COOH]CH2CH2C(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH]CH2CH2C(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOC1-6alkyl]CH2CH2C(═O)
• C(═O)N[CH2CH2OC(═O)CH2CH2CH(NH2)COOH]CH2CH2C(═O),C(═O)N[CH2CH2NHC(═O)
• CH2CH2CH(NH2)COOH](CR5R6)p(CR7R8)rC(═O)O(CR9R10)sC(═),C(═O)N[CH2CH2NHC(═O)
• CH2CH2CH(NH2)COOH](CR5R6)p(CR7R8)r OC(═O) (CR9R10)sC(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH](CR5R6)pC(═O)O(CR7R8)r
• (CR9R10)sC(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH](CR′R6)pOC(═O)(CR7R8)r
• (CR9R10)sC(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH]CH2CH2C(═O)OCH2CH2C(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH]CH2CH2OC(═O)CH2CH2C(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH]CH2CMe2C(═O)OCH2CH2C(═O),
• C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH]CH2CH2OC(═O)CH(Me)-CH2C(═O),
• C(═O)N[CH2CH2N(C1-6alkyl)C(═O)CH2CH2CH(NH2)COOH]CH2CH2C(═O),
• (S)—C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH]CH2CH2C(═O),
• (R)—C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH2)COOH]CH2CH2C(═O),
• (S)—C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH(C═O)R7)COOH]CH2CH2C(═O),
• (R)—C(═O)N[CH2CH2NHC(═O)CH2CH2CH(NH(C═O)R7)COOH]CH2CH2C(═O),
• (S)—C(═O)N[CH2CH2NHC(═O)CHNH(Me)]CH2CH2C(═O),
• (R)—C(═O)N[CH2CH2NHC(═O)CHNH(Me)]CH2CH2C(═O),
• (S)—C(═O)N[CH2CH2NHC(═O)CHNH(CH2CH2CH2CH2NH2)]CH2CH2C(═O),
• (R)—C(═O)N[CH2CH2NHC(═O)CHNH(CH2CH2CH2CH2NH2)]CH2CH2C(═O),
• (S)—C(═O)N[CH2CH2NHC(═O)CHNH(CH2CH2NH2)]CH2CH2C(═O), and
• (R)—C(═O)N[CH2CH2NHC(═O)CHNH(CH2CH2NH2)]CH2CH2C(═O), or
• any variant of above groups formed by repositioning(s), addition(s), or deletion(s) of the fragments C(═O), OC(═O), N(R5a)C(═O), P(═O)(OCR5R6)CF2, P(═O)(OH)CF2, or C(═O)N(R5a)SO2 therein;
• or
• alternatively, the optional group Z is comprised of the following structures, optionally connected to one to two amino acid residue(s) A12 or A13:
• (C1-12alkylene)OC(═O), OC(═O)(C1-12alkylene),
• (C1-12alkylene)OC(═O), C(═O)O(C1-12alkylene),
• (C1-12alkylene)C(═O),
• N(R5a)C(═O)(C1-12alkylene),
• (C1-12alkylene)N(R5a)C(═O), C(═O)N(R5a)(C1-12alkylene),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)O(CR5R6)O(CR7R8)r(CR9R10)sC(═O),
• P(═O)(OCR5R6)p(CR7R8)r(CR9R10)sC═O),
• C(═O)(CR7R8)p(CR9R10)rP(═O)(OCR5R6)m,
• P(═O)(NHCR5R6)p(CR7R8)r(CR9R10)sC═O),
• P(═O)(OCR5R6)CF2, P(═O)(OCR5R6)CF2(CR7R8)rC(═O),
• P(═O)(OH)CF2, P(═O)(OH)CF2(CR7R8)rC(═O),
• C(═O)(CR7R8)r(CR9R10)sP(═O)(NHCR5R6)p,
• C(═O)O(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)N(R5a)(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sOC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sN(R5a)C(═O), C(═O)CR5═CR7—(CR9R10)sC(═O),
• C(═O)OCR5═CR7—(CR9R10)sC(═O),
• C(═O)N(R5a)CR5═CR7—(CR9R10)sC(═O),
• C(═O)CR5═CR7—(CR9R10)sOC(═O),
• C(═O)CR5═CR7—(CR9R10)sN(R5a)C(═O),
• C(═O)N(R5a)SO2(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sN(R5a)SO2C═O),
• C(═O)(CR5R6)pS—S(CR7R8)r(CR9R10)sC(═O),
• C(═O)O(CR5R6)pS—S(CR7R8)r(CR9R10)sC(═O),
• C(═O)N(R5a)(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR5R6)pS—S(CR7R8)r(CR9R10)sOC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sN(R5a)C(═O),
• C(═O)(CR5R6)p(CR7R8)rS—S(CR9R10)sC(═O),
• C(═O)O(CR5R6)p(CR7R8)rS—S(CR9R10)sC(═O),
• C(═O)N(R5a)(CR5R6)p(CR7R8)r(CR9R10)sC(═O),
• C(═O)(CR5R6)pS—S(CR7R8)rS—S(CR9R10)sOC(═O),
• C(═O)(CR5R6)p(CR7R8)r(CR9R10)sN(R5a)C(═O),
• C(═O)CR5═CR7—S—S—(CR9R10)pC(═O),
• C(═O)OCR5═CR7—(CR9R10)pC(═O),
• C(═O)N(R5a)CR5═CR7—(CR9R10)rC(═O),
• C(═O)CR5═CR7—(CR9R10)pOC(═O),
• C(═O)CR5═CR7—(CR9R10)rN(R5a)C(═O);
• or any variant of the above Z groups formed by repositioning(s), addition(s), or deletion(s) of the fragments C(═O), OC(═O), N(R5a)C(═O), P(═O)(OCR5R6)CF2, P(═O)(OH)CF2, or C(═O)N(R5a)SO2 therein;
• and wherein when both amino acid residues A12 and A13 are incorporated at the left side of above groups to comprise the group Z, then residues A12 or A13 are interconnected with a peptide bond A12-A13;
• and
• when an optional group Z is absent, then the group R2 is directly connected to one of groups Y, A1, A2, A3, A4, A5, A6, A7 or A8.