TW201731849A - Antimicrobial compounds and methods of making and using the same - Google Patents

Abstract

The present invention relates generally to the field of antimicrobial compounds and to methods of making and using them. These compounds are useful for treating, preventing, and reducing the risk of microbial infections in humans and animals.

Description

Antimicrobial compound, and preparation method and use thereof Related application

The present application claims US Provisional Patent Application No. 61/252,478 (filed on October 16, 2009); U.S. Provisional Patent Application No. 61/314,287 (filed on March 16, 2010); Priority of U.S. Provisional Patent Application No. 61/358,201 (filed on June 24, 2010). The entire text of the aforementioned application is incorporated herein by reference.

In general, the invention relates to the field of antimicrobial compounds, methods of manufacture and uses thereof. These antimicrobial compounds are useful in the treatment, prevention and reduction of the risk of microbial infections in humans and animals.

Since the discovery of penicillin in the 1920s and the discovery of streptomycin in the 1940s, many novel compounds have been discovered or specifically designed for use as antibiotics. It was thought that the use of antibiotics could completely control or eradicate infectious diseases. However, such a view has been challenged because cell lines or microbial strains that are resistant to currently effective therapeutic agents continue to evolve. Almost every antibiotic developed for clinical use has finally encountered problems with drug-resistant bacteria. For example, gram-positive bacterial resistant strains such as anti-xanthinmycin staphylococci, anti-penicillin streptococci, and vancomycin-resistant enterococci have been discovered. Drug-resistant bacteria can cause serious or even fatal results in infected patients. See, for example, Lowry, FD "Antimicrobial Resistance: The Example of Staphylococcus aureus ," J. Clin. Invest. , vol . 111, no . 9 , pp. 1265-1273 (2003); and Gold, HS and Moellering, RC, Jr., "Antimicrobial-Drug Resistance," N. Engl. J. Med. , vol. 335, pp. 1445-53 (1996).

The discovery and development of novel antibacterial agents for decades has been the main focus of many pharmaceutical companies. However, in recent years, pharmaceutical companies have withdrawn from this field of pharmaceutical research and development. As a result of this withdrawal, the number of novel antibiotics entering the market has been very small. The lack of novel antibiotics is particularly disturbing, especially when there is an increase in bacteria that are resistant to current treatments in hospitals and communities.

In the study of novel antibiotics, researchers have attempted to combine or link a wide variety of antibiotic molecules to create multifunctional or hybrid compounds. Other researchers have attempted to make derivatives of known classes of antibiotics, such as telithromycin (sold under the trade name Ketek®), which is a derivative of erythromycin. However, the effectiveness of these methods is limited.

A method of developing novel antimicrobial compounds is to design modulators, such as inhibitors of the ribosome function of bacteria. By regulating or inhibiting the nucleus of bacteria With saccharide function, the antimicrobial compound can interfere with the necessary procedures (eg, RNA translation and protein synthesis) to provide antimicrobial efficacy. In fact, some antibiotics (such as erythromycin, clindamycin, and linezolid) are known to bind to bacterial ribosomes.

The present invention utilizes a structure-based drug design method to discover and develop novel antimicrobial drugs. This structure-based drug design approach begins with the design of new classes of antimicrobial compounds with high-resolution X-ray crystallisation of ribosomes with specific chemical structures, ribosome binding properties, and antimicrobial activity. This structure-based drug discovery method is described in Franceschi, F. and Duffy, EM, "Structure-based drug design meets the ribosome", Biochemical Pharmacology , vol. 71, pp. 1016-1025 (2006). ).

Based on this structure-based drug design method, the present invention describes new chemical classes of antimicrobial compounds for the treatment of bacterial infections in humans and animals. Without being bound by theory, it is believed that these compounds bind to ribosomes to inhibit the ribosome function of bacteria. Using these ribosome binding sites, the antimicrobial compounds of the present invention provide better activity than existing antibiotics, particularly against resistant bacterial strains.

The present invention utilizes a structure-based drug design method to discover and develop novel antimicrobial drugs. This structure-based drug design approach begins with the design of new classes of antimicrobial compounds with high-resolution X-ray crystallisation of ribosomes with specific chemical structures, ribosome binding properties, and desirable antimicrobial activity. This structure-based drug discovery method is described in Franceschi, F. and Duffy, EM, "Structure-based drug design meets the ribosome", Biochemical Pharmacology , vol. 71, pp. 1016-1025 ( 2006).

The present invention therefore meets an important continuing need to provide novel antimicrobial drugs, particularly antimicrobial drugs having activity against drug-resistant pathogenic bacteria.

Summary of invention

In general, the invention relates to the field of antimicrobial compounds, methods of manufacture and uses thereof. These antimicrobial compounds are useful in the treatment, prevention and reduction of the risk of microbial infections in humans and animals. The invention also provides pharmaceutically acceptable salts, esters, N-oxides, and prodrugs of these antimicrobial compounds.

The present invention provides a compound having the structure: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

among them Is a chemical part selected from the following: among them Representative of a fused 5 to 7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring system wherein T ¹ is a carbon atom or N, with the constraint that when T ¹ is N, DEF is absent, wherein T ² is a carbon atom or N, and the constraint is that -GHJ is absent when T ² is N, wherein T ¹ and T ^{2 are} not N at the same time, wherein V is independently selected from -CR ^4a - or -N-, and W is O, NR ¹ , NOR ¹ , or S, another option is W = a combination of HO- and H- linked to the same carbon atom or (C _1-8 alkyl) O- and H- linking the same carbon atom Combination; X Y stands for single or double bond, and the constraint is when X When Y is a single bond, X is selected from O, NR ² , and S(O) _n and Y is CR ³ , and when X When Y is a double bond, X is N and Y is a carbon atom, Z is selected from O, NR ⁴ , S(O) _n , or NH, R ^{1 is} selected from H and C _1-8 alkyl, and R ^{2 is} selected from H and C _1-8 alkyl, R ^{3 is} selected from H and C _1-8 alkyl, R ^{4 is} selected from H and C _1-8 alkyl, R ^{4a is} selected from H and C _1-8 alkyl, n is 0, 1, or 2, another option is -GHJ selected from Wherein each of H and J is independently selected, and CBA-, -DEF and -GHJ are chemical moieties, wherein A, D and G are independently selected from the group consisting of: (a) single bond, (b)- (C _1-8 alkyl)-, (c)-(C _2-8 alkenyl)-, (d)-(C _2-8 alkynyl)-, wherein i) is preceded by (b) to (d) 0 to 4 carbon atoms in any of the arbitrarily substituted by a moiety selected from the group consisting of -O-, S(O) _P , -NR ⁶ -, -(C=O)-, -S(O) _P NR ⁶ -, -NR ⁶ S(O) _P -, and -NR ⁶ S(O) _P NR ⁶ -, ii) Any of the foregoing (b) to (d) One or more R ⁵ groups are substituted, and iii) any of the foregoing (b) to (d) is optionally substituted with a -(C _1-8 alkyl)-R ⁵ group; (e)-O- , (f)-NR ⁶ -, (g)-S(O) _P -, (h)-C(O)-, (i)-C(O)O-, (j)-OC(O)- , (k)-OC(O)O-, (l)-C(O)NR ⁶ -, (m)-NR ⁶ CO-, (n)-NR ⁶ C(O)NR ⁶ -, (o) -C(=NR ⁶ )-, (p)-C(=NR ⁶ )O-, (q)-OC(=NR ⁶ )-, (r)-C(=NR ⁶ )NR ⁶ -,(s )-NR ⁶ C(=NR ⁶ )-, (t)-C(=S)-, (u)-C(=S)NR ⁶ -, (v)-NR ⁶ C(=S)-,( w)-C(O)S-, (x)-SC(O)-, (y)-OC(=S)-, (z)-C(=S)O-, (aa)-NR ⁶ ( CNR ⁶ )NR ⁶ -, (bb)-CR ⁶ R ⁶ C(O)- , (cc)-C(O)NR ⁶ (CR ⁶ R ⁶ ) _t -, (d d) a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, (ee) 3 to 14 membered saturated, unsaturated or aromatic a carbocyclic ring, and (ff)-(CR ⁶ R ⁶ ) _t -, wherein (dd) or (ee) is optionally substituted with one or more R ⁵ groups; B, E and H are independently selected from the group consisting of Group consisting of: (a) a single bond, (b) a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (c) a 3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring wherein (b) or (c) is optionally substituted with one or more R ⁵ groups; (d)-(C _1-8 alkyl) )-, (e)-(C _2-8 alkenyl)-, (f)-(C _2-8 alkynyl)-, wherein (i) is in any of the foregoing (d) to (f) 0 to 4 carbon atoms are arbitrarily replaced by a moiety selected from the group consisting of -O-, -S(O) _P -, -NR ⁶ -, -(C=O)-, -C(= NR ⁶ )-, -S(O) _P NR ⁶ -, -NR ⁶ S(O) _P -, and -NR ⁶ S(O) _P NR ⁶ -, (ii) preceding (d) to (f) Either arbitrarily substituted with one or more R ⁵ groups, and (iii) any of the foregoing (d) to (f) is optionally substituted with a -(C _1-8 alkyl)-R ⁵ group ; and (g)-(CR ⁶ R ⁶ ) _t -, C, F and J are independently selected from the group consisting of: (a) hydrogen, (c) F, (d) Cl, (e) Br, (f) I, (g) )-CF ₃ , (h)-CN, (i)-N ₃ , (j)-NO ₂ , (k)-NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (l)-OR ⁸ , (m )-S(O) _P (CR ⁶ R ⁶ ) _t R ⁸ , (n)-C(O)(CR ⁶ R ⁶ ) _t R ⁸ , (o)-OC(O)(CR ⁶ R ⁶ ) _t R ⁸ ,(p)-SC(O)(CR ⁶ R ⁶ ) _t R ⁸ ,(q)-C(O)O(CR ⁶ R ⁶ ) _t R ⁸ ,(r)-NR ⁶ C(O) (CR ⁶ R ⁶ ) _t R ⁸ , (s)-C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (t)-C(=NR ⁶ )(CR ⁶ R ⁶ ) _t R ⁸ , (u)-C(=NNR ⁶ R ⁶ )(CR ⁶ R ⁶ ) _t R ⁸ , (v)-C(=NNR ⁶ C(O)R ⁶ )(CR ⁶ R ⁶ ) _t R ⁸ ,(w )-C(=NOR ⁸ )(CR ⁶ R ⁶ ) _t R ⁸ ,(x)-NR ⁶ C(O)O(CR ⁶ R ⁶ ) _t R ⁸ ,(y)-OC(O)NR ⁶ ( CR ⁶ R ⁶ ) _t R ⁸ , (z)-NR ⁶ C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (aa)-NR ⁶ S(O) _P (CR ⁶ R ⁶ ) _t R ⁸ , (bb)-S(O) _P NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (cc)-NR ⁶ S(O) _P NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (dd)- NR ⁶ R ⁸ , (ee)-NR ⁶ (CR ⁶ R ⁶ )R ⁸ , (ff)-OH, (gg)-NR ⁸ R ⁸ , (hh)-OCH ₃ , (ii)-S(O) _P R ⁸ , (jj)-NC(O)R ⁸ , (kk)-NR ⁶ C(NR ⁶ )NR ⁶ R ⁸ , (ll) C _1-8 alkyl, (mm) C _2-8 alkenyl , (nn) C _2-8 alkynyl, (oo) a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, (pp) 3 to 14 membered saturated, unsaturated or aromatic Carbocycle, (qq)-(CR ⁶ R ⁶ ) _t NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (rr)-N[(CR ⁶ R ⁶ ) _t R ⁸ ][C=O(CR ⁶ R ⁶ ) _t R ⁸ ], (ss)-(CR ⁶ R ⁶ ) _t N[(CR ⁶ R ⁶ ) _t R ⁸ ][(CR ⁶ R ⁶ ) _t R ⁸ ], (tt)-(CR ⁶ R ⁶ ) _t NR ⁶ (C=O)(CR ⁶ R ⁶ ) _t R ⁸ , (uu)-haloalkyl, (vv)-C(O)(CR ⁶ )[(CR ⁶ R ⁶ ) _t R ⁸ ]R ⁸ ,(ww)-(CR ⁶ R ⁶ ) _t C(O)NR ⁸ R ⁸ , (xx)-(CR ⁶ R ⁶ ) _t C(O)O(CR ⁶ R ⁶ ) _t R ⁸ , (yy)-NR ⁶ C(O)CR ⁸ R ⁸ R ⁸ ,(zz)-N[(CR ⁶ R ⁶ ) _t R ⁸ ]C(O)R ⁸ , and (aaa)-S(O) _P NR ⁸ R ⁸ ; wherein (11) to (pp) are optionally substituted with one or more R ⁷ groups; R ^{5 is} selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br , (e)I, (f)-CF ₃ , (g)-CN, (h)-N ₃ , (i)-NO ₂ , (j)-NR ⁶ R ⁶ , (k)-OR ⁸ , ( l) -NR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (m)-C _1-8 alkyl, (n)-C _1-8 alkenyl, (o)-C _1-8 alkynyl, (p) - (C _1-8 alkyl) - (3-14 yuan saturated, unsaturated, or aromatic, containing one or more hetero atoms selected from nitrogen, oxygen and sulfur heteroatoms ), (Q) - (C 1-8 alkyl) - (3-14 yuan saturated, unsaturated or aromatic carbocyclic ring), (R & lt) - haloalkyl, (s) -SR ^6, ( t) - a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and (u) from 3 to 14 members saturated, unsaturated Or aromatic carbocyclic ring; another option is that the two R ⁵ groups together form a carbocyclic ring, wherein (m) to (r) and (t) to (u) are optionally substituted by one or more R ⁸ R ^{6 is} selected from: (a) hydrogen, (b)-C _1-8 alkyl or alternatively the two R ⁶ groups together form a carbocyclic ring, (c)-haloalkyl, (d)- a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and (e) from 3 to 14 members saturated, unsaturated or aromatic a carbocyclic ring; wherein (b) to (e) are optionally substituted by one or more R ⁸ ; R ^{7 is} selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, ( e) I, (f)-CF ₃ , (g)-CN, (h)-N ₃ , (i)-NO ₂ , (j)-NR ⁶ R ⁶ , (k)-OR ⁶ , (l) -NR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (m)-C _1-8 alkyl, (n)-C _1-8 alkenyl, (o)-C _1-8 alkynyl, (p)-( C _1-8 alkyl)-(containing one or more selected from the group consisting of nitrogen, oxygen and sulfur a heterocyclic 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring), (q)-(C _1-8 alkyl)- (3 to 14 membered saturated, unsaturated or aromatic) Carbocyclic), (r)-haloalkyl, (s)-NR ⁶ R ⁸ , (t)-OR ⁸ , (u)-(CR ⁶ R ⁶ ) _t NR ⁶ R ⁸ , (v)-CR ⁶ R ⁸ R ⁸ , (w)-SR ⁶ , (x)- a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, y) a 3- to 14-membered saturated, unsaturated or aromatic carbocyclic ring, (z)-(CR ⁶ R ⁶ ) _t C(O)NR ⁸ R ⁸ , (aa)-S(O) _P R ⁸ , (bb)-NR ⁶ C(O)NR ⁶ R ⁶ , (cc)-NR ⁶ C(O)R ⁶ , and (dd)-C(=NR ⁶ )NR ⁶ R ⁶ ; wherein (m) To (q) and (x) to (y) optionally substituted by one or more R ⁹ ; R ^{8 is} selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF ₃ , (g)-CN, (h)-N ₃ , (i)-NO ₂ , (j)-NR ⁶ R ⁹ , (k)-OR ⁹ , (l)- NR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (m)-C _1-8 alkyl, (n)-C _1-8 alkenyl, (o)-C _1-8 alkynyl, (p)-(C _1-8 alkyl)-(3- to 14-membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur), (q)-(C _{1- 8} alkyl) - (3-14 yuan saturated, unsaturated, An aromatic carbocyclic ring), (r) - a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (s)-3 to 14-membered saturated, unsaturated or aromatic carbocyclic ring, (t)-haloalkyl, (u)-C(O)(CR ⁶ R ⁶ ) _t R ⁹ , (v)-SR ⁶ , (w )-OC(O)(CR ⁶ R ⁶ ) _t R ⁹ ,(x)-NR ⁶ C(O)NR ⁶ R ⁹ ,(y)-NR ⁶ C(O)R ⁹ ,(z)-NR ⁶ (CNR ⁹ )(NR ⁶ R ⁶ ), (aa)-ONR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (bb)-C(=NR ⁹ )NR ⁶ R ⁶ ,(cc)-S(O) _P R ⁹ ,(dd)-(CR ⁶ R ⁶ ) _t C(O)NR ⁶ R ⁹ ,(ee)-(CR ⁶ R ⁶ ) _t OR ⁹ , and (ff)-(CR ⁶ R ⁶ ) _t NR ⁶ R ⁹ ; wherein (m) to (s) are optionally substituted by one or more R ⁹ ; R ^{9 is} selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e I, (f)-CF ₃ , (g)-CN, (h)-N ₃ , (i)-NO ₂ , (j)-NR ⁶ R ¹⁰ , (k)-OR ⁶ , (l)- NR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (m)-C(O)(CR ⁶ R ⁶ ) _t NR ⁶ R ⁶ , (n)-C _1-8 alkyl, (o)-C _1-8 Alkenyl, (p)-C _1-8 alkynyl, (q)- a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur , (r)-3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring, (s)-haloalkane ^{, (T) - (CR 6} R 6) t OR 6, (u) -O (CR 6 R 6) t NR 6 R 10, (v) -C (O) R 6, (w) -SR 6, (x)-C(O)OR ¹⁰ , (y)-S(O) _P R ⁶ , (z)-(C _1-8 alkyl)-(containing one or more selected from the group consisting of nitrogen, oxygen and sulfur a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring of a hetero atom, (aa)-(C _1-8 alkyl)-(3 to 14 membered saturated, unsaturated or aromatic carbon) Ring), (bb)-O(CR ⁶ R ⁶ ) _t OR ⁶ , (cc)-C(=NR ⁶ )NR ⁶ R ⁶ , (dd)-ONR ⁶ R ⁶ , (ee)-NR ⁶ C( O) NR ⁶ R ⁶ , (ff)-O(CR ⁶ R ⁶ ) _t OR ⁶ , (gg)-NR ⁶ C(O)R ⁶ , and (hh)-(CR ⁶ R ⁶ ) _t NR ⁶ R ¹⁰ ; wherein (n) to (r) and (z) to (aa) are optionally substituted by one or more R ¹⁰ ; R ^{10 is} selected from: (a) hydrogen, (b) F, (c) Cl, ( d) Br, (e) I, (f)-CF ₃ , (g)-CN, (h)-N ₃ , (i)-NO ₂ , (j)-NR ⁶ R ⁶ , (k)-OR ⁶ , (l)-NR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (m)-C(O)(CR ⁶ R ⁶ ) _t NR ⁶ R ⁶ , (n)-C _1-8 alkyl, (o -C _1-8 alkenyl, (p)-C _1-8 alkynyl, (q)- 3 to 14-membered saturated, unsaturated, one or more heteroatoms selected from nitrogen, oxygen and sulfur Or aromatic heterocyclic ring, (r)-3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring, (s)-haloalkyl ^{(t) - (CR 6 R} 6) t OR 6, (u) -O (CR 6 R 6) t NR 6 R 6, (v) -C (O) R 6, (w) -SR 6, ( x)-C(O)OR ⁶ , (y)-S(O) _P R ⁶ , (z)-(C _1-8 alkyl)-(containing one or more impurities selected from nitrogen, oxygen and sulfur Atomic 3- to 14-membered saturated, unsaturated or aromatic heterocyclic ring, (aa)-(C _1-8 alkyl)-(3 to 14-membered saturated, unsaturated or aromatic carbocyclic ring) ), (bb)-O(CR ⁶ R ⁶ ) _t OR ⁶ , (cc)-C(=NR ⁶ )NR ⁶ R ⁶ , (dd)-ONR ⁶ R ⁶ , (ee)-NR ⁶ C(O )NR ⁶ R ⁶ , (ff)-O(CR ⁶ R ⁶ ) _t OR ⁶ , (gg)-NR ⁶ C(O)R ⁶ , and (hh)-(CR ⁶ R ⁶ ) _t NR ⁶ R ⁶ Optionally, wherein either -DEF or -GHJ is absent, but neither -DEF nor -GHJ are present at the same time; p is 0, 1 or 2, and t is 0, 1, 2 or 3.

In addition to this, the present invention also provides a method of synthesizing the aforementioned compound. A therapeutically effective amount of one or more of the foregoing compounds and a pharmaceutically acceptable carrier for administration can be formulated for administration to a human or animal as an antimicrobial drug, particularly as an antibacterial drug, after synthesis. In certain systems, the compounds of the invention are useful in the treatment, prevention or reduction of the risk of microbial infection, or in the manufacture of a medicament for the treatment, prevention or reduction of the risk of microbial infection. Thus, the aforementioned compounds or compositions may be administered, for example, orally, parenterally, intravenously, otic, ocular, nasally, or topically to provide a human or animal effective amount of the compound.

The foregoing and other aspects and aspects of the present invention can be more fully understood by reference to the detailed description

Detailed description of the invention

The present invention provides a family that can be used as an antimicrobial drug, As a compound for antibacterial medicinal use.

The invention includes pharmaceutically acceptable salts, esters, tautomers, N-oxides, and prodrugs of the compounds of the invention.

The compounds described in the present invention may have asymmetric centers. The compounds of the present invention containing an asymmetrically substituted atom can be isolated to form an optically active or racemic form. It is well known in the art how to prepare an optically active form, for example via isolation of a racemic form or via synthesis from an optically active starting material. Geometric isomers of many olefins, C=N double bonds and the like can also be present in the compounds described herein, and all stable geometric isomers are contemplated by the present invention. The cis and trans geometric isomers of the compounds of the invention are described and can be isolated as a mixture of cis and trans geometric isomers or can be isolated as individual isomers. The present invention is intended to cover all chiral isoforms, non-image, isomeric, racemic, and geometric isomers of a structure unless a particular stereochemistry or isomer is specifically Designation. All methods used to make the compounds of the invention and intermediates for the manufacture of the compounds of the invention are considered to be part of the invention. All tautomers of the compounds presented or described are also considered to be part of the invention. Furthermore, the invention also includes metabolites of the compounds described in the invention.

The invention is intended to include all isotopes of atoms present in the compounds of the invention. Isotopes include atoms having the same atomic order but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Carbon isotopes include C-13 and C-14.

When any variable (e.g., R ⁶⁾ occurs in any constituent or formula for a compound points more than once, which is defined in the independent variable and defined each occurrence interval occurrences. Thus, for example, if a group is shown to be substituted with one or more R ⁶ moieties, each occurrence of R ^{6 is} independently selected from the definition of R ⁶ . Furthermore, combinations of substituents and/or variables are permissible as long as the combination results in a stable compound (within the normal valence of the specified atom).

The chemical structure showing the chemical bond in dotted lines indicates that the bond is arbitrarily present. For example, a dotted line next to a solid single line indicates that the key can be a single key or a double key.

When a bond of a substituent is shown to traverse a bond of two atoms bonded in a ring, the substituent may be bonded to any atom on the ring. When a substituent does not indicate an atom through which the remainder of the compound of the known formula is attached, the substituent may be linked via any atom in the substituent. Combinations of substituents and/or variables are permissible as long as the combination results in a stable compound.

In the case of a nitrogen atom in the compounds of the invention, these nitrogen atoms, as the case may be, may be converted to N-oxides by treatment with an oxidizing agent such as MCPBA and/or hydrogen peroxide. Thus, the nitrogen atom shown and claimed is believed to encompass the nitrogen atom shown and its N-oxide (N→O) derivative (as the case may be).

One method of developing improved anti-proliferative and anti-infective agents is to provide modulators of ribosome function (eg, inhibitors).

Ribosomes are ribonucleoproteins that are found in both prokaryotes and eukaryotes. Ribosomes are organelles responsible for protein synthesis. Ribosomes translate genetic information encoded in information RNA into proteins during gene expression (Garrett et al. (2000) " The Ribosome: Structure, Function, Antibiotics and Cellular Interactions ," American Society for Microbiology, Washington, DC ).

Ribosomes contain two non-peer ribonucleoprotein subunits. The larger subunit (also known as the "ribosomal large subunit") is about twice as large as the smaller subunit (also known as the "ribosomal small subunit"). The ribosomal small subunit binds to the information ribonucleic acid (mRNA) and mediates the interaction between the information ribonucleic acid (mRNA) and the transfer ribonucleic acid (tRNA) anticodon (the one on which the fidelity of the translation is dependent). The ribosomal large subunit catalyzes peptide bond formation (ie, peptidyl transferase reaction for protein synthesis) and includes at least three different transfer ribonucleic acid binding sites (referred to as amine thiol sites, peptidyl sites, and efflux sites) point). The amine thiol site or the A site accommodates the incoming amine thiol ribonucleic acid (providing its amino acid to the growing peptide chain). Furthermore, the A area of the A site is important. The peptidyl or P site houses a peptidyl transfer ribonucleic acid complex (ie, a transfer ribonucleic acid having its amino acid (part of the growing peptide chain)). After the dislocation transfer ribonucleic acid has donated its amino acid to the growing polypeptide chain, the excretion site or the E site accommodates the deactivating transfer ribonucleic acid.

Definition

"Isomerism" means that the compounds have the same molecular formula but differ in the nature or order of their atomic bonds, or their atoms are arranged differently in space. Isomers in which atoms are arranged differently in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "non-image isomers", and stereoisomers that are not superimposable by mirror images are referred to as "mirroromers" or sometimes as optical isomers. The carbon atoms that bind four different substituents are called " Chiral center".

"Chiral isomer" means a compound having at least one chiral center. Chiral isomers have two mirror images of opposite chirality and may exist as individual mirror image isomers or as a mixture of mirror image isomers. A mixture of individual mirror image isomers containing equal amounts of opposite chirality is referred to as a "racemic mixture." Compounds having more than one chiral center have 2 ^n-1 mirror image isomer pairs, where n is the number of chiral centers. Compounds having more than one chiral center may exist as individual non-image isomers or as a mixture of non-an image isomers (referred to as "non-mirromeric mixture"). When a chiral center is present, stereoisomers may be characterized by the absolute configuration (R or S) of the chiral center. Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. Substituents that are considered to be linked to a chiral center are classified according to the following: Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al, Angew. Chem. Inter . Edit . 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J., Chem. Educ . 1964, 41, 116) .

"Geometric isomers" means that their existence is attributed to the non-mirrored isomers that are hindered from rotating around the double bond. These configurations are named after the word cis and trans, or Z and E. The prefix indicates that the group is on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog precedence rule.

Additionally, the structures and other compounds discussed in this application include all of their restricted conformational isomers. "Constrained conformation isomer" is a three-dimensional Isomers in which the atoms of the two isomers are arranged differently in space. The presence of restricted conformational isomers is attributed to the limited rotation caused by the blockage of rotation of the large group around the central bond. The constrained isomers are typically present as a mixture, however due to the recent development of chromatographic techniques, it has been possible to separate the mixtures of the two constrained isomers in selected cases.

"Tautomer" means that the structure of the compound differs significantly in the arrangement of atoms but exists in an easy and fast equilibrium form. It will be understood that the compounds of formula I may be described as different tautomers. It is also understood that when a compound has a tautomeric form, the scope of the invention is intended to encompass all tautomeric forms, and the nomenclature of the compound does not exclude any tautomeric form.

Some of the compounds of the invention may exist as tautomeric forms, and the scope of the invention is also intended to encompass such tautomeric forms.

The compounds, salts and prodrugs of the present invention may exist in several tautomeric forms, including enol and imine types, and ketone and enamine forms, as well as geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the invention. The tautomer is present in solution as a mixture of tautomeric groups. Often a tautomer dominates in the solid state. Even though one tautomer may be described, the invention includes all tautomers of the compounds of the invention.

A tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This reaction results in a formal migration of hydrogen atoms associated with the switching of adjacent conjugated double bonds. Mutual variation in solutions that have the potential for tautomerism The chemical balance of the structure can be achieved. The exact ratio of tautomers depends on several factors including temperature, solvent, and pH. The concept of tautomers that can be converted by tautomerism is called tautomerism.

There are two types that are common among possible types of tautomerism. Simultaneous transfer of electrons and hydrogen atoms occurs in keto-enol tautomerism. Glucose exhibits cyclo-chain tautomerism. It comes from the reaction of one of the aldehyde groups (-CHO) in the sugar chain molecule with the hydroxyl group (-OH) in the same molecule to form a ring (annular) form.

The tautomerism is catalyzed by: base: 1. deprotonation; 2. formation of delocalized anions (such as enolates); 3. protonation at different positions of the anions; acid: 1. protonation; Deformation of non-localized cations; 3. Deprotonation at different positions adjacent to the cation.

Common tautomeric pairs are: keto-enol, guanamine-nitrile, indoleamine-indole imine, indoleamine--in the heterocyclic ring (eg nucleobase guanine, thymine, and cytosine) Amino acid tautomerism, amine-enamine, and enamine-enamine. The following examples are included to illustrate, and the invention is not limited to this example:

"Polymorphous crystal" or "polycrystalline" or "crystalline" means a crystal structure in which a compound (or a salt or solvate thereof) can be crystallized in different crystal packing arrangements, all having the same elemental composition. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability, and solubility. again Crystalline solvents, crystallization rates, storage temperatures, and other factors may cause a crystalline form to predominate. Polymorphic crystals of the compound can be crystallized under different conditions.

"Substituted" as used in the present invention means that any one or more hydrogens on a specified atom (usually a carbon atom, an oxygen atom, or a nitrogen atom) are substituted with a group selected from a specified group, provided that it does not exceed The normal valence of the specified atom, and the substitution results in a stable compound. When the substituent is a keto group (ie, =0), two hydrogens on the atom are substituted. The cyclic double bond used in the present invention is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, N=N, etc.).

The "cyclonic isomeric carbon" used in the present invention means an acetal carbon of a glycoside.

The "glycoside" used in the present invention is a cyclic acetal.

"Alkyl" as used in the present invention is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, a C _1-6 alkyl group is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkyl groups. Some examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, n-hexyl, positive Heptyl, and n-octyl.

"Alkenyl" as used in the present invention is intended to include a hydrocarbon chain of one or more unsaturated carbon-carbon bonds, such as vinyl and propylene, which may be present in a linear or branched configuration and which may be present at any stable point along the chain. base. For example, a C _2-6 alkenyl group is intended to include C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkenyl groups.

"Alkynyl" as used in the present invention is intended to include one or more unsaturated carbon-carbon bonded hydrocarbon chains, such as ethynyl groups, which may be present in a linear or branched configuration and may be present at any stable point along the chain. Propynyl. For example, a C _2-6 alkynyl group is intended to include C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkynyl groups.

Further, "alkyl", "alkenyl", and "alkynyl" are intended to include a moiety of a divalent group (ie having two points of attachment), and in the present invention an example of a divalent group is selected from these chemistry at D. When the group. Non-limiting examples of the divalent alkyl moiety is -CH ₂ CH ₂ -, i.e., bound via a covalent each end part of the remaining carbon atoms of the molecule and a C ₂ alkyl group. Alkyl divalent groups are also referred to as "alkylene" groups. Alkenyl divalent groups are also referred to as "alkenylene" groups. An alkynyl divalent group is also referred to as an "alkynylene" group.

The "cycloalkyl group" used in the present invention is intended to include a saturated ring group such as a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group. The C _3-8 cycloalkyl group is intended to include C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , and C ₈ cycloalkyl groups.

The "counter ion" used in the present invention is used to indicate a positively or negatively charged ion existing together with an oppositely charged ion. A non-limiting example of a counterion is an ion or group of ions that exhibits a charge or group of charges on an organic compound. Non-limiting examples of counterions include chloride, bromide, hydroxyl, acetate, sulfate, and ammonium.

As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo substituents.

As used herein, "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms substituted with one or more halogens (eg, -C _V F _W , where v=1) To 3 and w=1 to (2v+1)). Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

"Alkoxy" as used in the present invention refers to an alkyl group having the indicated number of carbon atoms as defined above, which is bonded through an oxygen bridge. The C _1-6 alkoxy group is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₃ , and C ₆ alkoxy groups. The C _1-6 alkoxy group is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , and C ₈ alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, A sec-pentyloxy group, a n-heptyloxy group, and a n-octyloxy group.

As used herein, "alkylthio" refers to an alkyl group having the indicated number of carbon atoms as defined above, joined by a sulfur bridge. The C _1-6 alkylthio group is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkylthio groups. The C _1-6 alkylthio group is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , and C ₈ alkylthio groups.

The "carbocycle" or "carbocyclic ring" as used in the present invention is intended to mean (unless otherwise specified) any stable 3,4,5,6,7,8,9,10,11, Or a 12-membered monocyclic, bicyclic, or tricyclic ring, either saturated, unsaturated (including partially unsaturated and fully unsaturated), or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl , adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclononane, [2.2.2] Dicyclooctane, indenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. The bridged ring shown above is also included within the definition of a carbocyclic ring (e.g., [2.2.2]bicyclooctane). Bridge ring with one or more carbon atoms joining two non-adjacent carbons When the atom. A suitable bridge is one or two carbon atoms. Please note that the bridge always converts a single-ring ring into a three-ring ring. Substituents for the rings listed when the ring is bridged may also be present on the bridge. Fused rings (such as naphthyl and tetrahydronaphthyl) and spiro rings are also included.

As used herein, "heterocycle" means (unless otherwise stated) a stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered monocyclic, bicyclic, or tricyclic ring. a ring that is saturated, unsaturated (including partially unsaturated and fully unsaturated), or an aromatic ring and consists of one or more carbon atoms and one or more (eg, one, or one to two, or 1 to 3, or 1 to 4, or 1 to 5, or 1 to 6 heteroatoms) consisting of ring heteroatoms independently selected from nitrogen, oxygen and sulfur and including any bicyclic or tricyclic group (wherein any of the aforementioned heterocyclic rings is fused or linked to a second ring (for example, a benzene ring)). The nitrogen and sulfur heteroatoms can be arbitrarily oxidized (i.e., N→O and S(O) _P , where p=1 or 2). When a nitrogen atom is included in the ring, the nitrogen atom is N or NH depending on whether it is bonded to a double bond within the ring (i.e., if hydrogen is required to maintain the trivalent of the nitrogen atom). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is H or another substituent as defined above). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom position which results in a stable structure. If the compound formed is stable, the heterocyclic ring described in the present invention may be substituted at a carbon atom or a nitrogen atom position. The nitrogen in the heterocycle can be optionally quaternized. Bridged rings can also be included within the definition of a heterocyclic ring. A bridged ring occurs when one or more atoms (ie, C, O, N, or S) are attached to two non-adjacent carbon or nitrogen atoms. Suitable bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. Substituents for the rings listed when the ring is bridged may also be present on the bridge. Spiro and fused rings are also included.

The "aromatic heterocyclic ring" or "heteroaryl group" used in the present invention is intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12 membered monocyclic or bicyclic aromatic ring. The ring is independently selected from carbon atoms and one or more (eg, one, or one to two, or one to three, or one to four, or one to five, or one to six heteroatoms). Heteroatom composition of nitrogen, oxygen and sulfur. In the case of a bicyclic heterocyclic aromatic ring, although both rings may be aromatic rings (e.g., quinoline), only one of the two rings needs to be an aromatic ring (e.g., 2,3-dihydroanthracene). The second ring may also be fused or bridged as defined by the preceding heterocyclic ring. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is H or another substituent as defined above). The nitrogen and sulfur heteroatoms can be arbitrarily oxidized (i.e., N→O and S(O) _P , where p=1 or 2). In some compounds, the total number of sulfur and oxygen atoms in the aromatic heterocycle is no more than one.

Examples of heterocyclic rings include, but are not limited to, acridinyl, azabicyclooctyl, azepanyl, azetidinyl, anthranyl, benzimidazolyl, benzofuranyl, benzothiofuranyl , benzothienyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzene And imidazolinyl, benzodioxanyl, benzooxadiazolyl, oxazolyl, 4aH-carbazolyl, porphyrinyl, chromogenic alkyl, chromogenyl, porphyrin, cycloheptyl, Decalhydroquinolyl, dihydrobenzodioxin, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furyl, furazolyl, Imidazolidinyl, imidazolidine, imidazolinyl, imidazolyl, imidazolinone, 1H-carbazolyl, terpene Base, porphyrinyl, pyridazinyl, fluorenyl, 3H-fluorenyl, ruthenium, isobenzofuranyl, isochroman, isoxazolyl, isoindolyl, isoindole Mercapto, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, methylbenzotriazolyl, methylfuranyl, methylimidazolyl, methylthiazolyl, morpholine , naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl 1,3,4-oxadiazolyl, oxazolidinyl, oxazolidinone, oxazolyl, hydroxydecyl, phenanthryl, phenanolyl, phenazinyl, phenothiazine, pheno Thio group, phenoxazinyl, pyridazinyl, piperazinyl, piperazinyl, piperidinyl, piperidenyl, piperidinone, 4-piperidinone, piperidone, acridine Base, fluorenyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, Pyridone, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, 2 H-pyrrolyl, pyrrolyl, quinazolinyl, quinolyl, 4H-quinazinyl, quinoxalinyl, quinolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, tetra Azolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1 , 3,4-thiadiazolyl, thiazino, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, sulfur dioxide morpholino, triazinyl, triazole And pyrimidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthene.

The phrase "pharmaceutically acceptable" as used in the present invention refers to no excessive toxicity, irritation, or allergies within the scope of well-thought-out medical decisions. Reactions, or other problems or complications, and reasonable benefits/hazards are commensurate with compounds, materials, compositions, and/or dosage forms that are suitable for use in contact with human and animal tissues.

The "pharmaceutically acceptable salt" as used in the present invention refers to a derivative of the disclosed compound, wherein the parent compound is modified by the method of producing an acid salt or a basic salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; alkali metal or organic salts of acidic groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the customary quaternary ammonium salts of, for example, non-toxic salts or parent compounds formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, non-toxic salts derived from inorganic acids and organic acids selected from the group consisting of 2-ethoxyoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid. , ascorbic acid, benzenesulfonic acid, benzoic acid, dicarboxylic acid, carbonic acid, citric acid, ethylenediaminetetraacetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, bran Aminic acid, glycolic acid, hydroxyethyl hydrazinyl benzoic acid, hexyl resorcinol acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxy maleic acid, hydroxynaphthoic acid, hydroxy Ethanesulfonic acid, lactic acid, lactaldehyde, dodecylsulfonic acid, maleic acid, hydroxysuccinic acid, hydroxyphenylacetic acid, methanesulfonic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid , phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, sec-acetic acid, succinic acid, amine sulfonic acid, sulfamic acid, sulfuric acid, tannic acid, tartaric acid, and toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing a basic moiety or an acidic moiety by conventional chemical methods. In general, the pharmaceutically acceptable salts of the present invention can be prepared by subjecting the free acid or base parent compound to stoichiometry in water or in an organic solvent or in a mixture of water and an organic solvent. A suitable base or acid reaction; in general, we prefer a non-aqueous medium like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. A list of suitable salts is found below: Remington's Pharmaceutical Sciences , 18th ed., Mack Publishing Company, Easton, PA, USA, p. 1445 (1990).

Since prodrugs are believed to enhance many of the desirable properties of the drug (e.g., solubility, bioavailability, manufacture, etc.), the compounds of the invention can be delivered in prodrug form. The invention is therefore intended to comprise a prodrug of a compound as claimed in the invention, a method of delivering the prodrug and a composition comprising the prodrug. "Prodrug" is intended to include any covalently bound carrier that releases the active parent drug of the invention in vivo when the prodrug is administered to a mammalian subject. The prodrugs of the present invention are made by modifying the functional groups present in the compound in a manner that is routinely manipulated or that the modifications are cleaved into the parent compound in vivo. Prodrugs include a compound of the invention wherein a hydroxy, amine, or thiol group is bonded to any group which, upon administration of a prodrug prior to the present invention, is cleaved to a mammalian subject to form a free hydroxyl group, a free amine, respectively. Base, or free hydrogenthio group. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.

As used herein, "stable compound" and "stable structure" mean a compound that is sufficiently robust to be isolated from the reaction mixture to a useful degree of purity and formulated into an efficacious therapeutic agent.

As used herein, "patient" means a human or animal subject (typically a mammal in an animal case) who is subjected to a surgical or invasive medical procedure. The patient or subject may be considered to be in need of a reduction in the risk of infection caused by a surgical or invasive medical procedure or a method of preventing the infection. The patient or subject may also be considered to require prevention during surgery.

"Treatment" as used in the present invention means providing a therapeutic intervention to cure or ameliorate an infection.

As used herein, "preventing" means completely or almost completely preventing infection, for example, when a patient or subject is at risk of becoming infected or developing an infection. Prevention can also include inhibition, ie, preventing the development of infection.

"Reducing risk" as used in the present invention means reducing the likelihood or probability of infection, for example, when a patient or subject is at risk of being infected or infected.

As used herein, "unsaturated" means that the compound has at least one degree of unsaturation (e.g., at least one multiple bond), and "unsaturated" includes partially unsaturated and fully unsaturated compounds.

The "effective amount" as used in the present invention refers to a dose of the compound of the present invention or a composition thereof which is effective when administered alone or in combination as an antimicrobial drug. For example, an effective dose refers to a dose administered to a patient or a subject, a composition, or a compound present in a medical device, which dose is sufficient to cause biological activity, such as anti-infective activity, such as antimicrobial activity, antibacterial activity, Antifungal activity, antiviral activity, or antiparasitic activity.

"Preventive effective dose" means being administered to prevent or reduce surgery or An effective dose of a compound or group of compounds of the invention that is at risk of infection by an invasive medical procedure.

It should be understood that the expressions "hydrogen bond acceptor-hydrogen bond acceptor-hydrogen bond donor" and "hydrogen bond acceptor-hydrogen bond acceptor-hydrogen bond acceptor" mean hydrogen bond acceptor and donor The relative orientation, and without limitation, the groups are directly bonded together, as it is contemplated that additional atoms or groups of atoms may be included in the aforementioned groups.

In the present specification, the singular forms also include the plural, unless the context clearly indicates otherwise. All scientific and technical terms used in the present invention have the same meaning as commonly understood by one of ordinary skill in the art, unless otherwise defined. In the case of inconsistency, this manual will be compared. "Mammal" as used in the present invention refers to both human and non-human patients.

As used herein, "therapeutically effective dose" means that the dose of a compound of the invention or a composition thereof present in or on the recipient is sufficient to cause biological activity, such as antimicrobial activity, antifungal activity, antiviral activity, Antiparasitic activity, diarrhea activity, and/or antiproliferative activity. The composition of the compound is preferably a synergistic composition. Synergism (e.g., as described by Chou and Talalay, Adv. Enzyme Regul. vol . 22, pp . 27-55 (1984)) occurs when the compound is administered in combination with an effect greater than when the compound is administered alone as a single agent. When the cumulative effect. In general, synergistic effects are most clearly demonstrated at suboptimal concentrations of the compound. Synergistic effects can be used to indicate lower cytotoxicity, increased anti-proliferative effects and/or anti-infective effects, or some other beneficial effects of the composition compared to individual components.

The "RNA microhelical binding site" as used in the present invention refers to a ribose functional site of a ribosome large subunit occupied by an RNA microhelium of Formula III. The RNA microhelical binding site defines at least a portion of the excipient site (E-site) or overlaps with the excretion site.

The "A site" as used in the present invention refers to a ribose functional site occupied by an amine thiotransfer ribonucleic acid molecule prior to participating in a peptide bond formation reaction.

The "E site" as used in the present invention refers to a ribose functional site occupied by a depurinated transfer ribonucleic acid molecule after participating in a peptide bond formation reaction.

The "P site" used in the present invention refers to a ribose functional site which is occupied by a peptidyl transfer ribonucleic acid molecule when participating in a peptide bond formation reaction.

The "A region" as used in the present invention refers to a portion of the A site in the center of the peptidyl transferase in which the amino acid moiety of the amine thiol ribonucleic acid binds to the A site portion, or the sin of linezolid The oxazolidinone ring binds to the A site portion.

As the ribosome or ribosomal subunit used and quoted in the present invention, we consider "part of" or "part of the three-dimensional structure" to mean at least three, prefer at least three to ten, and most prefer at least ten A portion of the three-dimensional structure of the ribosome or ribosomal subunit formed by the amino acid residue and/or nucleotide residue of the ribosome or ribosomal subunit (including charge distribution and hydrophilicity/hydrophobicity). The residue forming this portion may be, for example, (i) a linked residue based on, for example, the major sequence of a ribosome ribonucleic acid or ribosomal protein, and (ii) a three-dimensional structure forming a ribosome or a ribosomal subunit. The residue of the contiguous portion, or (c) the combination of the former. As the RNA microhelicals used and cited in the present invention, we consider "part of" or "one of the three-dimensional structure" "Partial" means a portion (including charge distribution and hydrophilicity/hydrophobicity) of the three-dimensional structure of an RNA microhelical formed by at least three of one or more core residues of Formula III, preferring at least three to ten atoms. The atom forming the moiety can be, for example, (i) a solvent-independent atom buried in the core of the RNA microhelium, (ii) a solvent-affected atom of the RNA microhelical, or (iii) a combination of the former. .

All percentages and ratios used in the present invention (unless otherwise specified) are by weight.

Throughout the description of the invention, the composition is described as having, including, or containing a specific component, or the procedure is described as having, including, or containing a specific processing step, and it is contemplated that the composition of the invention is also substantially It is also composed of the components described, and the procedure of the invention also consists essentially of or also by the described processing steps. Further, it should be understood that the order or sequence of steps in which certain actions are performed is not critical as long as the invention is practiced. In addition, two or more steps or actions can be performed simultaneously.

2. Compounds of the invention

The present invention provides a compound having the structure: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

among them Is a chemical part selected from the following: among them Representative of a fused 5 to 7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring system wherein T ¹ is a carbon atom or N, with the constraint that when T ¹ is N, DEF is absent, wherein T ² is a carbon atom or N, and the constraint is that -GHJ is absent when T ² is N, wherein T ¹ and T ^{2 are} not N at the same time, wherein V is independently selected from -CR ^4a - or -N-, and W is O, NR ¹ , NOR ¹ , or S, another option is W = a combination of HO- and H- linked to the same carbon atom or (C _1-8 alkyl) O- and H- linking the same carbon atom Combination; X Y stands for single or double bond, and the constraint is when X When Y is a single bond, X is selected from O, NR ² , and S(O) _n and Y is CR ³ , and when X When Y is a double bond, X is N and Y is a carbon atom, Z is selected from O, NR ⁴ , S(O) _n , or NH, R ^{1 is} selected from H and C _1-8 alkyl, and R ^{2 is} selected from H and C _1-8 alkyl, R ^{3 is} selected from H and C _1-8 alkyl, R ^{4 is} selected from H and C _1-8 alkyl, R ^{4a is} selected from H and C _1-8 alkyl, n is 0, 1, or 2.

In some systems the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein Further containing a hydrogen bond donor moiety or an additional hydrogen bond acceptor moiety.

In some systems the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein A chemical moiety that is a donor moiety that contains at least two hydrogen bond acceptor moieties and at least one hydrogen bond.

In some systems the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein the hydrogen bond acceptor moiety and the hydrogen bond donor moiety are hydrogen bond acceptors-hydrogen bonds Acceptor-hydrogen bond donor orientation. The "orientation" used above does not mean that the hydrogen bond donor moiety or the hydrogen bond acceptor moiety must be directly bonded together because there may be other intermediate atoms between the hydrogen bond donor moiety or the hydrogen bond acceptor moiety. Or an atomic group.

In some systems the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein the hydrogen bond acceptor moiety is within 5 Å of each other and the hydrogen bond donor moiety is Within 5 Å of the hydrogen bond acceptor portion.

In some systems the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein the hydrogen bond acceptor moiety is within 3 Å of each other and the hydrogen bond donor moiety is Within 3 Å of the hydrogen bond acceptor portion.

In some systems the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein the hydrogen bond acceptor moiety is contained within a ring structure wherein the ring structure is a single ring structure Or a fused polycyclic structure.

In some systems the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein It is a chemical moiety containing at least three hydrogen bond acceptor moieties.

In some systems the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein the hydrogen bond acceptor moiety is a hydrogen bond acceptor-hydrogen bond acceptor-hydrogen bond acceptor Body orientation. The "orientation" used above does not mean that the hydrogen bond donor moiety or the hydrogen bond acceptor moiety must be directly bonded together because there may be other intervening atoms or groups of atoms between the hydrogen bond acceptor moieties.

In some systems the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein each hydrogen bond acceptor moiety is in at least one other hydrogen bond acceptor moiety Within about 5Å.

In some systems the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein each hydrogen bond acceptor moiety is in at least one other hydrogen bond acceptor moiety About 3 Å or less.

In some systems the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein at least two of the hydrogen bond acceptor moieties are contained within a ring structure, wherein the ring Structure is single ring Structure or fused polycyclic structure.

In some systems the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein the hydrogen bond acceptor moiety is independently selected from the group consisting of carbonyl, sulfur Carbonyl, imine, alkyl substituted imido, fluorenylene, fluorenyl, fluorenyl, alkyl substituted fluorenyl, fluorenyl, decyl substituted by monoalkyl or dialkyl, oxygen An ether group (-O-), a sulfide (also known as a thioether group (-S-)), a hydroxyl group, an alkoxy group, an amine group, an amine group substituted with a monoalkyl or dialkyl group, and a nitro group.

In some systems the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein the hydrogen bond donor moiety is selected from the group consisting of: a hydroxyl group, a thiol group , amine groups, and monosubstituted amine groups.

In some systems the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein Containing structural parts

Wherein W is O, NR ¹ , NOR ¹ , or S, and the other option is W = a combination of HO- and H- linked to the same carbon atom or (C _1-8 alkyl) O- linked to the same carbon atom. Combined with H-; X Y stands for single or double bond, and the constraint is when X When Y is a single bond, X is selected from O, NR ² , and S(O) _n and Y is CR ³ , and when X When Y is a double bond, X is N and Y is a carbon atom, Z is selected from O, NR ⁴ or S(O) _n , R ^{1 is} selected from H and C _1-8 alkyl, and R ^{2 is} selected from H and C _{1 -8} alkyl, R ^{3 is} selected from H and C _1-8 alkyl, R ^{4 is} selected from H and C _1-8 alkyl, and n is 0, 1, or 2.

In some systems based on the compound of the present invention or a pharmaceutically acceptable salt, ester, tautomer thereof, or prodrug thereof, wherein W is O, NR ^1, NOR ^1, or S.

In some systems the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein Containing structural parts

Wherein Z is selected from O, NR ⁴ or S(O) _n ; R ^{4 is} selected from hydrogen and C _1-6 alkyl, and n is 0, 1, and 2.

In some systems the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein Containing structural parts

Wherein R ^{4 is} selected from the group consisting of H and C _1-6 alkyl.

In some systems based on the compound of the present invention or a pharmaceutically acceptable salt, ester, tautomer thereof, or prodrug thereof, wherein R ⁴ is hydrogen.

In some systems the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein Contains a pyrrolopyzinidine or a derivative thereof.

In some systems based on the compound of the present invention or a pharmaceutically acceptable salt, ester, tautomer thereof, or prodrug thereof, wherein R ⁴ is hydrogen.

In some systems the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein Containing structural parts

among them Representative of a fused 5 to 7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring system wherein V is independently selected from -CR ^4a - or -N-, W is O, NR ¹ , NOR ¹ Or S, another option is W = a combination of HO- and H- linked to the same carbon atom or a combination of (C _1-8 alkyl) O- and H- linking the same carbon atom; Y stands for single or double bond, and the constraint is when X When Y is a single bond, X is selected from O, NR ² , and S(O) _n and Y is CR ³ , and when X When Y is a double bond, X is N and Y is a carbon atom, Z is selected from O, NR ⁴ , S(O) _n , or NH, R ^{1 is} selected from H and C _1-8 alkyl, and R ^{2 is} selected from H and C _1-8 alkyl, R ^{3 is} selected from H and C _1-8 alkyl, R ^{4 is} selected from H and C _1-8 alkyl, R ^{4a is} selected from H and C _1-8 alkyl, n is 0, 1, or 2.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: among them Representative of a fused 5 to 7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring system wherein T ¹ is a carbon atom or N, with the constraint that when T ¹ is N, DEF is absent, wherein T ² is a carbon atom or N, and the constraint is that -GHJ is absent when T ² is N, wherein T ¹ and T ^{2 are} not N at the same time, wherein V is independently selected from -CR ^4a - or -N-, and W is O, NR ¹ , NOR ¹ , or S, another option is W = a combination of HO- and H- linked to the same carbon atom or (C _1-8 alkyl) O- and H- linking the same carbon atom Combination; X Y stands for single or double bond, and the constraint is when X When Y is a single bond, X is selected from O, NR ² , and S(O) _n and Y is CR ³ , and when X When Y is a double bond, X is N and Y is a carbon atom, Z is selected from O, NR ⁴ , S(O) _n , or NH, R ^{1 is} selected from H and C _1-8 alkyl, and R ^{2 is} selected from H and C _1-8 alkyl, R ^{3 is} selected from H and C _1-8 alkyl, R ^{4 is} selected from H and C _1-8 alkyl, R ^{4a is} selected from H and C _1-8 alkyl, n is 0, 1, or 2, another option is -GHJ selected from Wherein each of H and J is independently selected, and CBA-, -DEF and -GHJ are chemical moieties, wherein A, D and G are independently selected from the group consisting of: (a) single bond, (b)- (C _1-8 alkyl)-, (c)-(C _2-8 alkenyl)-, (d)-(C _2-8 alkynyl)-, wherein i) is preceded by (b) to (d) 0 to 4 carbon atoms in any of the arbitrarily substituted by a moiety selected from the group consisting of -O-, S(O) _P , -NR ⁶ -, -(C=O)-, -S(O) _P NR ⁶ -, -NR ⁶ S(O) _P -, and -NR ⁶ S(O) _P NR ⁶ -, ii) Any of the foregoing (b) to (d) One or more R ⁵ groups are substituted, and iii) any of the foregoing (b) to (d) is optionally substituted with a -(C _1-8 alkyl)-R ⁵ group; (e)-O- , (f)-NR ⁶ -, (g)-S(O) _P -, (h)-C(O)-, (i)-C(O)O-, (j)-OC(O)- , (k)-OC(O)O-, (l)-C(O)NR ⁶ -, (m)-NR ⁶ CO-, (n)-NR ⁶ C(O)NR ⁶ -, (o) -C(=NR ⁶ )-, (p)-C(=NR ⁶ )O-, (q)-OC(=NR ⁶ )-, (r)-C(=NR ⁶ )NR ⁶ -,(s )-NR ⁶ C(=NR ⁶ )-, (t)-C(=S)-, (u)-C(=S)NR ⁶ -, (v)-NR ⁶ C(=S)-,( w)-C(O)S-, (x)-SC(O)-, (y)-OC(=S)-, (z)-C(=S)O-, (aa)-NR ⁶ ( CNR ⁶ )NR ⁶ -, (bb)-CR ⁶ R ⁶ C(O)-, (cc)-C(O)NR ⁶ (CR ⁶ R ⁶ ) _t -, (dd a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (ee) 3 to 14 membered saturated, unsaturated or aromatic Carbocycle, and (ff)-(CR ⁶ R ⁶ ) _t -, wherein (dd) or (ee) is optionally substituted with one or more R ⁵ groups; B, E and H are independently selected from the following Group consisting of: (a) a single bond, (b) a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (c) a 3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring wherein (b) or (c) is optionally substituted with one or more R ⁵ groups; (d)-(C _1-8 alkyl) -, (e)-(C _2-8 alkenyl)-, (f)-(C _2-8 alkynyl)-, wherein (i) is 0 in any of the foregoing (d) to (f) The four carbon atoms are arbitrarily replaced by a moiety selected from the group consisting of -O-, -S(O) _P -, -NR ⁶ -, -(C=O)-, -C(=NR ⁶ )-, -S(O) _P NR ⁶ -, -NR ⁶ S(O) _P -, and -NR ⁶ S(O) _P NR ⁶ -, (ii) before (d) to (f) One is optionally substituted with one or more R ⁵ groups, and (iii) any of the foregoing (d) to (f) is optionally substituted with a -(C _1-8 alkyl)-R ⁵ group; And (g)-(CR ⁶ R ⁶ ) _t -, C, F and J are independently selected from the group consisting of: (a) hydrogen, (c) F, (d) Cl, (e) Br, (f) I, (g) )-CF ₃ , (h)-CN, (i)-N ₃ , (j)-NO ₂ , (k)-NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (l)-OR ⁸ , (m )-S(O) _P (CR ⁶ R ⁶ ) _t R ⁸ , (n)-C(O)(CR ⁶ R ⁶ ) _t R ⁸ , (o)-OC(O)(CR ⁶ R ⁶ ) _t R ⁸ ,(p)-SC(O)(CR ⁶ R ⁶ ) _t R ⁸ ,(q)-C(O)O(CR ⁶ R ⁶ ) _t R ⁸ ,(r)-NR ⁶ C(O) (CR ⁶ R ⁶ ) _t R ⁸ , (s)-C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (t)-C(=NR ⁶ )(CR ⁶ R ⁶ ) _t R ⁸ , (u)-C(=NNR ⁶ R ⁶ )(CR ⁶ R ⁶ ) _t R ⁸ , (v)-C(=NNR ⁶ C(O)R ⁶ )(CR ⁶ R ⁶ ) _t R ⁸ ,(w )-C(=NOR ⁸ )(CR ⁶ R ⁶ ) _t R ⁸ ,(x)-NR ⁶ C(O)O(CR ⁶ R ⁶ ) _t R ⁸ ,(y)-OC(O)NR ⁶ ( CR ⁶ R ⁶ ) _t R ⁸ , (z)-NR ⁶ C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (aa)-NR ⁶ S(O) _P (CR ⁶ R ⁶ ) _t R ⁸ , (bb)-S(O) _P NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (cc)-NR ⁶ S(O) _P NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (dd)- NR ⁶ R ⁸ , (ee)-NR ⁶ (CR ⁶ R ⁶ )R ⁸ , (ff)-OH, (gg)-NR ⁸ R ⁸ , (hh)-OCH ₃ , (ii)-S(O) _P R ⁸ , (jj)-NC(O)R ⁸ , (kk)-NR ⁶ C(NR ⁶ )NR ⁶ R ⁸ , (ll) C _1-8 alkyl, (mm) C _2-8 alkenyl , (nn) C _2-8 alkynyl, (oo) a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, (pp) 3 to 14 membered saturated, unsaturated or aromatic Carbocycle, (qq)-(CR ⁶ R ⁶ ) _t NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (rr)-N[(CR ⁶ R ⁶ ) _t R ⁸ ][C=O(CR ⁶ R ⁶ ) _t R ⁸ ], (ss)-(CR ⁶ R ⁶ ) _t N[(CR ⁶ R ⁶ ) _t R ⁸ ][(CR ⁶ R ⁶ ) _t R ⁸ ], (tt)-(CR ⁶ R ⁶ ) _t NR ⁶ (C=O)(CR ⁶ R ⁶ ) _t R ⁸ , (uu)-haloalkyl, (vv)-C(O)(CR ⁶ )[(CR ⁶ R ⁶ ) _t R ⁸ ]R ⁸ ,(ww)-(CR ⁶ R ⁶ ) _t C(O)NR ⁸ R ⁸ ,(xx)-(CR ⁶ R ⁶ ) _t C(O)O(CR ⁶ R ⁶ ) _t R ⁸ , (yy)-NR ⁶ C(O)CR ⁸ R ⁸ R ⁸ ,(zz)-N[(CR ⁶ R ⁶ ) _t R ⁸ ]C(O)R ⁸ , and (aaa)-S(O) _P NR ⁸ R ⁸ ; wherein (11) to (pp) are optionally substituted with one or more R ⁷ groups; R ^{5 is} selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br , (e)I, (f)-CF ₃ , (g)-CN, (h)-N ₃ , (i)-NO ₂ , (j)-NR ⁶ R ⁶ , (k)-OR ⁸ , ( l)-NR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (m)-C _1-8 alkyl, (n)-C _1-8 alkenyl, (o)-C _1-8 alkynyl, (p) - (C _1-8 alkyl) - (3-14 yuan saturated, unsaturated, or aromatic, containing one or more hetero atoms selected from nitrogen, oxygen and sulfur heteroatoms ), (Q) - (C 1-8 alkyl) - (3-14 yuan saturated, unsaturated or aromatic carbocyclic ring), (R & lt) - haloalkyl, (s) -SR ^6, ( t) - a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and (u) from 3 to 14 members saturated, unsaturated Or aromatic carbocyclic ring; another option is that the two R ⁵ groups together form a carbocyclic ring, wherein (m) to (r) and (t) to (u) are optionally substituted by one or more R ⁸ R ^{6 is} selected from: (a) hydrogen, (b)-C _1-8 alkyl or alternatively the two R ⁶ groups together form a carbocyclic ring, (c)-haloalkyl, (d)- a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and (e) from 3 to 14 members saturated, unsaturated or aromatic a carbocyclic ring; wherein (b) to (e) are optionally substituted by one or more R ⁸ ; R ^{7 is} selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, ( e) I, (f)-CF ₃ , (g)-CN, (h)-N ₃ , (i)-NO ₂ , (j)-NR ⁶ R ⁶ , (k)-OR ⁶ , (l) -NR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (m)-C _1-8 alkyl, (n)-C _1-8 alkenyl, (o)-C _1-8 alkynyl, (p)-( C _1-8 alkyl)-(containing one or more selected from the group consisting of nitrogen, oxygen and sulfur a heterocyclic 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring), (q)-(C _1-8 alkyl)- (3 to 14 membered saturated, unsaturated or aromatic) Carbocyclic), (r)-haloalkyl, (s)-NR ⁶ R ⁸ , (t)-OR ⁸ , (u)-(CR ⁶ R ⁶ ) _t NR ⁶ R ⁸ , (v)-CR ⁶ R ⁸ R ⁸ , (w)-SR ⁶ , (x)- a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, ( y) a 3- to 14-membered saturated, unsaturated or aromatic carbocyclic ring, (z)-(CR ⁶ R ⁶ ) _t C(O)NR ⁸ R ⁸ , (aa)-S(O) _P R ⁸ , (bb)-NR ⁶ C(O)NR ⁶ R ⁶ , (cc)-NR ⁶ C(O)R ⁶ , and (dd)-C(=NR ⁶ )NR ⁶ R ⁶ ; wherein (m) To (q) and (x) to (y) optionally substituted by one or more R ⁹ ; R ^{8 is} selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF ₃ , (g)-CN, (h)-N ₃ , (i)-NO ₂ , (j)-NR ⁶ R ⁹ , (k)-OR ⁹ , (l)- NR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (m)-C _1-8 alkyl, (n)-C _1-8 alkenyl, (o)-C _1-8 alkynyl, (p)-(C _1-8 alkyl)-(3- to 14-membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur), (q)-(C _{1- 8} alkyl) - (3-14 yuan saturated, unsaturated, An aromatic carbocyclic ring), (r) - a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (s)-3 to 14-membered saturated, unsaturated or aromatic carbocyclic ring, (t)-haloalkyl, (u)-C(O)(CR ⁶ R ⁶ ) _t R ⁹ , (v)-SR ⁶ , (w )-OC(O)(CR ⁶ R ⁶ ) _t R ⁹ ,(x)-NR ⁶ C(O)NR ⁶ R ⁹ ,(y)-NR ⁶ C(O)R ⁹ ,(z)-NR ⁶ (CNR ⁹ )(NR ⁶ R ⁶ ), (aa)-ONR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (bb)-C(=NR ⁹ )NR ⁶ R ⁶ ,(cc)-S(O) _P R ⁹ ,(dd)-(CR ⁶ R ⁶ ) _t C(O)NR ⁶ R ⁹ ,(ee)-(CR ⁶ R ⁶ ) _t OR ⁹ , and (ff)-(CR ⁶ R ⁶ ) _t NR ⁶ R ⁹ ; wherein (m) to (s) are optionally substituted by one or more R ⁹ ; R ^{9 is} selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e I, (f)-CF ₃ , (g)-CN, (h)-N ₃ , (i)-NO ₂ , (j)-NR ⁶ R ¹⁰ , (k)-OR ⁶ , (l)- NR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (m)-C(O)(CR ⁶ R ⁶ ) _t NR ⁶ R ⁶ , (n)-C _1-8 alkyl, (o)-C _1-8 Alkenyl, (p)-C _1-8 alkynyl, (q)- a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur , (r)-3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring, (s)-haloalkane ^{, (T) - (CR 6} R 6) t OR 6, (u) -O (CR 6 R 6) t NR 6 R 10, (v) -C (O) R 6, (w) -SR 6, (x)-C(O)OR ¹⁰ , (y)-S(O) _p R ⁶ , (z)-(C _1-8 alkyl)- (containing one or more selected from the group consisting of nitrogen, oxygen and sulfur a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring of a hetero atom, (aa)-(C _1-8 alkyl)-(3 to 14 membered saturated, unsaturated or aromatic carbon) Ring), (bb)-O(CR ⁶ R ⁶ ) _t OR ⁶ , (cc)-C(=NR ⁶ )NR ⁶ R ⁶ , (dd)-ONR ⁶ R ⁶ , (ee)-NR ⁶ C( O) NR ⁶ R ⁶ , (ff)-O(CR ⁶ R ⁶ ) _t OR ⁶ , (gg)-NR ⁶ C(O)R ⁶ , and (hh)-(CR ⁶ R ⁶ ) _t NR ⁶ R ¹⁰ ; wherein (n) to (r) and (z) to (aa) are optionally substituted by one or more R ¹⁰ ; R ^{10 is} selected from: (a) hydrogen, (b) F, (c) Cl, ( d) Br, (e) I, (f)-CF ₃ , (g)-CN, (h)-N ₃ , (i)-NO ₂ , (j)-NR ⁶ R ⁶ , (k)-OR ⁶ , (l)-NR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (m)-C(O)(CR ⁶ R ⁶ ) _t NR ⁶ R ⁶ , (n)-C _1-8 alkyl, (o -C _1-8 alkenyl, (p)-C _1-8 alkynyl, (q)- 3 to 14-membered saturated, unsaturated, one or more heteroatoms selected from nitrogen, oxygen and sulfur Or aromatic heterocyclic ring, (r)-3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring, (s)-haloalkyl ^{(t) - (CR 6 R} 6) t OR 6, (u) -O (CR 6 R 6) t NR 6 R 6, (v) -C (O) R 6, (w) -SR 6, ( x)-C(O)OR ⁶ , (y)-S(O) _P R ⁶ , (z)-(C _1-8 alkyl)-(containing one or more impurities selected from nitrogen, oxygen and sulfur Atomic 3- to 14-membered saturated, unsaturated or aromatic heterocyclic ring, (aa)-(C _1-8 alkyl)-(3 to 14-membered saturated, unsaturated or aromatic carbocyclic ring) ), (bb)-O(CR ⁶ R ⁶ ) _t OR ⁶ , (cc)-C(=NR ⁶ )NR ⁶ R ⁶ , (dd)-ONR ⁶ R ⁶ , (ee)-NR ⁶ C(O )NR ⁶ R ⁶ , (ff)-O(CR ⁶ R ⁶ ) _t OR ⁶ , (gg)-NR ⁶ C(O)R ⁶ , and (hh)-(CR ⁶ R ⁶ ) _t NR ⁶ R ⁶ Optionally, wherein either -DEF or -GHJ is absent, but neither -DEF nor -GHJ are present at the same time; p is 0, 1 or 2, and t is 0, 1, 2 or 3.

In some systems the invention relates to a compound of Formulas I, II, III, IV, Ia, IIa, IIIa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein A is: (a) a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, (b) 3 to 14 membered saturated, unsaturated or An aromatic carbocyclic ring, or (c) a single bond wherein (a) or (b) is optionally substituted with one or more R ⁵ groups.

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein B is ( a) -(C _1-8 alkyl)-, (b)-(C _2-8 alkenyl)-, (c)-(C _2-8 alkynyl)-, or (d) a single bond, wherein i The 0 to 4 carbon atoms in any of the foregoing (a) to (c) are arbitrarily replaced by a moiety selected from the group consisting of -O-, -S(O) _P -, -NR ⁶ -, - (C=O)-, -C(=NR ⁶ )-, -S(O) _P NR ⁶ -, and -NR ⁶ S(O) _P NR ⁶ -, ii) preceding (a) to (c) Either arbitrarily substituted with one or more R ⁵ groups, and/or iii) any of the foregoing (a) to (c) optionally via a -(C _1-8 alkyl)-R ⁵ group Replace.

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein C is ( a) NH ₂ , (b)-NHC (=NH)NH ₂ , or (c) hydrogen.

The present invention is a pharmaceutically acceptable salt, ester, tautomer, or prodrug of a compound of Formulas I, II, III, IV, Ia, IIa, IIIa, IVa.

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein A is a) 4 to 7 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, b) 4 to 7 membered saturated, unsaturated or aromatic Carbocycle, or c) a single bond wherein (a) or (b) is optionally substituted with one or more R ⁵ groups.

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein A is nitrogen Heterocycloheptyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furyl, tetrahydrofuranyl, tetra Hydropyridyl, azetidinyl, pyrrolidinyl, piperidinyl, or piperidenyl; wherein A is optionally substituted with one or more R ⁵ groups.

Alternatively, the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa or a pharmaceutically acceptable salt, ester, tautomer thereof A construct, or prodrug, wherein A is a single bond.

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein B is - (C _1-8 alkyl)-, wherein i) 0 to 4 carbon atoms are optionally substituted by a moiety selected from the group consisting of: -O-, -S(O) _P -, -NR ⁶ -, -(C= O)-, -S(O) _P NR ⁶ -, or -NR ⁶ S(O) _P NR ⁶ -, ii) (a) B is optionally substituted with one or more R ⁵ groups, and/or iii B is optionally substituted with a -(C _1-8 alkyl)-R ⁵ group.

Alternatively, the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein B is a single bond.

In some systems the invention relates to a compound of Formulas I, II, III, IV, Ia, IIa, IIIa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein C is - NHC(=NH)NH ₂ .

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein -DEF is a The group represents hydrogen.

In some systems the invention relates to a compound of Formulas I, II, III, IV, Ia, IIa, IIIa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein G is ( a) a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, (b) 3 to 14 membered saturated, unsaturated or aromatic a carbocyclic ring, or (c) a single bond wherein (a) or (b) is optionally substituted with one or more R ⁵ groups.

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein G is a a 4 to 7 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, b) 4 to 7 membered saturated, unsaturated or aromatic Carbocycle, or c) a single bond wherein (a) or (b) is optionally substituted with one or more R ⁵ groups.

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein G is nitrogen Heterocycloheptyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furyl, tetrahydrofuranyl, tetra Hydropyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperidenyl, or a single bond.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -DEF, -GHJ, W, X, Y, Z, V, T ¹ , and T ^{2 are} as defined above.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -DEF, -GHJ, W, X, Y, Z, and V are as defined above.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Where CBA-, -DEF, and -GHJ are as defined above.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -GHJ, W, X, Y, and Z are as defined above.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -GHJ, W, X, Y, Z, and V are as defined above in Formula I.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -DEF, W, X, Y, Z, and V are as defined above in Formula I.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -DEF, -GHJ, W, X, Y, Z, and V are as defined above in Formula I.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -DEF, -GHJ, W, X, Y, Z, V, T ¹ , and T ^{2 are} as defined in the above formula II.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -DEF, -GHJ, W, X, Y, Z, and V are as defined in Formula II above.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Where CBA-, -DEF, and -GHJ are as defined above.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -GHJ, W, X, Y, and Z are as defined in Formula II.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -GHJ, W, X, Y, Z, and V are as defined in Formula II.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -DEF, W, X, Y, Z, and V are as defined in Formula II.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -DEF, W, X, Y, Z, and V are as defined in Formula II.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -DEF, -GHJ, W, X, Y, Z, V, and K are as defined in Formula III.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -GHJ, W, X, Y, Z, V, and K are as defined in Formula III.

In some systems the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein Represents a fused 6-membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring system.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -DEF, -GHJ, W, X, Y, Z, V, and K are as defined in Formula III; and Q ¹ , Q ² , Q ³ , and Q ^{4 are} independently selected from a nitrogen atom, A carbon atom, or CH, wherein -DEF and -GHJ (when present) are each attached to a carbon atom.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -DEF, and -GHJ are as defined in Formula III.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -DEF, -GHJ, W, X, Y, Z, V, and K are as defined in Formula IV.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -GHJ, W, X, Y, Z, V, and K are as defined in Formula IV.

In some systems the invention relates to a compound of formula IV, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein Represents a fused 6-membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring system.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -DEF, -GHJ, W, X, Y, Z, V, and K are as defined in Formula IV; and Q ¹ , Q ² , Q ³ , and Q ^{4 are} independently selected from a nitrogen atom, A carbon atom, or CH, wherein -DEF and -GHJ (when present) are each attached to a carbon atom.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA-, -DEF, and -GHJ are as defined in Formula IV.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein A is (a) a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (b) 3 to 14 members saturated, not a saturated or aromatic carbocyclic ring, or (c) a single bond wherein (a) or (b) is optionally substituted with one or more R ⁵ groups; B is (a)-(C _1-8 alkyl )-, (b)-(C _2-8 alkenyl)-, (c)-(C _2-8 alkynyl)-, or (d) a single bond, wherein i) is preceded by (a) to (c) 0 to 4 carbon atoms in any of them are optionally substituted with a moiety selected from the group consisting of -O-, -S(O) _p -, -NR ⁶ -, -(C=O)-, -C( =NR ⁶ )-, -S(O) _p NR ⁶ -, and -NR ⁶ S(O) _p NR ⁶ -, ii) Any of the foregoing (a) to (c) optionally passes one or more R ⁵ group substituted, and/or iii) any of the foregoing (a) to (c) is optionally substituted with a -(C _1-8 alkyl)-R ⁵ group, and C is selected from (a) NH ₂ , (b)-NHC(=NH)NH ₂ , and (c) hydrogen.

In some systems the invention relates to a compound having the formula: Wherein A is azepanyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furyl, Tetrahydrofuranyl, tetrahydropyridyl, azetidinyl, pyrrolidinyl, piperidinyl, or piperidenyl, wherein A is optionally substituted with one or more R ⁵ groups; or A is a single bond; (a)-(C _1-8alkyl )-, wherein i) 0 to 4 carbon atoms in the preceding (a) are optionally substituted with a moiety selected from the group consisting of -O-, -S(O) _P -, -NR ⁶ -, -(C=O)-, -S(O) _P NR ⁶ -, and -NR ⁶ S(O) _P NR ⁶ -, ii) preceding (a) optionally one or more Substituting R ⁵ groups, and/or iii) preceding (a) optionally substituted with a -(C _1-8 alkyl)-R ⁵ group; or B is a single bond; C is (a) NH ₂ , ( b) -NHC(=NH)NH ₂ , or (c) hydrogen.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein CBA is selected from the group consisting of hydrogen,

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein G is (a) a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (b) 3 to 14 members saturated, not a saturated or aromatic carbocyclic ring, or (c) a single bond wherein (a) or (b) is optionally substituted with one or more R ⁵ groups.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein G is azepanyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furyl, Tetrahydrofuranyl, tetrahydropyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperidinyl, or a single bond.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein -GHJ is selected from the group consisting of: hydrogen, In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: hydrogen,

Where n is 0, 1, or 2.

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Where -GHJ is selected from:

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein B is a C _1-8 alkyl group; wherein each -HJ is independently selected from the group consisting of CF ₃ , OCF ₃ , and -(C _1-8 )alkyl-NH ₂ .

In some systems the invention relates to a compound of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof: Wherein each -HJ is independently selected from the group consisting of CF ₃ , OCF ₃ , and -(C _1-8 )alkyl-NH ₂ .

In some systems the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, which compound contains R ⁵ , wherein R ^{5 is} selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF ₃ , (g)-CN, (h)-N ₃ , (i)-NO ₂ , (j)-NH ₂ , (k)-OR ⁶ , (l)-NHC(=NH)NH ₂ , (m)-C _1-8 alkyl, (n)-C _1-8 alkenyl, (o)-C _1-8 Alkynyl, (p)-(C _1-8 alkyl)- (a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur) , (q)-(C _1-8 alkyl)-(3 to 14-membered saturated, unsaturated or aromatic carbocyclic ring), (r)-haloalkyl, (s)-SR ⁶ , (t a 3- to 14-membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and (u)-3 to 14-membered saturated, unsaturated Or an aromatic carbocyclic ring; another option is that the two R ⁵ groups together form a carbocyclic ring.

In some systems the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, which compound contains R ⁶ wherein R ^{6 is} selected from: (a) hydrogen, (b) -C _1-8 alkyl or alternatively wherein the two R ⁶ groups together form a carbocyclic ring, (c)-haloalkyl, (d)-containing one or more impurities selected from the group consisting of nitrogen, oxygen and sulfur A 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring of an atom, and (e) a -3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring.

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein W When present) is O, NR ¹ , NOR ¹ , or S.

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein X Y (when present) is a double bond and X is N and Y is a carbon atom.

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein R ⁵ is -OR ⁶ and R ⁶ is CF ₃ .

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein R ⁵ is CF ₃ .

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein -GHJ is selected from Wherein each -HJ is independently selected from -O-CF ₃ and -(C _1-8 alkyl)-NH ₂ .

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein R ^4a ( When present, it is hydrogen.

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein Z (when When present) is NR ⁴ .

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein R ⁴ is hydrogen.

In some systems the invention relates to a compound of Formula I, II, III, IV, Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, which binds to ribose body.

In some systems the invention relates to a compound of formula I, II, III, IV, Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester thereof, A tautomer, or a prodrug, which binds to a ribosome, wherein the ribosome is a ribosome of a bacterium.

In some systems the invention relates to a compound of any of the compounds of Table 1, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some systems the invention relates to a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, and a pharmaceutically acceptable carrier.

In some systems the invention relates to a method of treating or reducing the risk of a disease state in a human or animal, the method comprising administering to a human or animal in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, Ester, tautomer, or prodrug.

In some systems the invention relates to a method of treating a microbial infection in a human or animal, the method comprising administering to the human or animal an effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, tautomer thereof Structure, or prodrug.

In some systems the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, for the manufacture of a medicament for the treatment of a microbial infection in a human or animal.

In some systems the invention relates to a method of treating, preventing, or reducing the risk of a microbial infection in a human or animal, the method comprising administering to the human or animal an effective amount of Formula I, II, III, IV, Ia, a compound of IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or a compound of the present invention or a pharmaceutically acceptable compound thereof The use of a salt, ester, tautomer, or prodrug for the manufacture of a medicament for treating, preventing, or reducing the risk of microbial infection in a human or animal, wherein the microbial infection is selected from the group consisting of: Skin infections, gram-positive bacterial infections, gram-negative bacterial infections, nosocomial pneumonia, community-acquired pneumonia, post-viral pneumonia, nosocomial pneumonia/respirator-associated pneumonia, respiratory infections (eg Chronic respiratory tract infection (CRTI), acute pelvic inflammatory disease, complex skin and skin structure infections, skin and soft tissue infections (SSTI) (including simple skin and soft tissue infections (uSSTI) and complex skin and soft tissue infections), abdominal cavity Infectious diseases, complicated intra-abdominal infections, urinary tract infections, bacteremia, sepsis, endocarditis, atrioventricular pathway infections, vascular access to arteriovenous fistulas, meningitis, surgical prevention, peritoneal infections, Bone infection, joint infection, drug-resistant Staphylococcus aureus infection, vancomycin-resistant Enterococcus infection, resistance to linezolid microbial infection, charcoal Bacillus infection, soil Lavin's bacillus infection, bacillus Yersinia infections, and tuberculosis.

In some systems the invention relates to a method of treating, preventing, or reducing the risk of a complex intra-abdominal infection in a human or animal, the method comprising administering to the human or animal an effective amount of Formula I, II, III, IV, a compound of Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or a compound of the present invention or a pharmaceutically acceptable salt, ester, tautomer thereof Or a prodrug for use in the manufacture of a medicament for treating, preventing, or reducing the risk of a complex intra-abdominal infection in a human or animal, wherein the complex intra-abdominal infection is selected from a plurality of microbial infections caused by the following microorganisms (eg Abscess): Escherichia coli, Clostridium fusiformis, stomach Intestinal bacteria, Streptococcus pneumoniae, Bacteroides fragilis, Bacteroides bisporus, Bacteroides ovum, Bacteroides variabilis, Bacteroides bisporus, Streptococcus angina, Streptococcus faecalis, Enterococcus faecalis, Proteus mirabilis, Or Clostridium perfringens.

In some systems the invention relates to a method of treating, preventing, or reducing the risk of a complex skin and skin structure infection in a human or animal, the method comprising administering to the human or animal an effective amount of Formula I, II, III, a compound of IV, Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or a compound of the present invention, or a pharmaceutically acceptable salt, ester thereof, The use of an isomer, or a prodrug, for the manufacture of a medicament for treating, preventing, or reducing the risk of a complex skin and skin structure infection, wherein the complex skin and skin structure infection is selected from the group consisting of the following microorganisms: (no osteomyelitis): Staphylococcus aureus (xylene penicillin sensitive and drug resistant isolate), Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Bacteroides fragilis, Streptococcus pneumoniae, P. gingivalis, or P. eutropha.

In some systems the invention relates to a method of treating, preventing, or reducing the risk of community infectious pneumonia in a human or animal, the method comprising administering to the human or animal an effective dose of Formula I, II, III, IV, Ia a compound of IIa, IIIa, or IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or a compound of the present invention or a pharmaceutically acceptable salt, ester or tautomer thereof , or a prodrug for use in the manufacture of a medicament for treating, preventing, or reducing the risk of infectious pneumonia in a community, wherein the community infectious pneumonia is caused by the following: bacterial Streptococcus pneumoniae (penicillin) Sensitive and drug-resistant isolates (including cases with concurrent bacteremia), Haemophilus influenzae (including β-endoamine degrading enzyme-positive isolates), Moraxella mucosa, or atypical bacteria (like mildew) bacteria).

In some systems the invention relates to a method of treating, preventing, or reducing the risk of a complex urinary tract infection in a human or animal, the method comprising administering to the human or animal an effective amount of Formula I, II, III, IV, a compound of Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or a compound of the present invention or a pharmaceutically acceptable salt, ester, tautomer thereof Or a prodrug for use in the manufacture of a medicament for treating, preventing, or reducing the risk of a complicated urinary tract infection, wherein the complex urinary tract infection is selected from the group consisting of Escherichia coli, concurrent bacteremia, or Klebsiella pneumoniae Pyelonephritis caused by bacteria.

In some systems the invention relates to a method of treating, preventing, or reducing the risk of acute pelvic inflammatory disease in a human or animal, the method comprising administering to the human or animal an effective amount of Formula I, II, III, IV, Ia, a compound of IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or a compound of the present invention, or a pharmaceutically acceptable salt, ester, tautomer thereof, Or a prodrug for use in the manufacture of a medicament for treating, preventing, or reducing the risk of acute pelvic inflammatory disease, including, for example, postpartum uterine endomyocarditis, septic abortion, and post-operative gynecological infections. ) is caused by: Streptococcus agalactiae, Escherichia coli, Bacteroides fragilis, P. gingivalis, Streptococcus mutans, or Prevotella.

In some systems the invention relates to a treatment, prevention, or reduction A method for the risk of nosocomial pneumonia/respirator-associated pneumonia in a human or animal, the method comprising administering to the human or animal an effective amount of a compound of Formula I, II, III, IV, Ia, IIa, IIIa, or IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, for use in therapy, The use of a medicament for preventing or reducing the risk of nosocomial pneumonia/respirator-associated pneumonia, wherein the hospital's infectious pneumonia/respirator-associated pneumonia is caused by the following bacteria: Streptococcus pneumoniae (penicillin-sensitive and drug-resistant isolates) , Staphylococcus aureus (xylene penicillin-sensitive and drug-resistant isolates), Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter, Stenotrophomonas maltophilia, Haemophilus influenzae (including beta guilty) Amine-degrading enzyme-positive isolate), or Lungophilus vulgaris.

In some systems, the invention relates to a method of treating, preventing, or reducing the risk of a microbial infection caused by an aerobic or facultative Gram-positive microorganism in a human or animal, the method comprising administering to the human or animal An effective amount of a compound of Formula I, II, III, IV, Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or a compound of the present invention or The use of a pharmaceutically acceptable salt, ester, tautomer, or prodrug for the manufacture of a medicament for the treatment, prevention, or reduction of the risk of microbial infection caused by aerobic or facultative Gram-positive microorganisms, Wherein the aerobic or facultative gram-positive microorganism is selected from the group consisting of Staphylococcus aureus (xylene penicillin-sensitive and drug-resistant isolates), bacterial Streptococcus pneumoniae (penicillin sensitivity and drug resistance separation) Strain, Enterococcus (vancomycin sensitive and drug resistant isolate), no milk Streptococcus, Streptococcus pyogenes, or Staphylococcus epidermidis (xylene penicillin-sensitive and drug-resistant isolates).

In some systems the invention relates to a method of treating, preventing, or reducing the risk of a microbial infection caused by aerobic and facultative Gram-negative microorganisms in a human or animal, the method comprising administering to the human or animal an effective A dose of a compound of Formula I, II, III, IV, Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or a compound of the present invention or a pharmaceutical thereof Use of an acceptable salt, ester, tautomer, or prodrug for the manufacture of a medicament for treating, preventing, or reducing the risk of a microbial infection caused by aerobic or facultative Gram-negative microorganisms, wherein The aerobic and facultative Gram-negative microorganisms are selected from the group consisting of Escherichia coli (including ESBL and KPC-producing strains), Haemophilus influenzae (including β-endoproline-degrading enzyme-positive isolates), and grams. Leptospirillum pneumoniae (including ESBL and KPC isolates), Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Morganella morgani, Serratia marcescens, Pseudomonas aeruginosa, Acinetobacter baumannii Moraxella catarrhalis Proteus mirabilis, Citrobacter kawaii, Haemophilus parainfluenzae, Klebsiella acid-producing bacteria (including ESBL and KPC isolates), Proteus vulgaris, Providencia serrata, and S. Provi Dengsis.

In some systems the invention relates to a method of treating, preventing, or reducing the risk of a microbial infection caused by an anaerobic microorganism in a human or animal, the method comprising administering to the human or animal an effective dose of Formula I, II a compound of III, IV, Ia, IIa, IIIa, or IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or a compound according to the invention Or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof for use in the manufacture of a medicament for treating, preventing, or reducing the risk of microbial infection caused by anaerobic microorganisms, wherein the anaphylaxis Oxygen microorganisms are: Bacteroides fragilis, Bacteroides bisporus, Bacteroides ovum, Bacteroides variabilis, Bacteroides bisporus, Clostridium fusiformis, gastrointestinal bacteria, Streptococcus pneumoniae, Pseudomonas aeruginosa , two-way Prevo, common Bacteroides, Clostridium perfringens, or Fusobacterium.

In some systems the invention relates to a method of treating or reducing the risk of microbial infection in a human or animal, the method comprising administering to the human or animal an effective amount of Formula I, II, III, IV, Ia, IIa, IIIa Or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof The use of a medicament for treating, preventing, or reducing the risk of microbial infection, wherein the microorganism is a Legionella vulgaris.

In some systems the invention relates to a method or use wherein a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, is administered through the ear, eye, nose, mouth, parenteral, or Partially persuaded.

In some systems the invention relates to a process for the synthesis of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some systems the invention relates to a medical device comprising a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some systems the invention relates to a medical device comprising a compound of the invention, wherein the medical device is a stent.

3. Synthesis of the compounds of the invention

The invention provides methods for making the compounds of the invention. The following reaction schemes 1a through 5a generally depict exemplary routes for the synthesis of the compounds of the invention. More specific chemical details are provided in the examples.

4. Characterization of the compounds of the invention

The compounds selected and/or optimized (as soon as they are fabricated) can be assayed using the various assays familiar to those skilled in the art to determine whether a compound is biologically active. For example, a molecule can be characterized by conventional assays, including but not limited to the assays described below, to determine if a molecule has an expected activity, binding activity, and/or binding specificity.

In addition, high speed drug screening can be used to increase the speed of analysis using this assay. Therefore, it is possible to rapidly screen the following activities of the molecules described in the present invention: (for example) anticancer activity, antibacterial activity, antifungal activity, antiparasitic activity, or antiviral activity. Again, techniques known in the art can be used to detect how a compound interacts with a ribosome or ribosome subunit, and/or how effectively the compound acts as a modulator of protein synthesis (e.g., an inhibitor). A generalized methodology for performing high speed drug screening is described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-speed drug screening can use one or more different detection techniques, including but not limited to the following Narrator.

(1) Surface binding studies. A wide variety of binding assays can be used to screen for the binding activity of new molecules. One method of detection includes surface plasmon resonance technology (SPR), which can be used to assess the binding properties of molecules of interest associated with ribosomes, ribosomal subunits or fragments thereof.

Surface plasmon resonance technology methodology instantly measures the interaction between two or more macromolecules by the generation of quantum mechanical surface plasmons. A device (BIAcore Biosensor RTM from Pharmacia Biosensor, Piscataway, NJ) provides a multicolor beam focusing between gold foil (provided in the form of a disposable biosensor wafer) and buffer compartment (adjustable by the user) Interface. A one hundred nanometer thick "hydrosol" is applied to the gold foil, and the hydrosol is composed of a carboxymethylated dextran that provides covalentity for the analyte of interest. Immobilized matrix. The plasmon resonance increases when the focused beam and the free electron cloud of the gold foil interact. The wavelength of the reflected light (optimally developing resonance) is attenuated. By illuminating the reflected polychromatic light through the enthalpy into the component wavelength and measuring the frequency of the attenuation, BIAcore establishes an optical interface that accurately reports the resulting surface plasmon resonance behavior. In the design as described above, the plasmon resonance (attenuation spectrum) is sensitive to mass in the attenuation field (substantially consistent with the thickness of the hydrosol). If one component of the interaction pair is immobilized on the hydrosol and the interaction partner is provided through the buffer compartment, the interaction between the two components can be measured instantaneously, the measurement taking the accumulation of mass in the attenuation field and Based on the corresponding plasmon resonance effect measured by the attenuation spectrum. This system allows for the rapid and sensitive measurement of molecular interactions in real time without the need to label any component.

(2) Fluorescence polarization. Fluorescence polarization (FP) is a measure of the IC ₅₀ and Kd values that can be easily applied to protein-protein, protein-ligand, or RNA-ligand interactions in order to obtain an association reaction between two molecules. technology. One of the molecules of interest in this technique is conjugated to a fluorophore. Generally this is the smaller molecule in the system (the compound of interest in this case). The sample mixture (containing both the ligand-probe conjugate and the ribosome, the ribosomal subunit and its fragments) was excited by vertically polarized light. The light is absorbed by the probe fluorophore and is emitted again after a while. The degree of polarization of the emitted light is measured. The polarization of the emitted light depends on several factors, but the most important is the viscosity of the solution and the apparent molecular weight of the fluorophore. With appropriate control, the change in polarization of the emitted light depends only on the apparent molecular weight change of the fluorophore, and secondly on whether the probe-ligand conjugate is free or bound to the receptor in solution. Binding detection based on fluorescence polarization has several important advantages, including measurement of IC ₅₀ and Kd values under real homogeneous equilibrium conditions, speed of analysis, ease of automation, and screening in turbid suspensions and colored solutions. ability.

(3) Protein synthesis. It is expected that in addition to being characterized by the aforementioned biochemical assays, compounds of interest may also be considered as modulators of functional activity of ribosomes or ribosomal subunits (eg, inhibitors of protein synthesis).

In addition, more specific inhibition of protein synthesis inhibition can be carried out by administering the compound of interest to all organisms, tissues, organs, organelles, cells, cells or subcellular extracts, or purified ribosomal preparations, Further, the pharmacological properties and inhibitory properties thereof are observed by measuring, for example, the inhibitory constant IC ₅₀ of inhibiting protein synthesis. Incorporation of ³ H leucine or ³⁵ S methionine or similar experiments can be performed to study protein synthesis activity. A change in the amount or rate of intracellular protein synthesis in the presence of the molecule of interest indicates that the molecule of interest is a protein synthesis regulator. A decrease in the rate or amount of protein synthesis indicates that the molecule of interest is a protein synthesis inhibitor.

(4) Antimicrobial testing and other assessments. In addition, the compound of interest can be detected in the cell for anti-proliferative or anti-infective properties. For example, in the case where the target organism is a microorganism, the activity of the compound of interest can be detected by culturing the microorganism of interest in a medium (a compound with or without interest). Growth inhibition can indicate that the molecule of interest can act as a protein synthesis inhibitor. More specifically, the antibacterial pathogen activity of the compound of interest can be demonstrated by the ability of the compound to inhibit the growth of a given human pathogen strain. To this end, a group of bacterial strains can be assembled to include a wide variety of target pathogen species, and the target pathogen species containing the drug resistance mechanism have been characterized. The use of this set of microorganisms allows the determination of structure-activity relationships not only for efficacy and spectroscopy but also for the purpose of eliminating drug resistance mechanisms.

The minimum inhibitory concentration (MICs) is determined via a microdilution method (typically a final volume of 100 microliters) according to the draft outlined by The Clinical and Laboratory Standards Institute [CLSI;formerly the National Committee for Clinical Laboratory Standards (NCCLS)]. See CLSI: Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically;approved standard-fifth edition.Wayne, PA: NCCLS; 2000. Detection can also be performed in a microtiter plate according to the conventional methodology published by CLSI. See CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Seventh Edition. CLSI Document M7-A7[ISBN 1-56238-587-9] CLSI, 940 West Valley Road, Suite 1400, Wayne Pennsylvania 19087-1898 USA, 2006).

The antimicrobial and other medicinal properties of the compounds can be further evaluated in a variety of in vivo mammalian assays such as mouse or rat peritonitis infection models, skin and soft tissue models (often referred to as femoral models), or mouse pneumonia models. . There are models of sepsis or organ infection that are familiar to those skilled in the art. These efficacy models can be used as part of the evaluation process and can be used as a guide for potential efficacy in the human body. Endpoints can vary between bacterial load reduction and lethality. For lethal endpoints, the results are often expressed as PD ₅₀ values, or the dose of the agent protects 50% of the animals from death.

The medicinal properties of the compounds can also be further evaluated using recombinant human enzyme systems or by measuring the inhibition of cytochrome P450 enzymes and second phase metabolic enzyme activities using more complex systems such as human liver microsomes. Furthermore, compounds can also be assessed as enzyme substrates for these metabolic enzyme activities. These activities can be used to determine the potential of a compound to cause a drug to interact with a drug or to produce a metabolic product that is either retained or not useful for antimicrobial activity.

Compounds can also be tested for solubility and Caco-2 cells to assess the oral bioavailability of the compounds. Caco-2 cells are cell lines derived from human epithelial tissue that allow for the absorption of the drug and measurement by a single cell layer of Caco-2 cells (usually implanted in a 24-well microtiter plate (equipped with a 1 micron membrane) well). Free drug concentration can be found at the basal end of the monolayer (evaluation of drugs through the intestine The amount of the single cell layer was measured. Appropriate control to ensure single cell layer integrity and gap junction tightness is required. Drug delivery of P-glycoprotein agents can be assessed using the same system. P-glycoprotein is a pump located at the top of the cell membrane of cells that form a polarized monolayer. This pump can eliminate the active absorption or passive absorption through the cell membrane of Caco-2 cells resulting in less drug passing through the intestinal epithelium. These results are often accomplished along with solubility measurements and these factors are believed to contribute to the oral bioavailability of mammals. Measurement of oral bioavailability of animals and humans (final) using conventional pharmacokinetic experiments will determine absolute oral bioavailability.

The experimental results can also be used to model a model that is expected to contribute to the physicochemical parameters that are expected to contribute to the medicinal properties. When the model is validated, the experimental methodology can be reduced with increased confidence in model predictability.

5. Condensation and administration

The compounds of the invention are useful for the prevention or treatment of a wide variety of human or other animal (including mammalian or non-mammalian) conditions including, for example, bacterial infections, fungal infections, viral infections, diarrhea, parasitic Pest disease, and cancer. It is our intention (if specified) that the active molecules of the invention can be incorporated into any suitable carrier prior to use. The dosage of the active molecule, the mode of administration, and the use of the appropriate carrier will depend on the intended recipient and target organism. The compounds of the present invention for use in livestock and human medical formulations typically comprise a compound of the invention coexisting with a pharmaceutically acceptable carrier.

From the standpoint of compatibility with the other components of the blend, the carrier should be "acceptable" and not deleterious to the recipient. Pharmaceutically available at this point Accepted carriers are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, delayed absorbents, and the like, which are compatible with pharmaceutical administration. The use of media and agents for pharmaceutically active substances is well known in the art. However, any conventional medium or agent that is incompatible with the active compound is excluded, and its use in the composition is carefully considered. Supplementary active compounds (designated or designed in accordance with the invention and/or well known in the art) can also be incorporated into the compositions. The conjugates are conveniently present in a single dosage form and can be made by any of the methods well known in the art of pharmacy/microbiology. In general, some of the blends are made by combining the compound with a liquid carrier or a very fine solid carrier or both, and then, if desired, the product to form the desired blend.

The pharmaceutical compositions of this invention should be formulated to be compatible with their intended route of administration. Examples of routes of administration include: oral, otic, ocular, nasal, or parenteral (e.g., intravenous, intradermal, inhalation, transdermal (topical), transmucosal, and rectal) administration. A solution or suspension for parenteral, intradermal, or subcutaneous administration may include the following ingredients: a sterile diluent (eg, water for injection, physiological saline, qualitative oil, polyethylene glycol, glycerin, propylene glycol, or Other synthetic solvents); antibacterial agents (such as benzyl alcohol or methyl paraben); antioxidants (such as ascorbic acid or sodium bisulfite); chelating agents (such as ethylenediaminetetraacetic acid); buffers (such as acetic acid) a salt, citrate or phosphate); and a permeability modifier (such as sodium chloride or glucose). The pH can be adjusted by an acid or a base such as hydrochloric acid or sodium hydroxide.

Solutions useful for oral or parenteral administration can be made by any of the methods well known in the art of pharmacy, for example at Remington's The method described in Pharmaceutical Sciences, (Gennaro, A., ed.), Mack Pub., (1990). Formulations for parenteral administration may also include: glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration. The parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic. Suppositories for rectal administration can also be made by mixing the drug with a non-irritating excipient such as cocoa butter, other glycerides, or other compositions which are solid at room temperature and liquid at body temperature. . Blends can also include, for example, polyalkylene glycols (e.g., polyethylene glycol), vegetable oils, and hydrogenated naphthalenes. Blends for direct administration may include glycerin and other highly viscous compositions. Other potentially useful parenteral vehicles for these drugs include ethylene vinyl acetate copolymer granules, osmotic pumps, implantable infusion systems, and liposomes. The blend for administration by inhalation may contain an excipient such as lactose, or may be an aqueous solution containing, for example, polyoxyethylene-9-dodecylate, glycocholate, and deoxycholate. ), or an oily solution administered as a nasal drop, or a gel administered intranasally. Indwelling enema can also be used for rectal delivery.

The compositions of the present invention suitable for oral administration can be in the form of discrete units (for example, capsules, gelatin capsules, sachets, lozenges, tablets, or lozenges, each containing a predetermined dose of the drug); Or a granule composition; a solution or a suspension of an aqueous liquid or a non-aqueous liquid; or an oil-in-water or water-in-oil emulsion. The drug can also be administered in the form of a bolus, expectorant, or paste. Tablets can be made by compressing or molding the drug arbitrarily with one or more accessory ingredients. Compressed tablets may be optionally combined with a binder, lubricant, inert diluent, surfactant, or Drug compression of a form of a fluidity (for example, a powder or a granule) in which a dispersant is mixed is produced. The molded lozenge can be made by molding a mixture of the powdered medicament moistened with an inert liquid diluent and a suitable carrier in a suitable machine.

Oral compositions generally include an inert diluent or an edible carrier. The active compound and excipients can be mixed for oral purposes. An oral composition for use as a mouthwash manufactured using a liquid carrier includes a compound in a liquid carrier, and the oral composition is administered orally and snorted and spit or swallowed. Pharmaceutically compatible binders and/or adjuvants can be included as part of the oral composition. Tablets, pills, capsules, tablets, and the like, may contain any of the following components or similar properties: a binder (eg, microcrystalline cellulose, gum tragacanth, or gelatin); an excipient (eg, starch or Lactose); a disintegrant (such as alginic acid, Primogel, or corn starch); a lubricant (such as magnesium stearate or Sterotes); a slip agent (such as colloidal cerium oxide); a sweetener (such as sucrose or saccharin); Or a flavoring agent (such as mint, methyl salicylate, or an orange flavoring agent).

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (water-soluble) or dispersions and sterile powders for the preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include: physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). Suitable carriers should be stable under the conditions of manufacture and storage and should be preserved to prevent the contaminating action of microorganisms such as bacteria and fungi. A suitable carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example) Glycerin, propylene glycol, and liquid polyethylene glycol), and mixtures of the foregoing. Proper fluidity can be maintained, for example, by the use of a coating (e.g., lecithin), maintaining the desired particle size in the dispersion, and the use of a surfactant. In many cases, it is preferred to include isotonic agents, such as sugars, polyols (e.g., mannitol, sorbitol), or sodium chloride in the pharmaceutical compositions. Prolonged absorption of the injectable compositions can result from the inclusion of a delayed absorbent (e.g., aluminum monostearate and gelatin) in the composition.

Sterile injectable solutions can be prepared by combining the required amount of active compound with a suitable solvent and one or combination of the previously recited components (as appropriate), followed by sterilization. In general, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains the base dispersion medium and the additional ingredients from the foregoing. In the case of sterile powders for the manufacture of sterile injectable solutions, the method of manufacture comprises vacuum drying and lyophilization which produces the active ingredient plus powder of any additional desired constituents from the aforementioned filter sterilized solution.

The compositions suitable for intra-articular administration may be in the form of a sterile aqueous preparation of a drug, which may be in the form of a microcrystalline form, such as an aqueous microcrystalline suspension. Liposomal blends or biodegradable polymer systems can also be used to present drugs for intra-articular and intraocular administration.

Blends suitable for topical administration (including ocular treatment) include liquid or semi-liquid preparations such as rubs, lotions, gels, coatings, oil-in-water or water-in-oil emulsions (eg creams, ointments, Or a paste), or a solution or suspension (eg, a drop). Topically administered compositions for the skin surface can be dispersed by dispersing the drug in a dermatologically acceptable carrier (eg lotion, cream, soft) Made in cream, or soap). It is particularly useful to be able to form a film or layer on the skin for topical application and removal of the carrier. For topical administration of the inner tissue surface, the agent can be dispersed in a liquid tissue adhesive or other material known to enhance sorption of the tissue surface. For example, hydroxypropylcellulose or a fibrinogen/thrombin solution can be advantageously used. Alternatively, a tissue coating solution (eg, a pectin-containing blend) can be used.

For inhalation therapy, inhalation with a spray can, a nebulizer, or a nebulizer (automatic or aerosol) can be used. The blend may be in the form of a fine powder for pulmonary administration, the fine powder being from a powder inhaler or an auto-propelled powder blend. In the case of a self-propelling solution and a spray composition, the effect can be achieved by selecting a valve having the desired spray characteristics (i.e., a spray capable of producing a desired particle size), or by intrusion as a controlled particle size suspension. The active component of the powder is reached. For inhalation administration, the compound can also be delivered in the form of an aerosol spray from a high pressure container or dispenser or nebulizer containing a suitable propellant, such as carbon dioxide gas.

Systemic administration can also be via transmucosal or transdermal. For transmucosal or transdermal delivery, penetrants suitable for the permeation barrier are used in the formulation. Such penetrants are generally well known in the art and include (e.g., for transmucosal administration) detergents and bile salts. Transmucosal administration can be achieved by the use of nasal sprays or suppositories. For transdermal administration, the active compound is typically formulated into ointments, salves, gels, or creams well known in the art.

The active compound can be made together with a carrier which will protect the compound Prepare for rapid elimination of the body into, for example, controlled release blends, including buried plants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods of making controlled release of the compositions will be apparent to those skilled in the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be made according to methods well known to those skilled in the art, such as those described in U.S. Patent 4,522,811.

Oral or parenteral compositions can be formulated in a single dosage form that is easy to administer and consistent in dosage. A single dosage form refers to a single dosage of substantially discrete units for a subject to be treated; each unit contains a previously determined dosage calculated to produce the desired therapeutic effect in the presence of the desired pharmaceutical carrier. Active compound. The specifications of the single dosage form of the present invention are governed by the following and are directly dependent on the unique characteristics of the active compound, the particular therapeutic effect achieved, and the limitations inherent in the art of mixing active compounds for treating an individual. In addition, it can be administered quickly or continuously, or can be administered continuously from an external device (for example, an IV bag) via intravenous, intramuscular, or intraperitoneal administration.

Where it is desired to adhere to the surface of the tissue, the composition may include a drug dispersed in a fibrinogen-thrombin composition or other bioadhesive. The compound can then be applied, sprayed or otherwise applied to the desired tissue surface. Alternatively, the medicament may be formulated for administration to a human or other mammal, for example, by a therapeutically effective dose, by ear, eye, nose, parenteral or oral administration, and the therapeutically effective dose is, for example, provided at a time sufficient to cause the desired effect. The drug concentration is given to the target tissue.

Where the active compound is to be used as part of a transplant procedure, the active compound can be provided to the living tissue or organ to be transplanted prior to removal of the tissue or organ from the donor. Active compounds can be provided to the donor. Alternatively (or in addition to), once removed from the donor, the organ or living tissue can be placed in a preservation solution containing the active compound. In all cases, the active compound can be administered directly to the desired tissue (via injection into the tissue), or can be used using any of the methods and compositions described in the present invention and/or well known in the art. Systemic administration (eg, via the ear, eye, nose, mouth, or parenteral). Any commercially available preservation solution is advantageously employed where the drug contains a portion of the tissue or organ preservation solution. For example, useful solutions well known in the art include Collins solution, Wisconsin solution, Belzer solution, Eurocollins solution, and lactated Ringer's solution.

The compounds of the invention can be administered directly to the tissue via administration to a medical device placed in contact with the tissue. An example of a medical device is a stent that contains or is coated with one or more of the compounds of the present invention.

For example, the active compound can be applied to a stent located at a site of vascular injury. The scaffold can be made by any of the methods well known in the art of pharmacy. See, for example, Fattori, R. and Piva, T., "Drug Eluting Stents in Vascular Intervention," Lancet, 2003, 361, 247-249; Morice, MC, "A New Era in Treatment of Coronary Disease?" European Heart Journal, 2003, 24, 209-211; and Toutouzas, K. et al., "Sirolimus-Eluting Stents: A Review of Experimental and Clinical Findings, "Z. Kardiol., 2002, 91(3), 49-57. The stent may be made of stainless steel or another biocompatible metal, or may be made of a biocompatible polymer. The active compound can be bound to the surface of the stent, can be embedded and released from the polymeric material coated on the stent, or can be surrounded by and surrounded by the carrier surrounding the stent and released through the carrier. The stent can be used to Or a plurality of active compounds are administered to the tissue adjacent to the stent.

The active compounds specified or designed by the methods described in the present invention can be administered to an individual to treat a condition (prophylaxis or treatment). Gene pharmacology (i.e., studies of the relationship between individual genotypes and the response of an individual to a foreign compound or drug) can be considered along with the treatment. By altering the relationship between the dose of the pharmacologically active drug and the blood concentration, differences in the metabolic effects of the therapeutic agent can result in severe toxicity or treatment failure. Thus, the resident or clinician may consider whether to apply knowledge gained in meaningful pharmacogenetic studies to determine whether to administer and modify the dosage and/or therapeutic therapy to be treated with the drug.

In therapeutic use for treating or combating bacterial infections in a mammal, the compound or its pharmaceutical composition will provide and maintain a concentration (i.e., dose) of active ingredient in the animal that is effectively treated by the antimicrobial, or blood. The dose of medium or tissue content is administered by ear, eye, nose, mouth, parenteral, and/or topical. Generally, an effective dose of the active ingredient will range from about 0.1 to about 100, more preferably from about 1.0 to about 50 mg/kg body weight per day. The dose is also likely to depend on the following variables: the type and extent of the disease or indication being treated, and the overall patient-specific The state of health, the relative biological efficacy of the delivered compound, the drug blend, the presence and type of excipients in the blend, and the route of administration. Furthermore, it should be understood that in order to quickly achieve the desired blood or tissue content, the initial dose to be administered may be increased above the aforementioned upper limit, or the initial dose may be less than the optimal dose and the daily dose may be in a particular situation. The course of treatment can be gradually improved. If desired, the daily dose can also be divided into multiple doses, for example two to four times a day.

Various disease states or conditions in humans and other mammals have been found to be caused or mediated by nonsense mutations or missense mutations. These mutations cause or intermediate a disease state or condition by adversely affecting, for example, protein synthesis, folding, trafficking, and/or function. A significant proportion of diseases or conditions are believed to be caused by nonsense mutations or missense mutations, examples of which are: hemophilia (human eighth coagulation factor gene), neurofibromatosis (NF1 and NF2 genes) , pigmented retinitis (human USH2A gene), bullous skin disease (COL7A1 gene) of bullous epidermolysis, cystic fibrosis (cystic fibrosis transmembrane regulatory factor gene), breast and ovary Cancer (BRCA1 and BRCA2 genes), Duchenne muscle dystrophy (muscle atrophin gene), colon cancer (mismatch repair genes, mainly in MLH1 and MSH2), lysosomal storage diseases (such as Niemann's disease) Acidic neurophospholipidase gene)). See Sanders CR, Myers JK. Disease-related misassembly of membrane proteins. Annu Rev Biophys Biomol Struct. 2004; 33:25-51; National Center for Biotechnology Information (US) Genes and disease Bethesda, MD: NCBI, NLM ID: 10113860 ;and Raskó, István; Downes, C S Genes in medicine: molecular biology and human genetic disorders 1st ed. London; New York: Chapman & Hall, 1995. NLM ID: 9502404. A compound of the invention may be used to treat or prevent a non-meaning mutation or missense mutation caused by administration of an effective amount of the invention to a mammal in need thereof to inhibit a non-meaning mutation or missense mutation involved in the disease state. The disease state of the mammal.

Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker Avance 300 or Avance 500 spectrometer, or in some cases on a GE-Nicolet 300 spectrometer. Typical reaction solvents are high performance liquid chromatography (HPLC) grades or American Chemical Society (ACS) grades and anhydrous (obtained from the manufacturer unless otherwise indicated). "Chromatography" or "purified via tannin" refers to flash column chromatography using silica gel (EM Merck, Silica Gel 60, 230-400 mesh) (unless otherwise indicated).

The compounds of the invention can be made using known chemical changes adapted to the particular conditions at hand.

Some of the abbreviations used in the experimental details for the synthesis of the following examples are defined below: h or hr = hour; min = minutes; mol = mole; mmol = millimolar; M = molar concentration; μM=micromolar concentration; g=gram; μg=microgram; rt=room temperature; L=liter; mL=ml; Et ₂ O=diethyl ether; THF=tetrahydrofuran; DMSO=dimethyl hydrazine; EtOAc=acetic acid Ester; Et ₃ N = triethylamine; i-Pr ₂ NEt or DIPEA = diisopropylethylamine; CH ₂ Cl ₂ = dichloromethane; CHCl ₃ = trichloromethane; CDCl ₃ = deuterated chloroform; CCl ₄ = carbon tetrachloride; MeOH = methanol; CD ₃ OD = deuterated methanol; EtOH = ethanol; DMF = dimethylformamide; BOC = tert-butoxycarbonyl; CBZ = benzyloxycarbonyl; TBS = Tert-butyldimethylformamidin; TBSCl=tert-butyldimethylchloromethane; TFA=trifluoroacetic acid; DBU=diazabicycloundecene; TBDPSCl=tert-butyldiphenylchlorodecane; Hunig's Base=N,N-diisopropylethylamine;DMAP=4-dimethylaminopyridine; CuI=copper iodide; MsCl=methanesulfonium chloride; NaN ₃ = sodium azide; Na ₂ SO ₄ = sodium sulfate; NaHCO ₃ = sodium bicarbonate; NaOH = sodium hydroxide; MgSO ₄ = magnesium sulfate; K ₂ CO ₃ = potassium carbonate; KOH = potassium hydroxide; NH ₄ OH = ammonium hydroxide; NH ₄ Cl = ammonium chloride; SiO ₂ = cerium oxide; Pd-C = palladium / carbon; Pd (dppf) Cl ₂ = Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II).

Exemplary compounds synthesized in accordance with the present invention are listed in Table 1. Bold or dashed bonds are shown to indicate a particular stereochemistry of the chiral center, while wavy bonds indicate that the substituents can be in any orientation or indicate that the compound is a mixture. Also understand that in order to preserve space, the chemical structure of some compounds has been divided into two parts with two junction points (each junction point is indicated by a traversing key). See, for example, Compound 755, which is depicted in the following two parts:

But consistent with the complete chemical structure below:

The compounds of the invention can be made, formulated, and delivered in the form of salts, esters, and prodrugs. For convenience, the compounds are shown generally (without indicating a particular salt, ester, or prodrug form).

The compounds of the invention are shown in Table 1. LCMS (liquid phase mass spectrometry) data is provided (in the case of availability). Indicated by "NA" when data is not available. LCMS data (except as otherwise specified) was provided using the pattern [M+H]+ convention for m/z.

In a further system the compounds of the invention do not comprise a compound having the structure:

The compounds of the invention can be made using synthetic chemistry techniques well known to those skilled in the art.

Example Example 1 - Synthesis of Compound 682

{3-[(4-Bromo-benzyl)-tert-butoxycarbonyl-amino]-propyl}-carbamic acid tert-butyl ester:

A solution of 1-bromo-4-bromomethyl-benzene (17.79 g, 71.17 mmol) in toluene (50 mL) was added at 80 ° C for 30 minutes. Tri-amino 3-propyl-propyl-aminecarboxylate (16.1 g) was added dropwise. , 92.51 mmol), a mixture of triethylamine (29.6 ml, 213.5 mmol) in toluene (200 mL). The resulting mixture was heated at 80 ° C for 2 hours and then cooled to 0 ° C. Di-tert-butyl carbonate (23.5 g, 107.80 mmol) was added at 0 °C. After 2 hours, the mixture was warmed to room temperature and stirred overnight, diluted with ethyl acetate (500 mL) and washed with water (300mL) and brine (300mL). The organic solution was concentrated and purified by flash chromatography eluting elut elut elut elut ¹ NMR (300MHz, CDCl ₃ ): δ 7.44 (d, J = 8.4 Hz, 2H), 7.01 (br, 2H), 5.16 (br.s, 0.5H), 4.62 (br.s, 0.5H), 4.34 (br, 2H), 3.40 (m, 2H), 3.10 (m, 2H), 1.65 (m, 2H), 1.43 (br.s, 18H).

(3-tert-Butoxycarbonylamino-propyl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxolane-2-yl)-benzene Tert-butyl methyl]-aminecarboxylate:

{3-[(4-Bromo-benzyl)-tert-butoxycarbonyl-amino]-propyl}-carbamic acid tert-butyl ester (16.15 g, 36.46 mmol) at 80 ° C under argon atmosphere, boric acid double Mixture of pinacol ester (10.20g, 40.11mmol), KOAc (10.72g, 109.38mmol), Pd(PPh ₃ ) ₄ (0) (2.03g, 1.82mmol) and dimethylformamide (80mL) 16 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The organic solution was concentrated and purified by flash chromatography eluting elut elut elut elut ¹ NMR (300MHz, CDCl ₃ ): δ 7.76 (d, J = 8.1 Hz, 2H), 7.01 (br.s, 2H), 5.16 (br.s, 0.5H), 4.62 (br.s, 0.5H) , 4.40 (br, 2H), 3.28 (m, 2H), 3.08 (m, 2H), 1.50 (m, 2H), 1.43 (br.s, 18H), 1.34 (s, 12H).

2-(4-{[tert-Butoxycarbonyl-(3-tert-butoxycarbonylamino-propyl)-amino]-methyl}-phenyl)-3-methoxy-methyl acrylate:

(3-tert-Butoxycarbonylamino-propyl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxolane-2-yl)- tert-Butyl benzyl]-aminecarboxylate (6.00 g, 12.25 mmol), 2-iodo-3-methoxy-methyl acrylate (4.45 g, 18.38 mmol), K ₃ PO ₄ (7.79 g, 36.75 mmol) , Pd(PPh ₃ ) ₄ (0) (0.68 g, 0.61 mmol), a mixture of dioxane (60 mL) and water (12 mL) was degassed and heated at 80 ° C for 20 hours under an argon atmosphere. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The organic solution was concentrated and purified by flash chromatography eluting elut elut elut ¹ NMR (300MHz, CDCl ₃ ): δ 7.56 (s, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.20 (br.d, 2H), 5.20 (br.s, 0.5H), 4.62 ( Br.s, 0.5H), 4.39 (br, 2H), 3.86 (s, 3H), 3.74 (s, 3H), 3.27 (m, 2H), 3.08 (m, 2H), 1.62 (m, 2H), 1.50 (br.d, 9H), 1.43 (s, 9H). LCMS (EI) m/z: 501 (M+Na ⁺ ).

(3-{tert-Butoxycarbonyl-[4-(7-oxyl-1,7-dihydro-imidazo[1,2-a]pyrimidin-6-yl)-benzyl]-amino} -propyl)-tert-butyl formate:

Add 0.5 M sodium methoxide in methanol (0.5 mL, 0.25 mmol) to 2-(4-{[tert-butoxycarbonyl-(3-tert-butoxycarbonylamino-propyl)-amino]-methyl}- A mixture of phenyl)-3-methoxy-methyl acrylate (97 mg, 0.2 mmol), 1H-imidazol-2-ylamine sulfate (29 mg, 0.223 mmol), and ethanol (10 mL). The resulting mixture was refluxed for 18 hours and then aq. MeOH (0.5 mL, 0.5 mmol). The reaction mixture was concentrated, diluted with EtOAc EtOAc (EtOAc) The ethyl acetate solution was concentrated. The crude product was purified by flash chromatography eluting elut elut elut elut ¹ NMR (300MHz, CD ₃ OD): δ 8.40 (s, 1H), 7.59 (br.s, 2H), 7.29 (m, 4H), 4.46 (s, 2H), 3.23 (m, 2H), 3.02 ( m, 2H), 1.68 (m, 2H), 1.52 (br.d, 9H), 1.42 (s, 9H). LCMS (El) m/z: 498.1 (M+H ⁺ ).

6-{4-[(3-Amino-propylamino)-methyl]-phenyl}-1H-imidazo[1,2-a]pyrimidin-7-one hydrochloride (salt of compound 563) Acid salt):

Dissolve {(3-{tert-butoxycarbonyl-[4-(7-oxy-1,7-dihydro-imidazo[1,2-a]pyrimidin-6-yl) by dichloromethane (5 mL) tert-Butyl benzyl]-amino}-propyl)-carbamate (48 mg, 0.097 mmol), which was taken from trifluoroacetic acid (1 mL) and stirred at room temperature for 2 hr. The reaction mixture was concentrated, EtOAc EtOAc EtOAcjjjjjjjj ¹ NMR (300MHz, CD ₃ OD): δ 8.90 (s, 1H), 7.79 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.67 (s, 1H), 4.33 (s, 2H), 3.23 (t, J = 8.1 Hz, 2H), 3.06 (t, J = 7.5 Hz, 2H), 2.15 (m, 2H). LCMS (EI) m/z: 297.1 (M+H ⁺ ).

N-{3-[4-(7-Aoxy-1,7-dihydro-imidazo[1,2-a]pyrimidin-6-yl)-benzylamino]-propyl}-oxime Hydrochloride (564):

N,N-Di-tert-butoxycarbonyl-1-carboxylpyrazole (22 mg, 0.07 mmol) was added to compound 563 (26 mg, 0.07 mmol), N,N-diisopropylethylamine (90 mg, 0.70 mmol) In a mixture with dimethylformamide (10 mL). The reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc. The organic solution was concentrated and purified with EtOAc EtOAc EtOAc EtOAc (EtOAc Add trifluoroacetic acid (1 mL). The resulting mixture was stirred overnight and concentrated. The residue was added with EtOAc (3 mL). ¹ NMR (300MHz, D ₂ O): δ 8.41 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 2.1 Hz) , 1H), 7.35 (d, J = 2.1 Hz, 1H), 4.27 (s, 2H), 3.25 (t, J = 6.9 Hz, 2H), 3.12 (m, 2H), 1.96 (m, 2H). LCMS (El) m/z: 339.7 (M+H ⁺ ).

N-(3-{(4-Amino-butyl)-[4-(7-oxy-1,7-dihydro-imidazo[1,2-a]pyrimidin-6-yl)-benzene Methyl]-amino}-propyl)-hydrazine hydrochloride (hydrochloride of compound 616):

N,N-Di-tert-butoxycarbonyl-1-carboxylpyrazole (22 mg, 0.07 mmol) was added to compound 563 (26 mg, 0.07 mmol), N,N-diisopropylethylamine (90 mg, 0.70 mmol) In a mixture with dimethylformamide (10 mL). The reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc. The organic solution was concentrated and purified with EtOAc EtOAc EtOAc EtOAc (EtOAc

The thiolated compound (27 mg, 0.05 mmol), tert-butyl (3-oxy-propyl)-aminecarboxylate (9 mg, 0.05 mmol), acetic acid (6 mg, 0.1 mmol) and dichloromethane The mixture was stirred for 30 minutes, then sodium cyanoborohydride (13 mg, 0.2 mmol) was taken. The resulting mixture was stirred overnight, diluted with dichloromethane (15 mL) and brine. The methylene chloride solution was concentrated and purified with EtOAc EtOAc EtOAc EtOAc EtOAc

The tertiary amine product (13 mg, 0.017 mmol) was dissolved in dichloromethane (3 mL). The resulting mixture was stirred overnight and concentrated. The residue was added with EtOAc (3 mL), EtOAc (EtOAc) ¹ NMR (300MHz, CD ₃ OD): δ 8.99 (s, 1H), 7.86 (d, J = 2.1 Hz, 1H), 7.81 (br.s, 4H), 7.74 (d, J = 2.1 Hz, 1H) , 4.55 (s, 2H), 3.36 (m, 6H), 3.05 (m, 2H), 2.22 (m, 2H), 2.09 (m, 2H). LCMS (El) m/z: 396.9 (M+H ⁺ ).

{4-[2-(4-Bromo-phenyl)-7-oxy-1,7-dihydro-imidazo[1,2-a]pyrimidin-6-yl]-benzyl}-( 3-tert-Butoxycarbonylamino-propyl)-carbamic acid tert-butyl ester:

Add 0.5 M sodium methoxide in methanol (12 mL, 6 mmol) to 2-(4-{[tert-butoxycarbonyl-(3-tert-butoxycarbonylamino-propyl)-amino]-methyl}-phenyl )-3-methoxy-methyl acrylate (5.70 g, 11.92 mmol), 5-(4-bromo-phenyl)-1H-imidazol-2-ylamine (2.84 g, 11.92 mmol) and ethanol (60 mL) In the mixture. The resulting mixture was refluxed for 18 h and then aq. The reaction mixture was concentrated, diluted with EtOAc EtOAc (EtOAc) The ethyl acetate solution was concentrated. The crude product was purified by flash chromatography eluting elut elut elut ¹ NMR (300MHz, CDCl ₃ ): δ 7.96 (s, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.54 (m, 2H), 7.35 (s, 1H), 7.27 (d, J = 8.1 Hz, 2H), 5.25 (br.s, 0.5H), 4.70 (br.s, 0.5H), 4, 44 (s, 2H), 3.29 (m, 2H), 3.11 (m, 2H), 1.67 ( m, 2H), 1.52 (br.d, 9H), 1.44 (s, 9H). LCMS (EI) m/z: 654 (M+H ⁺ ).

6-{4-[(3-Amino-propylamino)-methyl]-phenyl}-2-(4-bromo-phenyl)-1H-imidazo[1,2-a]pyrimidine- 7-keto hydrochloride (hydrochloride of compound 617):

Dissolve {4-[2-(4-bromo-phenyl)-7-oxy-1,7-dihydro-imidazo[1,2-a]pyrimidin-6-yl in dichloromethane (5 mL) tert-Butyl phenylmethyl}-(3-tert-butoxycarbonylamino-propyl)-aminecarboxylate (100 mg, 0.153 mmol) was obtained from trifluoroacetic acid (1 mL). The reaction mixture was concentrated, EtOAc EtOAc EtOAcjjjjjjj ¹ NMR (300MHz, CD ₃ OD): δ 8.99 (s, 1H), 8.24 (s, 1H), 7.75 (m, 8H), 4.30 (s, 2H), 3.32 (t, J = 8.1 Hz, 2H) , 3.09 (t, J = 7.5 Hz, 2H), 2.17 (m, 2H). LCMS (EI) m/z: 454 (M+H ⁺ ).

4-[6-(4-{[tert-Butoxycarbonyl-(3-tert-butoxycarbonylamino-propyl)-amino]-methyl}-phenyl)-7-oxy-1,7 -Dihydro-imidazo[1,2-a]pyrimidin-2-yl]-benzoic acid 2,5-dioxy-pyrrolidin-1-yl ester:

{4-[2-(4-Bromo-phenyl)-7-oxy-1,7-dihydro-imidazo[1,2-a]pyrimidin-6-yl]- in a sealed tube Benzyl}-(3-tert-butoxycarbonylamino-propyl)-carbamic acid tert-butyl ester (1.50 g, 2.3 mmol), hydroxybutaneimine (0.40 g, 3.45 mmol), 9,9- a mixture of dimethyl-4,5-bis(diphenylphosphino)xanthene (67 mg, 0.115 mmol), palladium acetate (26 mg, 0.115 mmol), triethylamine (700 mg, 6.9 mmol), and DMSO (3 mL) Degassed and refilled with carbon monoxide (20 psi). The reaction mixture was heated at 80 ° C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (30 mL). The methylene chloride solution was concentrated and purified by flash chromatography eluting with EtOAc ¹ NMR (300MHz, CDCl ₃ ): δ 8.14 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H), 7.96 (s, 1H), 7.64 (d, J = 9.1 Hz, 2H), 5.59 (s, 1H), 7.45 (d, J = 9.1 Hz, 2H), 5.25 (br.s, 0.5H), 4.69 (br.s, 0.5H), 4.45 (s, 2H), 3.29 (m, 2H), 3.11 (m, 2H), 2.92 (s, 4H), 1.67 (m, 2H), 1.52 (br.d, 9H), 1.44 (s, 9H). LCMS (EI) m/z: 715 (M+H ⁺ ).

6-{4-[(3-Amino-propylamino)-methyl]-phenyl}-2-[4-(piperazine-1-carbonyl)-phenyl]-1H-imidazo[1 , 2-a]pyrimidin-7-one hydrochloride (hydrochloride of compound 682):

4-[6-(4-{[tert-Butoxycarbonyl-(3-tert-butoxycarbonylamino-propyl)-amino]-methyl}-phenyl)-7-oxy group at room temperature -1,7-dihydro-imidazo[1,2-a]pyrimidin-2-yl]-benzoic acid 2,5-dioxy-pyrrolidin-1-yl ester, 1-tert-butoxycarbonylpiper A mixture of the oxazine ( 229 mg, 1.23 mmol) and dichloromethane (5 mL) was stirred overnight, concentrated and purified by flash chromatography (0 to 10% methanol in dichloromethane) 330 mg, yield 76%). ¹ NMR (300MHz, CDCl ₃ ): δ 8.03 (s, 1H), 7.85 (d, J = 13.8 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.42 (s, 1H), 7.26 (d, J = 13.8 Hz, 2H), 5.35 (br.s, 0.5H), 4.95 (br.s, 0.5H), 4.44 (s, 2H), 3.70 (m, 2H), 3.44 (m, 6H), 3.20 (m, 2H), 3.10 (m, 2H), 1.67 (m, 2H), 1.52 (br.d, 9H), 1.48 (s, 9H) 1.44 (s, 9H). LCMS (EI) m/z: 786 (M+H ⁺ ).

The guanamine product (330 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 2 hr. The reaction mixture was concentrated, EtOAc EtOAc EtOAcjjjjjjj ¹ NMR (300MHz, CD ₃ OD): δ 9.02 (s, 1H), 8.34 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 4.35 (s, 2H), 3.90 (br.s, 4H), 3.34 (m, 2H), 3.25 (t, J = 7.5 Hz, 2H), 3.12 (t, J = 7.8 Hz, 2H), 2.17 (m, 2H). LCMS (El) m/z: 486.1 (M+H ⁺ ).

Example 2 - Synthesis of pyrrolopyrimidine

Synthesis of Compound 3:

Compound 2 (65.0 g, 373 mmol) was dissolved in ethanol (150 mL). The flask was purged with argon. Then, Compound 1 (55.93 g, 373 mmol) was added, and the mixture was stirred at room temperature for 2 hr. Then, the reaction solution was taken for 20 minutes, and a suspension of sodium borohydride (14.18 g, 373 mmol) in toluene (150 mL) at 0 ° C was added to the mixture. The ice bath was removed and the resulting mixture was stirred at room temperature for 3 hours. 1N Hydrochloric acid (750 mL) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. Potassium carbonate (205.9 g, 1.49 mol), di-tert-butyl dicarbonate (81.41 g, 373 mmol) and tetrahydrofuran (200 mL) were added to the solution and stirred at room temperature for 23 hours. The reaction solution was taken up in ethyl acetate and 1:1 brine/water. The aqueous layer was washed with ethyl acetate (2 x 300 mL). The combined organic layer was washed with brine (500 mL) dried over sodium sulfate. The crude product was purified by EtOAc EtOAc (EtOAc) ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.43 (bs, 18H), 1.63 (m, 2H), 2.95-3.30 (m, 4H), 4.45 (m, 2H), 5.93 (bs, 1H), 7.22 ( Bs, 1H), 7.34 (bs, 1H), 7.78 (d: 8 Hz, 1H), 8.19 (d: 8 Hz, 1H).

Synthesis of Compound 5:

Methanol (3 L) and water (750 mL) were added to a mixture of compound 3 (42.28 g, 103.5 mmol) and compound 4 (24.54 g, 103.5 mmol). The mixture was vigorously stirred at room temperature for 30 minutes while being open to air. Take Cu(OAc) _{2 one by one} . H ₂ O (20.67 g, 103.5 mmol) and TMEDA (18.63 mL, 124.3 mmol) were added. The solution was stirred at room temperature for 5 hours while open to air. Once the reaction was complete, the solution was concentrated to 0.7 L and then the solution was partitioned between dichloromethane (700 mL) and 20% aqueous ammonia/water (500 mL) saturated with ammonium chloride. The aqueous layer was washed with dichloromethane (500 mL, 200 mL). The combined organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by Combi flash chromatography (A: dichloromethane B: 15:1 methylene chloride/2N ammonia in methanol, 0 to 100% B, 2 330 g column). The product was obtained as a white solid (35.52g, yield 58%); LCMS (ESI) : m / e 600 (M + H) +.

Synthesis of Compound 6:

Compound 5 (10.0 g, 16.68 mmol) was dissolved in tetrahydrofuran (40 mL). The flask was purged with argon. Pyridine (40 mL) and BzCl (3.10 mL, 26.69 mmol) were then added. The solution was stirred at room temperature for 3 hours under an argon atmosphere. Methanol (4 mL) was added, and the mixture was stirred at room temperature for 10 min, then the mixture was partitioned between ethyl acetate (200 mL), heptane (100 mL) and 5% potassium hydrogen carbonate / water (200 mL). The aqueous layer was washed with ethyl acetate (100 mL, 50 mL). The combined organic layer was washed with 5% EtOAc EtOAc (EtOAc)EtOAc. The crude product was purified by Combi flash chromatography (0 to 100% ethyl acetate / heptane, 1 330 g column) for 55 min. The product obtained white powder (9.81g, yield 84%); LCMS (ESI) : m / e 704 (M + H) +.

Synthesis of Compound 8:

3,5-Dibromobenzoic acid 7 (3.35 g, 11.97 mmol) was dissolved in dimethylformamide (30 mL). TBTU (5.38 g, 16.76 mmol) was added, and the solution was stirred at 22 ° C for 5 minutes under an argon atmosphere. Diisopropylethylamine (4.95 mL, 29.92 mmol) was added, followed by the addition of piperazine S, S-dioxide (2.26 g, 16.76 mmol). The mixture was stirred at 22 ° C for 24 hours, then the mixture was partitioned between ethyl acetate (200 mL) and EtOAc. The organic phase was washed with water (200 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified via flash chromatography (200 g) eluting with EtOAc EtOAc Compound 8 (1.72 g, yield 36%) was obtained as a solid. ^{1 H-NMR (300MHz, DMSO} -d6) δ 3.10-3.30 (m, 4H), 3.64 (m, 2H), 3.98 (m, 2H), 7.75 (d: 2.0Hz, 2H), 7.97 (t: 2.0 Hz, 1H).

Synthesis of Compound 9:

Compound 8 (1.72 g, 4.33 mmol), N-tert-butoxycarbonylpiperazine (931 mg, 5.0 mmol), potassium carbonate (1.26 g, 9.1 mmol), cuprous iodide (83 mg, 0.43 mmol), and L- Proline (100 mg, 0.87 mmol) was suspended in dimethyl hydrazine (15 mL). The mixture was purged with argon, and then the mixture was stirred at 85 ° C for 20 hours under an argon atmosphere. The mixture was cooled to rt. EtOAc (EtOAc)EtOAc. The crude product was purified by flash chromatography (200 g) (2% EtOAc (EtOAc) The solid compound 9 (0.65 g, yield 30%) was obtained. ¹ H-NMR (300MHz, DMSO-d6) δ 1.42 (s, 9H), 3.12-3.28 (m, 8H), 3.44 (m, 4H), 3.64 (m, 2H), 4.00 (m, 2H), 7.02 (bs, 2H), 7.17 (bs, 1H).

Synthesis of Compound 10:

Compound 9 (0.63 g, 1.25 mmol) was dissolved in tetrahydrofuran (10 mL). The solution was placed in a pressure vessel and purged with argon, followed by cuprous iodide (60 mg, 0.313 mmol), Pd(PPh ₃ ) ₄ (145 mg, 0.125 mmol), triethylamine (1.40 mL, 10 mmol) and Trimethylcarbinyl acetylene (0.353 mL, 2.5 mmol) was added. Seal the pressure vessel and stir the mixture at 45 to 50 °C. After 3 hours, the mixture was diluted with EtOAc (EtOAc) (EtOAc) A semisolid (1.2 g) was obtained which was taken up in methanol (70 mL). The solution was purged with argon, potassium carbonate (1.0 g) was added, and the mixture was stirred at 45 ° C for 30 minutes under an argon atmosphere. The mixture was filtered, concentrated and purified by flash chromatography eluting eluting To give a white solid foam compound 10 (0.425g, yield 76%); LCMS (ESI) : m / e 448 (M + H) +.

Synthesis of Compound 11:

Compound 6 (669 mg, 0.95 mmol) and Compound 10 (425 mg, 0.95 mmol) were placed in a pressure vessel, and anhydrous dimethylformamide (15 mL) was added. The solution was flushed with argon, then cuprous iodide (46 mg, 0.24 mmol), Pd(PPh ₃ ) ₄ (110 mg, 0.095 mmol), triethylamine (1.06 mL, 7.6 mmol) was added and the pressure vessel was sealed. The mixture was stirred at 22 ° C for 15 minutes. It was then warmed to 80 to 85 ° C and the mixture was stirred for 14 hours. It was cooled to the ring temperature, then methanol (10 mL) was added, the pressure vessel was sealed, and the mixture was stirred at 90 ° C for 3 hours. Cooled to ambient temperature, the mixture was taken distributed saturated KH ₂ PO ₄ / water (250 mL) and ethyl acetate (200mL), the take brine (150 mL) The organic phase was washed, dried over sodium sulphate above, filtered, and concentrated. The crude product was purified by flash chromatography (150 g) EtOAc (EtOAc:EtOAc To give a yellow solid compound 11 (490mg, yield 56%); LCMS (ESI) : m / e 920 (M + H) +.

Synthesis of Compounds 12A and 12B:

The compound 11 (490 mg, 0.533 mmol) was dissolved in dichloromethane (20 mL), then trifluoroacetic acid (20 mL) was added and the mixture was stirred at 22 ° C for 40 min. Dichloromethane (30 mL) was added and the mixture was concentrated in vacuo to a viscous oil. Water (3 mL) and ethanol (70 mL) were added, and the mixture was concentrated to give crude compound 12A. The solid residue was dissolved in [(10% methanol-90% water) + 0.15% trifluoroacetic acid] (40 mL). Take the solution (10mL) and inject it into Dynamax 41.4mm, C-18 preparative high performance liquid chromatography unit (protection + column), spend 10 minutes to 10% to 55% (methanol / water + 0.15% trifluoroacetic acid) Solvent gradient elution. The complex pure chromatographic fraction was concentrated to dryness along with ethanol. The sample was treated with 1N aqueous hydrochloric acid (5 mL) and ethanol (70 mL) and concentrated. This operation was repeated to obtain a solid, from the water - acetonitrile (4: 1) the solid was lyophilized to give a yellow powder of compound 12B (78mg); LCMS (ESI ): m / e 619 (M + H) +.

Synthesis of Compound 13:

The solvent [(10% methanol-90% water) + 0.15% trifluoroacetic acid] mixture solution (30 mL, 0.40 mmol) previously described for compound 12A was concentrated to a viscous oil together with ethanol. A sample of dimethylformamide (10 mL) and diisopropylethylamine (0.53 mL, 3.2 mmol) was dissolved to dissolve the sample. N,N'-Di-tert-butoxycarbonyl-1-carboxyrylpyrazole (149 mg, 0.48 mmol) was added, and the mixture was stirred at 22 ° C for 15 hours. Ethanol (80 mL) was added and the mixture was concentrated in vacuo (<1 mm Hg, 45 ° C) to afford viscous oil. A mixture of dichloromethane (25mL) and trifluoroacetic acid (30mL) dissolved the viscous oil. The mixture was stirred at 22 ° C for 2 hours, then dichloromethane (70 mL) was added and the mixture was concentrated, and the residue was dissolved in methanol (30 mL) and treated with Amberslyst A26 (OH) resin (10 g). The mixture was stirred for 1 hour, filtered and the filtrate was concentrated to a semi solid. The sample was purified by preparative high performance liquid chromatography Dynamax 41.4mm, C-18 preparative high performance liquid chromatography unit (protection + column), and spent 10 minutes to 10% to 55% (methanol / water + Solvent gradient elution of 0.15% trifluoroacetic acid). The complex pure chromatographic fraction was concentrated to dryness along with ethanol. The sample was treated with 1N aqueous hydrochloric acid (5 mL) and ethanol (70 mL) and concentrated. This operation was repeated to obtain a solid, from the water - acetonitrile (4: 1) the solid was lyophilized to give compound as a yellow powder 13 (122mg); LCMS (ESI ): m / e 661 (M + H) +.

Example 3 - Synthesis of Compound 2009a ("a" series) and 2029a ("b" series)

Synthesis of 2a and 2b:

The hydrazine salt 12 (5.24 g, 9.88 mmol), 1a (or 1b) (2.65 g, 9.88 mmol), potassium carbonate (1.36 g, 9.88 mmol) and 18-crown-6 (catalytic amount) were heated under reflux in an argon atmosphere. A mixture of toluene (50 mL) solution was taken overnight. Upon completion, the mixture was cooled to room temperature and water was added. The aqueous layer was extracted with ethyl acetate (3 x 75 mL). The residue was purified via silica gel chromatography (2:1Heptane /EtOAc). Compound 2a was cleanly isolated as a mixture of E and Z isomers (3.78 g, yield 87%).

Synthesis of 3a and 3b:

A 10% palladium on carbon (0.76 g, 20% w/w) was added to a flask containing an ethyl acetate solution of quinone imine 2a (3.78 g, 8.58 mmol) (or 2b). The flask was evacuated and filled with hydrogen via a balloon assembly. Stirring was continued for 45 minutes at room temperature during which time the contents were flushed with argon. The mixture was filtered through celite, and then solvent was evaporated to yield the desired product 3a (3.77 g).

Synthesis of 4a and 4b:

3a (3.70 g, 8.37 mmol) (or 3b) was dissolved in absolute ethanol in a screw cap pressure tube. Hydrazine hydrate (1.62 mL, 33.5 mmol) was added to the solution and heated at 65 ° C for 8 hours. After cooling to room temperature, the slurry was filtered to remove the white solid by-product, and the resulting solution was concentrated to dryness. Water was added and the aqueous layer was extracted three times with ethyl acetate. The combined organics were then washed with water and brine and dried over sodium sulfate. Evaporation of the solvent gave aqqqqqqqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ 14.9 mmol) treatment. After stirring for 1 hour, water was added and the organic layer was collected, dried over sodium sulfate and evaporated. The crude residue was purified by silica gel chromatography (2:1Heptane/ethyl acetate) to afford viscous oil 4a (3.06 g, yield 92%).

Synthesis of 5a and 5b:

Compound 5a (and 5b) was produced via the same two steps as the Sonogashira deprotection sequence for the synthesis of alkyne 10. Starting from 4a (1.5 g), the desired product (0.69 g, yield 53%) was obtained.

Synthesis of 7a and 7b:

Pyrrolopyrimidines 7a and 7b were produced from the common intermediate 6 and the coupling of the alkyne 5a and 5b according to the aforementioned procedure for the synthesis of 11. 5a (690mg) starts to give an orange-brown solid of the desired compound (1.23 g of, yield 81%); LCMS (ESI) : m / e 863.4 (M + 1) +.

Synthesis of 8a and 8b:

7a (0.60 g, 0.69 mmol) (and 7b) was deprotected with trifluoroacetic acid in the manner described in the manufacture of the previous 12A (authorized remarks: provisional patent application number). This conversion was carried out for 2 hours by treating the starting material with 6N hydrochloric acid (8 mL) and absolute ethanol (30 mL) at 50 °C. The solvent was evaporated, the crude residue was then taken from any one of a route step (without further purification) to the next; LCMS (ESI): m / e 663.3 (M + 1) +.

Synthesis of 9a and 9b:

The oxime formation was carried out according to the draft used to make compound 13 (authorized remark: provisional patent application number), except that the starting material 8a (~0.48 g, 0.65 mmol) (and 8b) was used as a crude oil or semi-solid. No methanol-water solution is used. Anhydrous ethanol (35 mL) was taken to dissolve the protected hydrazine intermediate, followed by 6N hydrochloric acid (10 mL) to remove the tert-butoxycarbonyl group. The solution was heated to 70 ° C for 3 hours. The mixture was concentrated immediately after cooling and further dried by azeotropy with additional absolute ethanol. The yellow-brown solid was used directly in the next step without further purification.

Synthesis of 11a and 11b:

Trifluoroacetic acid (30 mL) was taken in an argon atmosphere to dissolve hydrazine 9a (or 9b). The thioanisole (0.5 mL) was added dropwise, and the solution was stirred at room temperature for 3 to 4 hours. The solvent was evaporated immediately after completion to give an oil or semi-solid. Diethyl ether was added and a liquid layer containing most of the residual thioanisole was poured out. Next, [(20% methanol-90% water) + 0.15% trifluoroacetic acid] (20 mL) was taken to dissolve the crude 10a. The solution (10 mL) was injected onto Dynamax 41.4 mm, C-18 preparative high performance liquid chromatography unit (protection + column), and spent 10 minutes at 10% to 65% (methanol / water + 0.15% trifluoroacetic acid). Solvent gradient elution. The complex pure chromatographic fraction was concentrated to dryness along with ethanol. The sample was treated with 1N aqueous hydrochloric acid (5 mL) and ethanol (70 mL) and concentrated. This operation was repeated to obtain a solid, from the water - acetonitrile (4: 1) the solid was lyophilized to give compound 11a as a yellow powder (171mg); LCMS (ESI) m / e 571.2 (M + 1) +; 1 H NMR (300MHz, D ₂ O) δ 1.50-1.61 (m, 4H), 1.87-1.97 (m, 2H), 2.56 (bs, 2H), 2.87 (bs, 2H), 3.08 (t, J = 6.9 Hz, 2H) ), 3.20 (t, J = 6.9 Hz, 2H), 4.25 (s, 2H), 6.60 (s, 1H), 7.02 (s, 1H), 7.21 (s, 1H), 7.32 (s, 1H), 7.41 (d, J = 8.7, 2H), 7.57 (d, J = 8.7 Hz, 2H), 8.28 (s, 1H)

11b data: LCMS (ESI) m/e 555.3 (M+1) ⁺ ; ¹ H NMR (300 MHz, D ₂ O) 61.33-1.46 (m, 4H), 1.72-1.80 (m, 2H), 2.44-2.47 (m, 2H), 2.70-2.75 (m, 2H), 2.84 (t, J = 8.0 Hz, 2H), 3.03 (t, J = 8.0 Hz, 2H), 4, 09 (s, 2H), 6.51 ( s, 1H), 7.25-7.27 (m, 3H), 7.40-7.44 (m, 3H), 7.51 (s, 1H), 8.13 (s, 1H).

Example 4 - Synthesis of Triazolopyrimidinone

Reaction Scheme 1. Synthetic route for the manufacture of [1,2,4]triazolo[1,5-a]pyrimidin-5-one

Example: 6-{4-[(3-Amino-propylamino)-methyl]-phenyl}-2-(4-fluoro-phenyl)-3H-[1,2,4]triazolo[ 1,5-a]pyrimidin-5-one

5-(4-Fluorophenyl)-3-amino-1,2,4-triazole (0.50 g, 2.81 mmol) was added to 2-(4-{[tert-butoxycarbonyl-(3-tert-butoxy) A solution of methyl carbonylamino-propyl)-amino]-methyl}-phenyl)-3-methoxy-methyl acrylate (1.13 g, 2.16 mmol) in methanol (10 mL). A 0.5 M sodium methoxide solution in methanol (5.6 mL, 2.81 mmol) was added dropwise, and the orange mixture was gradually warmed to 50 ° C and kept at 50 ° C overnight. Methanol was removed in vacuo immediately after completion and the residue was taken in dichloromethane (100 mL) and water (100 mL). The organic layer was collected, dried over sodium sulfate and concentrated to an orange-yellow precipitate. The crude precipitate was loaded onto a ruthenium tube column and eluted under the following conditions: eluted with 100:0 dichloromethane/methanol at a flow rate of 40 mL/min for 5 minutes; at a flow rate of 40 mL/95/5 dichloromethane/methanol. The mixture was eluted for 15 minutes; eluted with 90:10 dichloromethane/methanol at a flow rate of 40 mL/min for 15 minutes; the desired product was collected from the column. The solvent was evaporated to give a pale yellow solid. The solid was then dissolved by taking dichloromethane (10 mL) then trifluoroacetic acid (3 mL) was added to remove the tert-butoxycarbonyl protecting group. A complete transition was seen after 1 hour at room temperature. Dichloroethane (10 mL) was added, followed by removal of the volatiles under reduced pressure. The addition of 1N hydrochloric acid (about 3 mL) was followed by evaporation of water to accelerate the formation of the hydrochloride. Lyophilized from 1N hydrochloric acid / acetonitrile to give the desired product as a white powder (396 mg) (from over 90% tert-butoxycarbonyl protected ^{compound): 1 H NMR (300MHz,} DMSO) δ 1.99-2.09 (m, 2H , CH ₂ ), δ 2.90-3.02 (m, 4H, NCH ₂ ), δ 4.17 (bs, 2H, CH ₂ Ar), δ 7.38 (t, J = 8.9 Hz, 2H, Ar), δ 7.66 (d, J = 8.4 Hz, 2H, Ar), δ 7.76 (d, J = 8.4 Hz, 2H, Ar), δ 8.07-8.12 (m, 3H, Ar, NH), δ 8.99 (s, 1H, CH=C) , δ 9.54 (bs, 2H, NH), δ 13.4 (bs, 1H, NH); LCMS (ES ⁺ ) m/z 393.0 (MH ⁺ ).

N-(3-{4-[2-(4-Fluoro-phenyl)-5-oxy-3,5-dihydro-[1,2,4]triazolo[1,5-a] Pyrimidine-6-yl]-benzylamino}-propyl)-indole

Triethylamine (0.301 mL, 2.16 mmol) was added to a suspension of EtOAc (250 mg, 0.54 mmol Next, N,N'-bis-tert-butoxycarbonyl-1-carboxyrylpyrazole (167 mg, 0.54 mmol) was added to the solution, and the progress of the reaction was monitored by LCMS. After 5 hours, the solvent was azeotroped with toluene/ethanol (a small amount of dimethylformamide remained). The crude material was taken up in dichloromethane and water. The layers were separated and the aqueous phase was extracted twice with additional dichloromethane. The combined organics were washed with brine, dried over sodium sulfate and concentrated to give a crude mixture. Purification by preparative thin layer chromatography (2000 [mu]m plate, 10%MeOH / dichloromethane) The deprotection of the diamine and the formation of the hydrochloride were carried out in the manner described above, and lyophilized to give 145 mg (yield: 53%): ¹ H NMR (300 MHz, DMSO) δ 1.86-1.93 (m, 2H, CH) ₂ ), δ 2.89-2.95 (m, 2H, NCH ₂ ), δ 3.20-3.27 (m, 2H, NCH ₂ ), δ 4.19 (bs, 2H, CH ₂ Ar), δ 7.35 (t, J = 9.0 Hz) , 2H, Ar), δ 7.63 (d, J = 7.8 Hz, 2H, Ar), δ 7.68 (d, J = 7.8 Hz, 2H, Ar), δ 8.07-8.12 (m, 2H, Ar), δ 8.99 (s, 1H, CH=C), δ 9.35 (bs, 2H, NH), δ 13.4 (bs, 1H, NH); LCMS (ES ⁺ ) m/z 435.3 (MH ⁺ ).

Example 5 - Synthesis of Compound 562

3-(2,4-Dioxy-3,4-dihydro-2H-pyrimidin-1-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (4):

A suspension of 1 (1 g, 5.3 mmol) and 2 (1.26 g, 5.87 mmol) in tetrahydrofuran was added dropwise to DIAD (1.16 mL, 5.87 mmol) and stirred at room temperature overnight. The clear solution was concentrated under reduced pressure to a viscous liquid. The crude mixture was purified via silica gel flash chromatography (50 to 60% ethyl acetate-heptane) to afford pure. LCMS (EI) m/z 408.1 (M+Na ⁺ ). _{^{1 H NMR (300MHz, CDCl 3}} ): δ 7.94 (2H, d), 7.67 (1H, t), 7.50 (2H, t), 7.27 (1H, d), 5.87 (1H, d), 5.14 (1H, m), 3.78 (1H, dd), 3.54 (3H.m), 2.34 (1H, m), 2.11 (1H, m), 1.49 (9H, s). A solution of 3 (2 g) in 2N ammonia-methanol (30 mL) was stirred at room temperature overnight. The solution was evaporated under reduced pressure to give abr. LCMS (EI) m / z 281.1 (M + H) + 1 H NMR (300MHz, CDCl 3): δ 9.41 (1H, bs), 7.18 (1H, d), 5.78 (1H, d), 5.17 (1H, m), 3.76 (1H, dd), 3.52 (3H.m), 2.33 (1H, m), 2.07 (1H, m), 1.48 (9H, s).

3-(5-Bromo-2,4-dioxy-3,4-dihydro-2H-pyrimidin-1-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (5)

To a mixture of 4 (0.6 g, 2.13 mmol) and N-bromosuccinimide (0.456 g, 2.56 mmol) was added dimethylformamide (15 mL) and stirred at room temperature for 3 to 4 hours. The solution was taken up in ethyl acetate (50 mL) and 10% sodium thiosulfate (40 mL). The organic layer was separated, washed with brine (3×50 mL), dried over anhydrous sodium sulfate The crude material was purified via EtOAc (EtOAc) elute _{^{1 H NMR (300MHz, CDCl 3}} ): δ 9.08 (1H, bs), 7.43 (1H, s), 5.14 (1H, m), 3.78 (1H, dd), 3.53 (3H.m), 2.35 (1H, m), 2.08 (1H, m), 1.49 (9H, s).

3-{5-(2-tert-butoxycarbonylamino-phenyl)-2,4-dioxy-3,4-dihydro-2H-pyrimidin-1-yl}-pyrrolidine-1-carboxylate Tert-butyl acid ester (7)

Dioxane (8 mL) and water (2 mL) were added 5 (0.515 g, 1.43 mmol), 6 (0.547 g, 1.72 mmol), Pd(PPh ₃ ) ₄ (0.165 g, 10 mol%) and potassium carbonate (0.592 g) , 4.29 mmol) in a mixture. The suspension was purged under argon under vacuum and heated at 90 ° C in a sealed tube. After 15 hours, the solution was concentrated, and the residue was partitioned between ethyl acetate (50mL) and brine (30mL). The organic layer was separated, EtOAc (EtOAc m. LCMS (EI) m / z 495.1 (M + Na) +. _{^{1 H NMR (300MHz, CDCl 3}} ): δ 9.28 (1H, b), 7.75 (1H, d), 7.40 (1H, t), 7.28 (1H, s), 7.12 (1H, t), 7.05 (1H, d), 5.23 (1H, m), 5.11 (1H, dd), 3.45 (3H, m), 2.35 (1H, m), 2.11 (1H, m), 1.48 (9H, s), 1.45 (9H, s ).

3-pyrrolidin-3-yl-3,9-dihydro-1,3,9-triaza-indol-2-one (9)

Dichloromethane (5 mL) was taken first, then triethylamine (0.176 mL, 1.27 mmol) and N,N-dimethylaminopyridine (0.039 g, 0.312 mmol) were added to 7 (0.3 g, 0.635 mmol) and 2- A mixture of toluenesulfonium chloride (0.278 g, 1.27 mmol). The reaction solution was stirred for 3 hours under an inert atmosphere, then diazabicycloundecene (0.191 mL, 1.27 mmol) was added and stirred at room temperature overnight. Passive cold water passivation and the mixture was taken in ethyl acetate (50 mL) and brine (30 mL). The organic layer was separated, washed with brine (3×30 mL), dried over anhydrous sodium sulfate and evaporated. The crude material was obtained, which was purified EtOAcjjjjjj _{^{1 H NMR (300MHz, CDCl 3}} ): δ 8.11 (1H, d), 8.09 (1H, s), 7.60 (1H, d), 7.42 (1H, t), 7.27 (1H, t), 5.44 (1H, m), 3.86 (1H, m), 3.60 (1H, m), 2.48 (1H, m), 2.25 (1H, m), 1.73 (9H, s), 1.51 (9H, m). A solution of 8 (0.2 g) in dichloromethane (10 mL) was taken from trifluoroacetic acid (3 mL) and stirred at room temperature for 2 hr. The solution was evaporated under reduced pressure and dried in vacuo to give 9. LCMS (EI) m / z 276.3 (M + Na) +. This 9 trifluoroacetate was used in the next step without further purification.

2-{4-[3-(2-Aoxy-2,9-dihydro-1,3,9-triaza-indol-3-yl)-pyrrolidin-1-yl]}-isoindole哚-1,3-diketone (11):

A solution of triethylamine (0.245 mL, 1.762 mmol) in acetonitrile (10 mL) was taken and purified from EtOAc (EtOAc) After a lapse of 3 days, the solution was concentrated and purified EtOAcqqqqqqq LCMS (EI) m / z 456.1 (M + H) +.

{4-[3-(2-Aoxy-2,9-dihydro-1,3,9-triaza-indol-3-yl)-pyrrolidin-1-yl]}-aminocarboxylic acid tert-butyl Ester (12):

An excess of hydrazine (0.1 mL) was added to a solution of 11 (0.08 g, 0.176 mmol) in ethanol (8 mL) and stirred at room temperature for 3 hrs and then heated to 50 ° C for 3 hr. The solution was concentrated, and the residue was dissolved in tetrahydrofuran (3 mL) and water (3 mL). Then, di-tert-butyl dicarbonate (0.384 g, 1.76 mmol) and potassium carbonate (0.1 g, 0.7 mmol) were added and stirred at room temperature overnight. The solution was concentrated under reduced pressure and the residue was crystallised from ethyl acetate (30mL) and brine (30mL). The organic layer was separated and extracted with ethyl acetate (4 x 10 mL). All organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified via flash chromatography (10% MeOH in dichloromethane) to afford 12. LCMS (EI) m / z 426 (M + H) +. _{^{1 H NMR (300MHz, CDCl 3}} ): δ 8.93 (1H, s), 7.71 (2H, dd), 7.38 (1H, t), 7.20 (1H, t), 5.67 (1H, bt), 4.75 (1H, m), 3.29 (1H, t), 3.20 (2H, d), 3.10 (1H, d), 2.60 (4H, m), 2.23 (1H, q), 1.90 (1H, m), 1.62 (4H, bs) ), 1.43 (9H, s).

胍 Intermediate 13:

Trifluoroacetic acid (1 mL) was added to a solution of 12 (40 mg) dichloromethane (4 mL) The solution was evaporated under reduced pressure and co- evaporated with dichloromethane (3×3 mL). The trifluoroacetate salt was treated with 0.6 N hydrochloric acid (2 mL). After 2 hours, the solution was lyophilized. LCMS (EI) m / z 325.8 (M + H) +. _{^{1 H NMR (300MHz, D 2}} O): δ 8.65 (1H, s), 7.69 (1H, d), 7.37 (1H, dd), 7.28 (1H, t), 7.22 (1H, t), 5.15 (1H , m), 4.05 (1H, d), 4.01 (1H, t), 3.60 (1H, t), 3.30 (3H, m), 3.00 (2H, t), 2.98 (1H, m), 2.54 (1H, m), 1.80 (2H, m), 1.72 (2H, m). First, dimethylformamide (2 mL) was taken, then N,N-diisopropylethylamine (0.131 mL, 0.753 mmol) was added to the hydrochloride (0.03 g, 0.0753 mmol) and (t-butoxycarbonylimine) A mixture of tert-butyl 15 -(pyridazol-1-yl-methyl)-aminecarboxylate (0.035 g, 0.113 mmol). The solution was stirred at ambient temperature for 2 hours and then diluted with ethyl acetate (30 mL). The ethyl acetate layer was washed with brine (3×20 mL), dried over anhydrous sodium sulfate. The crude material was purified by EtOAc EtOAc EtOAc EtOAc LCMS (El) m/z 568.2 (M+H) ⁺ . _{^{1 H NMR (300MHz, CDCl 3}} ): δ 8.97 (1H, s), 8.41 (1H, bt), 7,67 (2H, dd), 7.36 (1H, t), 7.18 (1H, t), 5.67 ( 1H,m),3.51(2H,q),3.32(1H,q),3.15(1H,d),2.63(4H,m),2.10(1H,m),1.99(1H,m),1.70(4H , m), 1.48 (9H, s), 1.47 (9H, s).

N-{4-[3-(2-Aoxy-2,9-dihydro-1,3,9-triaza-indol-3-yl)-pyrrolidin-1-yl]-butyl} -胍(14):

Trifluoroacetic acid (2 mL) was added to a solution of compound 13 (0.028 g) in dichloromethane (4 mL). The solution was concentrated, evaporated with methylene chloride (3.times.4 mL), dried in vacuo, EtOAc (EtOAc) LCMS (EI) m/z 368.2 (M+H) ⁺ . _{^{1 H NMR (300MHz, D 2}} O): δ 8.67 (1H, s), 7.68 (1H, d), 7.32 (1H, dd), 7.29 (1H, t), 7.20 (1H, t), 5.14 (1H , m), 4.14 (1H, d), 3.93 (1H, t), 3.50 (1H, t), 3.24 (2H, m), 3.16 (2H, t), 2.70 (1H, m), 2.67 (1H, m), 2.65 (1H, m), 1.70 (2H, m), 1.57 (2H, m).

Example 6 - Synthesis of Compound 602

(3-tert-Butoxycarbonylamino-propyl)-[4-(2-oxy-2,10-dihydro-benzo[4,5]imidazo[1,2-a]pyrimidine-3 -yl)-benzyl}-carbamic acid tert-butyl ester (5)

Add 0.5 M sodium methoxide in methanol (10 mL, 5 mmol) to 2-iodo-3-methoxy-methyl acrylate (1, 1.21 g, 5 mmol), 1H-benzimidazol-2-ylamine (2, 0.67) A mixture of g, 5 mmol) and ethanol (30 mL). The resulting mixture was refluxed for 3 hours and concentrated to give 3-iodo-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-2-one (3). (3-tert-Butoxycarbonylamino-propyl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxolane-2-yl)- tert-Butyl benzyl]-aminecarboxylate (4,490 mg, 1 mmol), 3 (311 mg, 1 mmol), K ₂ CO ₂ (414 g, 3 mmol), Pd(PPh ₃ ) ₄ (0) (41 mg, 0.05 mmol) A mixture of ethanol (6 mL), dioxane (2 mL) and water (2 mL) was degassed and heated at 80 ° C for 20 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with water (300mL) and brine (300mL). The organic solution was concentrated and purified by flash chromatography eluting elut elut elut LCMS (EI) m / z: 570 (M + Na) +.

3-{4-[(3-Amino-propylamino)-methyl]-phenyl}-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-2-one hydrochloride (601):

The compound 5 (170 mg, 0.31 mmol) was dissolved in dichloromethane (5 mL), then trifluoroacetic acid (1 mL) was added and stirred at room temperature for 2 hr. The reaction mixture was concentrated, EtOAc EtOAcjjjjjjjjjjj ¹ NMR (300MHz, CD ₃ OD): δ 9.43 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.75 (d, J = 7.8 Hz) , 3H), 7.69 (t, J = 8.2 Hz, 1H), 7.62 (t, J = 8.2 Hz, 1H), 4.35 (s, 2H), 3.25 (t, J = 8.1 Hz, 2H), 3.10 (t , J = 7.5 Hz, 2H), 2.18 (m, 2H). LCMS (El) m/z: 348.1 (M+H ⁺ ).

N-{3-[4-(2-Aoxy-2,10-dihydro-benzo[4,5]imidazo[1,2-a]pyrimidin-3-yl)-benzylamino) ]-propyl}-hydrazine hydrochloride (602):

N,N-Di-tert-butoxycarbonyl-1-carboxylpyrazole (50 mg, 0.16 mmol) was added to compound 6 (110 mg, 0.16 mmol), N,N-diisopropylethylamine (720 mg, 5.8 mmol) In a mixture with acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight, diluted with water (30 mL) and ethyl acetate. The organic solution was concentrated and purified with EtOAc EtOAc EtOAc (EtOAc) Trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred overnight and concentrated. The residue was added with EtOAc (3 mL). ¹ NMR (300MHz, CD ₃ OD): δ 9.41 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 7.8 Hz) , 3H), 7.68 (t, J = 8.2 Hz, 1H), 7.60 (t, J = 8.2 Hz, 1H), 4.34 (s, 2H), 3.31 (m, 2H), 3.20 (t, J = 7.5 Hz) , 2H), 2.07 (m, 2H). LCMS (El) m/z: 390.1 (M+H ⁺ ).

Example 7 - Antimicrobial activity

The compounds of the invention are tested for antimicrobial activity. These data are presented in Table 2. The minimum inhibitory concentration (MICs) of the compounds of the present invention against E. coli strain ATCC 25922 was determined using standard microdilution assays. The data is indicated by the following symbols: "+" indicates that the compound has a minimum inhibitory concentration value of 16 micrograms/ml or less; "-" indicates that the compound has a minimum inhibitory concentration value greater than 16 micrograms/ml. “N/A” means that no data is available. Those skilled in the art will recognize that compounds can be evaluated against other bacteria, and the representation of data against E. coli activity is illustrated and is in no way intended to limit the scope of the invention. Depending on the performance activity desired to be collected, the compounds of the invention can be assayed against a range of other microorganisms. Moreover, the choice of "+", "-" and "N/A" notation and conversion value of 16 micrograms/ml are also illustrated and are in no way intended to limit the scope of the invention. For example, "-" does not indicate that the compound necessarily lacks activity or utility, and indicates that the compound has a minimum inhibitory concentration value against the designated microorganism of greater than 16 micrograms per milliliter.

Incorporated by reference

The entire text of each of the patent documents and scientific papers herein is hereby incorporated by reference in its entirety for all purposes.

Claim equivalent

The present invention may be embodied in other specific forms without departing from the spirit and scope of the invention. The foregoing embodiments are therefore to be considered in all respects The scope of the invention is to be construed as being limited by the scope of the appended claims.

Claims (13)

A method of preparing a compound having the formula: or a pharmaceutically acceptable salt or tautomer thereof, Another option is -GHJ is Wherein each H and J are independently selected; A is selected from the group consisting of: (b)-(C _2-8 alkyl)-, (c)-(C _2-8 alkenyl)-, (d)-(C _2-8 alkynyl)-, wherein i) 0 to 4 carbon atoms in any of the foregoing (b) to (d) are arbitrarily selected from the group consisting of the following Partial substitution: S(O) _P , -NR ⁶ -, -S(O) _P NR ⁶ -, -NR ⁶ S(O) _P -, and -NR ⁶ S(O) _P NR ⁶ -, Ii) any of the foregoing (b) to (d) is optionally substituted with one or more R ⁵ groups, and iii) any of the foregoing (b) to (d) is optionally subjected to - (C _1- Substituted by an ₈ alkyl)-R ⁵ group, (e)-O-, (f)-NR ⁶ -, (g)-S(O) _P -, (h)-C(O)-, (i) -C(O)O-, (j)-OC(O)-, (k)-OC(O)O-, (l)-C(O)NR ⁶ -, (m)-NR ⁶ CO-, (n)-NR ⁶ C(O)NR ⁶ -, (o)-C(=NR ⁶ )-, (p)-C(=NR ⁶ )O-, (q)-OC(=NR ⁶ )- , (r)-C(=NR ⁶ )NR ⁶ -, (s)- NR ⁶ C(=NR ⁶ )-, (t)-C(=S)-, (u)-C(=S)NR ⁶ -, (v)-NR ⁶ C(=S)-, (w)-C(O)S-, (x)-SC(O)-, (y)-OC(=S)-, (z )-C(=S)O-, (aa)-NR ⁶ (CNR ⁶ )NR ⁶ -, (bb)-CR ⁶ R ⁶ C(O)-, (cc)-C(O)NR ⁶ (CR ⁶ R ⁶⁾ _t - 3 to 14 membered saturated heterocyclic ring, (dd) containing one or more nitrogen atoms, (ee) containing one or a 6, 7, 8, 9, 10, 11, 12, 13 or 14-membered saturated heterocyclic ring selected from the group consisting of oxygen and sulfur, (ff) containing one or more selected from the group consisting of nitrogen, a 3- to 14-membered unsaturated or aromatic heterocyclic ring of a hetero atom consisting of oxygen and sulfur, and a (gg) 3 to 14-membered saturated, unsaturated or aromatic carbon ring, wherein , (ee), (ff) or (gg) optionally substituted with one or more R ⁵ groups; G is independently selected from the group consisting of: (b) - (C _1-8 alkyl) -, (c)-(C _2-8 alkenyl)-, (d)-(C _2-8 alkynyl)-, wherein i) is 0 in any of the preceding (b) to (d) The four carbon atoms are arbitrarily replaced by a moiety selected from the group consisting of -O-, S(O) _P , -NR ⁶ -, -(C=O)-, -S(O) _P NR ⁶ -, -NR ⁶ S(O) _P -, and -NR ⁶ S(O) _P NR ⁶ -, ii) Any of the foregoing (b) to (d) optionally passes through one or more R ⁵ groups Substituting, and iii) any of the foregoing (b) to (d) is optionally substituted with a -(C _1-8 alkyl)-R ⁵ group; (e)-O-, (f)-NR ⁶ -, (g)-S(O) _P -, (h)-C(O)-, (i)-C(O)O- , (j)-OC(O)-, (k)-OC( O)O-, (l)-C(O)NR ⁶ -, (m)-NR ⁶ CO-, (n)-NR ⁶ C(O)NR ⁶ -, (o)-C(=NR ⁶ ) - ^{(p) -C (= NR 6} ) O -, (q) -OC (= NR 6) -, (r) -C (= NR 6) NR 6 -, (s) -NR 6 C (= NR 6 )-, (t)-C(=S)-, (u)-C(=S)NR ⁶ -, (v)-NR ⁶ C(=S)-, (w)-C(O)S- , (x)-SC(O)-, (y)-OC(=S)-, (z)-C(=S)O-, (aa)-NR ⁶ (CNR ⁶ )NR ⁶ -, (bb -CR ⁶ R ⁶ C(O)-, (cc)-C(O)NR ⁶ (CR ⁶ R ⁶ ) _t -, (dd) contains one or more groups selected from the group consisting of nitrogen, oxygen and sulfur a group of 3 to 14 membered saturated, unsaturated or aromatic heterocyclic rings of heteroatoms, (ee) 3 to 14 membered saturated, unsaturated or aromatic carbocyclic rings, and (ff)-(CR ⁶ R ⁶ ) _t —, wherein (dd) or (ee) is optionally substituted with one or more R ⁵ groups; B and H are independently selected from the group consisting of: (b) one or more selected a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring of a hetero atom of the group consisting of nitrogen, oxygen and sulfur, (c) a 3 to 14 membered saturated, unsaturated or aromatic carbon a ring wherein (b) or (c) is optionally substituted with one or more R ⁵ groups; (d)-(C _1-8 alkyl)-, (e)-(C _2-8 alkenyl)- (f)-(C _2-8 alkynyl)-, wherein (i) 0 to 4 carbon atoms in any of the foregoing (d) to (f) are arbitrarily selected from the group consisting of the following Group Alternative points: -O -, - S (O ) P -, - NR 6 -, - (C = O) -, - C (= NR 6) -, - S (O) P NR 6 -, - NR 6 S(O) _P -, and -NR ⁶ S(O) _P NR ⁶ -, (ii) any of the foregoing (d) to (f) is optionally substituted with one or more R ⁵ groups, and Iii) any of the foregoing (d) to (f) is optionally substituted with a -(C _1-8 alkyl)-R ⁵ group; and (g)-(CR ⁶ R ⁶ ) _t -, C and J Independently selected from the group consisting of: (a) hydrogen, (c)F, (d)Cl, (e)Br, (f)I, (g)-CF ₃ , (h)-CN, ( i)-N ₃ , (j)-NO ₂ , (k)-NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (l)-OR ⁸ , (m)-S(O) _P (CR ⁶ R ⁶ _t R ⁸ , (n)-C(O)(CR ⁶ R ⁶ ) _t R ⁸ , (o)-OC(O)(CR ⁶ R ⁶ ) _t R ⁸ , (p)-SC(O)( CR ⁶ R ⁶ ) _t R ⁸ , (q)-C(O)O(CR ⁶ R ⁶ ) _t R ⁸ , (r)-NR ⁶ C(O)(CR ⁶ R ⁶ ) _t R ⁸ ,(s )-C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (t)-C(=NR ⁶ )(CR ⁶ R ⁶ ) _t R ⁸ , (u)-C(=NNR ⁶ R ⁶ ) (CR ⁶ R ⁶ ) _t R ⁸ , (v)-C(=NNR ⁶ C(O)R ⁶ )(CR ⁶ R ⁶ ) _t R ⁸ , (w)-C(=NOR ⁸ )(CR ⁶ R ⁶ ) _t R ⁸ , (x)-NR ⁶ C(O)O(CR ⁶ R ⁶ ) _t R ⁸ , (y)-OC(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (z) -NR ⁶ C(O)NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (aa)-NR ⁶ S(O) _P (CR ⁶ R ⁶ ) _t R ⁸ , (bb)-S(O) _P NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (cc)-NR ⁶ S(O) _P NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (dd)-NR ⁶ R ⁸ , (ee)-NR ⁶ (CR ⁶ R ⁶ )R ⁸ , (ff)-OH, (gg)-NR ⁸ R ⁸ , (hh)-OCH ₃ , (ii)-S(O) _P R ⁸ , (jj)-NC( O) R ⁸ , (kk)-NR ⁶ C(NR ⁶ )NR ⁶ R ⁸ , (ll) C _1-8 alkyl, (mm) C _2-8 alkenyl, (nn) C _2-8 alkynyl (oo) a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (pp) 3 to 14 dollar saturated , unsaturated or aromatic carbocyclic ring, (qq)-(CR ⁶ R ⁶ ) _t NR ⁶ (CR ⁶ R ⁶ ) _t R ⁸ , (rr)-N[(CR ⁶ R ⁶ ) _t R ⁸ ][C=O(CR ⁶ R ⁶ ) _t R ⁸ ], (ss)-(CR ⁶ R ⁶ ) _t N[(CR ⁶ R ⁶ ) _t R ⁸ ][(CR ⁶ R ⁶ ) _t R ⁸ ] , (tt)-(CR ⁶ R ⁶ ) _t NR ⁶ (C=O)(CR ⁶ R ⁶ ) _t R ⁸ , (uu)-C _1-6 haloalkyl, (vv)-C(O) ( CR ⁶ )[(CR ⁶ R ⁶ ) _t R ⁸ ]R ⁸ ,(ww)-(CR ⁶ R ⁶ ) _t C(O)NR ⁸ R ⁸ ,(xx)-(CR ⁶ R ⁶ ) _t C( O)O(CR ⁶ R ⁶ ) _t R ⁸ ,(yy)-NR ⁶ C(O)CR ⁸ R ⁸ R ⁸ ,(zz)-N[(CR ⁶ R ⁶ ) _t R ⁸ ]C(O) R ⁸ , and (aaa)-S(O) _P NR ⁸ R ⁸ ; wherein (11) to (pp) are optionally substituted with one or more R ⁷ groups; R ^{5 is} selected from: (a) hydrogen, ( b) F, (c) Cl, (d) Br, (e) I, (f)-CF ₃ , (g)-CN, (h)-N ₃ , (i)-NO ₂ , (j)-NR ⁶ R ⁶ , (k)-OR ⁸ , (l)-NR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (m)-C _1-8 alkyl, (n)-C _2-8 alkenyl, (o) -C _2-8 alkynyl, (p)-(C _1-8 alkyl)- (3 to 14-membered saturated, containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, Unsaturated or aromatic heterocyclic ring), (q)-(C _1-8 alkyl)-(3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring), (r)-C _{1- 6} haloalkyl, (s)-SR ⁶ , (t) - 3 to 14 membered saturated, unsaturated or aromatic containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur a heterocyclic ring, and a (u)-3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring; the other option is that the two R ⁵ groups together form a carbocyclic ring, wherein (m) to (r) and (t) to (u) optionally substituted with one or more R ⁸ ; R ^{6 is} selected from: (a) hydrogen, (b)-C _1-8 alkyl or alternatively the two R ⁶ groups together Forming a carbocyclic ring, (c)-C _1-6 haloalkyl, (d) - a 3 to 14 membered saturated, unsaturated, one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur Or aromatic heterocycle, and (e)-3 to 14 a saturated, unsaturated or aromatic carbocyclic ring; wherein (b) to (e) are optionally substituted by one or more R ⁸ ; R ^{7 is} selected from: (a) hydrogen, (b) F, (c )Cl, (d)Br, (e)I, (f)-CF ₃ , (g)-CN, (h)-N ₃ , (i)-NO ₃ , (j)-NR ⁶ R ⁶ , ( k)-OR ⁶ , (l)-NR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (m)-C _1-8 alkyl, (n)-C _2-8 alkenyl, (o)-C _{2- 8} alkynyl, (p)-(C _1-8 alkyl)- (a 3 to 14 membered saturated, unsaturated or containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur) Aromatic heterocycle), (q)-(C _1-8 alkyl)-(3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring), (r)-C _1-6 haloalkyl , (s)-NR ⁶ R ⁸ , (t)-OR ⁸ , (u)-(CR ⁶ R ⁶ ) _t NR ⁶ R ⁸ , (v)-CR ⁶ R ⁸ R ⁸ , (w)-SR ⁶ (x)- a 3- to 4-membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (y)-3 to 4 a saturated, unsaturated or aromatic carbocyclic ring, (z)-(CR ⁶ R ⁶ ) _t C(O)NR ⁸ R ⁸ , (aa)-S(O) _P R ⁸ , (bb)- NR ⁶ C(O)NR ⁶ R ⁶ , (cc)-NR ⁶ C(O)R ⁶ , and (dd)-C(=NR ⁶ )NR ⁶ R ⁶ ; wherein (m) to (q) and x) to (y) arbitrarily through one or more Substituted with R ^9; R ⁸ is selected from: (a) hydrogen, (b) F, (c ) Cl, (d) Br, (e) I, (f) -CF 3, (g) -CN, (h) -N ₃ , (i)-NO ₂ , (j)-NR ⁶ R ⁹ , (k)-OR ⁹ , (l)-NR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (m)-C _1-8 Alkyl, (n)-C _2-8 alkenyl, (o)-C _2-8 alkynyl, (p)-(C _1-8 alkyl)- (containing one or more selected from nitrogen, oxygen and a 3 to 14-membered saturated, unsaturated or aromatic heterocyclic ring of a hetero atom consisting of sulfur, (q)-(C _1-8 alkyl)- (3 to 14-membered saturated, not a saturated or aromatic carbocyclic ring), (r) - a 3 to 14 membered saturated, unsaturated or aromatic complex containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Ring, (s)-3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring, (t)-C _1-6 haloalkyl, (u)-C(O)(CR ⁶ R ⁶ ) _t R ⁹ ,(v)-SR ⁶ ,(w)-OC(O)(CR ⁶ R ⁶ ) _t R ⁹ ,(x)-NR ⁶ C(O)NR ⁶ R ⁶ ,(y)-NR ⁶ C (O)R ⁹ , (z)-NR ⁶ (CNR ⁹ )(NR ⁶ R ⁶ ), (aa)-ONR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (bb)-C(=NR ⁹ )NR ⁶ R ⁶ , (cc)-S(O) _P R ⁹ , (dd)-(CR ⁶ R ⁶ ) _t C(O)NR ⁶ R ⁹ , (ee)-(CR ⁶ R ⁶ ) _t OR ⁹ , and ^{(ff) - (CR 6 R} 6) t NR 6 R 9; wherein (m) to (s) arbitrarily substituted with a A plurality of substituents R ^9; R ⁹ is selected from: (a) hydrogen, (b) F, (c ) Cl, (d) Br, (e) I, (f) -CF 3, (g) -CN, ( h)-N ₃ , (i)-NO ₂ , (j)-NR ⁶ R ¹⁰ , (k)-OR ⁶ , (l)-NR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (m)-C ( O)(CR ⁶ R ⁶ ) _t NR ⁶ R ⁶ , (n)-C _1-8 alkyl, (o)-C _2-8 alkenyl, (p)-C _2-8 alkynyl, (q) a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (r) -3 to 14-membered saturated, Unsaturated or aromatic carbocyclic ring, (s)-C _1-6 haloalkyl, (t)-(CR ⁶ R ⁶ ) _t OR ⁶ , (u)-O(CR ⁶ R ⁶ ) _t NR ⁶ R ¹⁰ , (v)-C(O)R ⁶ , (w)-SR ⁶ , (x)-C(O)OR ¹⁰ , (y)-S(O) _P R ⁶ ,(z)-(C _1-8 alkyl)-(a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur), (aa) -(C _1-8 alkyl)-(3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring), (bb)-O(CR ⁶ R ⁶ ) _t OR ⁶ , (cc)-C ( =NR ⁶ )NR ⁶ R ⁶ ,(dd)-ONR ⁶ R ⁶ ,(ee)-NR ⁶ C(O)NR ⁶ R ⁶ ,(ff)-O(CR ⁶ R ⁶ ) _t OR ⁶ ,(gg -NR ⁶ C(O)R ⁶ , and (hh)-(CR ⁶ R ⁶ ) _t NR ⁶ R ¹⁰ ; ) to (r) and (z) to (aa) optionally substituted with one or more R ¹⁰ ; R ^{10 is} selected from: (a) hydrogen, (b) F, (c) Cl, (d) Br, ( e) I, (f)-CF ₃ , (g)-CN, (h)-N ₃ , (i)-NO ₂ , (j)-NR ⁶ R ⁶ , (k)-OR ⁶ , (l) -NR ⁶ (CNR ⁶ )NR ⁶ R ⁶ , (m)-C(O)(CR ⁶ R ⁶ ) _t NR ⁶ R ⁶ , (n)-C _1-8 alkyl, (o)-C _{2- 8} alkenyl, (p)-C _2-8 alkynyl, (q)- 3 to 14-membered saturated, unsaturated containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur Or aromatic heterocyclic ring, (r) -3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring, (s)-C _1-6 haloalkyl, (t)-(CR ⁶ R ⁶ ) _t OR ⁶ , (u)-O(CR ⁶ R ⁶ ) _t NR ⁶ R ⁶ , (v)-C(O)R ⁶ , (w)-SR ⁶ , (x)-C(O)OR ⁶ , (y)-S(O) _P R ⁶ , (z)-(C _1-8 alkyl)-(3 to 14 containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur a saturated, unsaturated or aromatic heterocyclic ring), (aa)-(C _1-8 alkyl)-(3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring), (bb) -O(CR ⁶ R ⁶ ) _t OR ⁶ ,(cc)-C(=NR ⁶ )NR ⁶ R ⁶ ,(dd)-ONR ⁶ R ⁶ ,(ee)-NR ⁶ C(O)NR ⁶ R ⁶ , (ff)-O(CR ⁶ R ⁶ ) _t OR ⁶ , (gg)-NR ⁶ C(O)R ⁶ , and (hh )-(CR ⁶ R ⁶ ) _t NR ⁶ R ⁶ ; p is 0, 1 or 2, and t is 1, 2 or 3, the method comprising formulating a compound of the formula Reaction with a compound of the formula The method of claim 1, wherein A is selected from the group consisting of: (a) a 3 to 14 membered saturated, unsaturated or containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. An aromatic heterocyclic ring, and (b) a 3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring wherein (a) or (b) is optionally substituted with one or more R ⁵ groups; From: (a)-(C _1-8 alkyl)-, (b)-(C _2-8 alkenyl)-, and (c)-(C _2-8 alkynyl)-, wherein i) is in front The 0 to 4 carbon atoms in any of (a) to (c) are arbitrarily replaced by a moiety selected from the group consisting of -O-, -S(O) _P -, -NR ⁶ - , -(C=O)-, -C(=NR ⁶ )-, -S(O) _P NR ⁶ -, and -NR ⁶ S(O) _P NR ⁶ -, ii) front (a) to (c) Any of arbitrarily substituted with one or more R ⁵ groups, and iii) any of the foregoing (a) to (c) optionally via a -(C _1-8 alkyl)-R ⁵ group Substituted, and C is selected from the group consisting of: (a) NH ₂ , (b)-NHC (=NH)NH ₂ , and (c) hydrogen. The method of claim 2, wherein A is selected from the group consisting of: azepanyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl. , cyclohexadienyl, dihydropyridyl, furyl, tetrahydrofuranyl, tetrahydropyridyl, azetidinyl, pyrrolidinyl, piperidinyl, and piperidenyl Wherein any of the preceding A is optionally substituted with one or more R ⁵ groups; B is selected from (a)-(C _1-8 alkyl)-, wherein i) is 0 in the preceding (a) The four carbon atoms are arbitrarily replaced by a moiety selected from the group consisting of -O-, -S(O) _P -, -NR ⁶ -, -(C=O)-, -S(O) _P NR ⁶ -, and -NR ⁶ S(O) _P NR ⁶ -, ii) preceding (a) optionally substituted with one or more R ⁵ groups, and iii) preceding (a) optionally by - (C _{1 -8} alkyl) -R ⁵ groups; and C is selected _{from: (a) NH 2, (} b) -NHC (= NH) NH 2, and (c) hydrogen. The method of claim 3, wherein the CBA- is selected from the group consisting of hydrogen, The method of claim 1, wherein G is selected from the group consisting of: (a) a 3 to 14 membered saturated, unsaturated or containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. An aromatic heterocyclic ring, (b) a 3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring, and (c) a single bond; wherein (a) or (b) is optionally subjected to one or more R ⁵ Replacement of the group. The method of claim 2, wherein R ^{5 is} selected from the group consisting of: (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF ₃ , (g )-CN, (h)-N ₃ , (i)-NO ₂ , (j)-NH ₂ , (k)-OR ⁶ , (l)-NHC(=NH)NH ₂ , (m)-C _{1 -8} alkyl, (n)-C _1-8 alkenyl, (o)-C _1-8 alkynyl, (p)-(C _1-8 alkyl)- (containing one or more selected from nitrogen, a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring of a hetero atom consisting of oxygen and sulfur, (q)-(C _1-8 alkyl)- (3 to 14-membered saturated) , an unsaturated or aromatic carbocyclic ring), (r)-haloalkyl, (s)-SR ⁶ , (t)-containing one or more selected from the group consisting of nitrogen, oxygen and sulfur a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring of an atom, and a (u)-3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring; the other option is two R ⁵ groups. The clusters form a carbon ring together. The method of claim 2, wherein R ^{6 is} selected from the group consisting of: (a) hydrogen, (b)-C _1-8 alkyl or alternatively the two R ⁶ groups together form a carbocyclic ring, (c) a haloalkyl group, (d)- a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, and (e a -3 to 14 membered saturated, unsaturated or aromatic carbocyclic ring. The method of claim 5, wherein G is selected from the group consisting of: azepanyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexyl Dienyl, dihydropyridyl, furyl, tetrahydrofuranyl, tetrahydropyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperidenyl, and single bonds. The method of claim 8, wherein -GHJ is selected from the group consisting of: hydrogen, The method of claim 9, wherein each -GHJ is selected from the group consisting of: hydrogen, Wherein n is 0, 1 or 2, and wherein R ⁵ is as defined in item 6 of the scope of the patent application. The method of any one of claims 1 to 10, wherein the compound of the formula is a compound that binds to a ribosome The method of claim 11, wherein the ribosome is a bacterial ribosome. The method of claim 1, wherein the compound of the formula is any one of the compounds of Table 1, or a pharmaceutically acceptable salt or tautomer thereof