KR20120101392A - Antimicrobial compounds and methods of making and using the same - Google Patents

Abstract

The present invention generally relates to the field of antimicrobial compounds and methods for their preparation and methods of use. These compounds are useful for treating, preventing, and mitigating the risk of microbial infections in humans and animals.

Description

ANTIMICROBIAL COMPOUNDS AND METHODS OF MAKING AND USING THE SAME}

This application discloses US Provisional Application No. 61 / 252,478, filed Oct. 16, 2009; US Provisional Application No. 61 / 314,287, filed March 16, 2010; And US Provisional Application No. 61 / 358,201, filed June 24, 2010, with priority. The contents of the aforementioned applications are incorporated herein by reference in their entirety.

The present invention generally relates to the field of antimicrobial compounds and methods for their preparation and methods of use. These compounds are useful for treating, preventing and mitigating the risk of microbial infections in humans and animals.

Since the discovery of penicillin in the 1920s and streptomycin in the 1940s, many new compounds have been discovered or specifically designed for use as antibiotics. At one time, these treatments could be used to completely control or eliminate infectious diseases. However, this view has been questioned as microorganisms or cell lines that are resistant to currently available therapeutic agents continue to evolve. Almost all antibiotics developed for clinical use eventually face the problem of the emergence of resistant bacteria. For example, resistant strains of Gram-positive bacteria such as methicillin resistant staphylococcus , penicillin-resistant streptococcus , and vancomycin resistant enterococcus have been developed. Resistant bacteria can have serious and fatal consequences for infected patients. 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).

For decades, many pharmaceutical companies have focused on the discovery and development of new antibacterial agents. Nevertheless, in recent years pharmaceutical companies have escaped this field of research and drug development. As a result of that escape, very few new antibiotics entered the market. This lack of new antibiotics is particularly disturbing when the number of bacteria resistant to current therapeutics increases, both in hospitals and in community settings.

In the study of new antibiotics, researchers attempted to combine or link various parts of antibiotic molecules to produce multifunctional or hybrid compounds. Other researchers have tried to produce a derivative of a known class of antibiotics, e.g., trade name Ketek ^® Terry teuroma of, derivatives of erythromycin as marketed, who. However, these approaches have only had limited success.

An approach to developing novel antimicrobial compounds is to design regulators of bacterial ribosomal function, such as inhibitors. By regulating or inhibiting bacterial ribosomal function, such antimicrobial compounds can interfere with essential processes such as RNA translation and protein synthesis, providing antimicrobial effects. Indeed, some antibiotic compounds such as erythromycin, clindamycin, and linezolid are known to bind to ribosomes.

The present invention utilizes a structure-based drug design approach to discover and develop novel antimicrobial agents. This approach starts with the high resolution X-ray crystals of ribosomes to design a new class of antimicrobial compounds with specific chemical structures, ribosomal binding characteristics, and antimicrobial activity. This structure-based drug discovery approach is described in the following publications: 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 approach, the present invention describes a chemical class of novel antimicrobial compounds useful for treating bacterial infections in humans and animals. Without being bound by theory, it is believed that these compounds bind to limosomes and inhibit bacterial ribosomal function. Using these ribosome binding sites, the antimicrobial compounds of the present invention can provide better activity than current antibiotic compounds, especially against resistant bacterial strains.

The present invention utilizes a structure-based drug design approach to discover and develop novel antimicrobial agents. This approach starts with the high resolution X-ray crystals of ribosomes to design a new class of antimicrobial compounds with specific chemical structures, ribosomal binding characteristics, and the desired antimicrobial activity. This structure-based drug discovery approach is described in the following publications: Franceschi, F. and Duffy, EM, "Structure-based drug design meets the ribosome", Biochemical Pharmacology , vol. 71, pp. 1016-1025 (2006).

Accordingly, the present invention fulfills an important ongoing need for providing novel antimicrobial agents with activity against resistant pathogenic bacterial organisms, in particular for antimicrobial agents.

The present invention generally relates to the field of antimicrobial compounds and methods for their preparation and methods of use. These compounds are useful for treating, preventing, and mitigating the risk of microbial infections in humans and animals. The present invention also provides pharmaceutically acceptable salts, esters, N -oxides, and prodrugs of these compounds.

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

은In this formula,

silver

또는

or

Is a chemical moiety selected from

는 융합된 5 내지 7원 포화, 불포화, 또는 방향족 탄소환 또는 복소환 고리계를 나타내며,

Represents a fused 5- to 7-membered saturated, unsaturated, or aromatic carbocyclic or heterocyclic ring system,

T ¹ is a carbon atom or N so that when T ¹ is N, -DEF is absent,

T ² is a carbon atom or N so that when T ² is N, -GHJ is absent,

Both T ¹ and T ² are not N at the same time,

V is independently selected from -CR ^4a -or -N-,

W is O, NR ^1, NOR ^1, or S, alternatively W = Both the combinations of both the H- and HO- bonded to the same carbon atom or both bind to the same carbon atom (C _{1 -8} alkyl Is selected from a combination of O- and H-,

X --- Y is a single bond or a double bond, then, X --- Y is is selected from when the single bond, X is O, NR ^2, and S (O) _n, Y is CR ^3, X - When Y is a double bond, X is N, Y is a carbon atom,

Z is selected from the group consisting of O, NR ⁴ , S (O) _n , or NH,

R ¹ is selected from H and C _{1 -8} alkyl,

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;

에서 선택되고, 여기서 Alternatively -GHJ

Selected from where

Each of H and J is independently selected;

C-B-A-, -D-E-F, and -G-H-J are chemical moieties, wherein

A, D and G are independently

(a) a single _{bond, (b) - (C 1} -8 -alkyl) -, (c) - (C _{2 -8} alkenyl) -, (d) - (C _{2 -8} alkynyl) (where, i In any of (b)-(d) immediately above) 0-4 carbon atoms are -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 -optionally substituted with a moiety selected from the group consisting of

ii) any of (b)-(d) immediately above is at least one R ⁵ Optionally substituted with a group,

iii) any of (b)-(d) immediately above _is- (C _1-8 alkyl) -R ⁵ Optionally substituted with a 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) nitrogen, 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of oxygen, and sulfur,

(ee) 3-14 membered saturated, unsaturated, or aromatic carbocyclic rings, and

(ff)-(CR ⁶ R ⁶ ) _t-

Selected from the group consisting of

(Dd) or (ee) is optionally substituted with one or more R ⁵ groups;

B, E, and H are independently

(a) a single bond,

(b) a 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

(c) a 3-14 membered saturated, unsaturated, or aromatic carbocycle 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) immediately above (d In any of)-(f) 0-4 carbon atoms are selected from -O-, -S (O) _p- , -NR ⁶ -,-(C = O)-, -C (= NR ⁶ )-, Optionally substituted with a moiety selected from the group consisting of -S (O) _p NR ^6- , -NR ⁶ S (O) _p- , and -NR ⁶ S (O) _p NR ^6- ,

ii) any of (d)-(f) immediately above is at least one R ⁵ Optionally substituted with a group,

iii) immediately above, (d) - Any of (f) - (C _{1 -8-alkyl)} -R ⁵ Optionally substituted with groups), and

(g)-(CR ⁶ R ⁶ ) _t-

It is selected from the group consisting of;

C, F, and J are independently

(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 group, ( mm) 3-14 membered saturated, unsaturated containing one or more heteroatoms selected from the group consisting of C _2-8 alkenyl groups, (nn) C _2-8 alkynyl groups, (oo) nitrogen, oxygen, and sulfur , Or aromatic heterocycle, (pp) 3-14 membered 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) -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

Is selected from the group consisting of

(Ll) to (pp) are optionally substituted with one or more R ⁷ groups;

R ⁵ is (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)} - (containing 1 or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle), (q)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (r) -haloalkyl, (s ) -SR ⁶ , (t)-a 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (u) -3-14 members Selected from saturated, unsaturated, or aromatic carbocyclic rings,

Alternatively, two R ⁵ groups together form a carbocycle, wherein

(M) to (r) and (t) to (u) are optionally substituted with one or more R ⁸ ;

R ⁶ is (a) hydrogen, (b) -C _{1 -8-alkyl,} (c) - haloalkyl, (d) - 3- containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur A 14 membered saturated, unsaturated, or aromatic heterocycle, and (e) a 3-14 membered saturated, unsaturated, or aromatic carbocycle, or alternatively two R ⁶ groups together form a carbocycle, wherein

(B) to (e) are optionally substituted with one or more R ⁸ ;

R ⁷ is (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 1 or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle), (q)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (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 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (y) -3-14 membered saturated, unsaturated, or aromatic carbocycles , (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) are optionally substituted with one or more R ⁹ ;

R ⁸ is (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)} - (containing 1 or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle), (q)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (r) -nitrogen, oxygen, and 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of sulfur, (s) -3-14 membered saturated, unsaturated, or aromatic carbocycles, (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 with one or more R ⁹ ;

R ⁹ is (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 ) of nitrogen, oxygen, and sulfur _{^{- t NR 6 R 6, (}} n) -C 1-8 alkyl, (o) -C _{1 -8} alkenyl, (p) -C _{1 -8} alkynyl, (q) 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group, (r) -3-14 membered saturated, unsaturated, or aromatic carbocycles, (s) -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) At least one heteroatom selected from the group consisting of -C (O) OR ¹⁰ , (y) -S (O) _p R ⁶ , (z)-(C _1-8 alkyl)-(nitrogen, oxygen, and sulfur) Containing 3-14 membered saturated, unsaturated, or aromatic heterocycle), (aa)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (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 with one or more R ¹⁰ ;

R ¹⁰ is (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) - consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group, (r) -3-14 membered saturated, unsaturated, or aromatic carbocycles, (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) At least one heteroatom selected from the group consisting of -C (O) OR ⁶ , (y) -S (O) _p R ⁶ , (z)-(C _1-8 alkyl)-(nitrogen, oxygen, and sulfur) Containing 3-14 membered saturated, unsaturated, or aromatic heterocycle), (aa)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (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 ;

If desired, groups -D-E-F or groups -G-H-J are absent, but neither -D-E-F and -G-H-J are absent at the same time;

p is 0, 1, or 2,

t is 0, 1, 2, or 3.

The present invention also provides a method for synthesizing the compound. After synthesis, a therapeutically effective amount of one or more compounds may be formulated with a pharmaceutically acceptable carrier for administration to a human or animal for use as an antimicrobial agent, in particular an antibacterial agent. In certain embodiments, the compounds of the invention are useful for the treatment, prevention or alleviation of the risk of microbial infection or for the manufacture of a medicament for treating, preventing or alleviating the risk of microbial infection. Thus, such compounds or agents can be administered, eg, via oral, parenteral, intravenous, ear, eye, nose, or topical routes to provide an effective amount of the compound to a human or animal.

These and other aspects and embodiments of the invention can be more fully understood by reference to the following detailed description and claims.

The present invention provides a family of compounds that can be used as antimicrobial agents, more specifically as antibacterial agents.

The present invention includes pharmaceutically acceptable salts, esters, tautomers, N-oxides, and prodrugs thereof.

The compounds described herein can have an asymmetric center. Compounds of the invention containing asymmetrically substituted atoms can be isolated in optically active or racemic forms. Methods of preparing optically active forms are known in the art, for example by separating racemic forms or by synthesis from optically active starting materials. Numerous geometric isomers for olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such suitable isomers are contemplated herein. Cis and trans geometric isomers of the compounds of the invention are described and can be isolated as a mixture of isomers or as individual isomeric forms. Unless specifically mentioned specific stereochemistry or isomeric forms, it is meant all chiral, diastereomeric, racemic, and geometric isomeric forms of the structure. All processes used to prepare the compounds of the invention and the intermediates made therein are considered part of the invention. All tautomers of the compounds shown or described are also considered part of the present invention. The invention also encompasses metabolites of the compounds described herein.

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

If any variable (eg, R ⁶ ) is present more than once in any component or formula for a compound, its definition for each existence is independent of its definition in all other entities. Thus, for example, if a group is shown to be substituted with any one or more R ⁶ portion, R ⁶ in each present is selected independently from the definition of R ^6. Combinations of substituents and / or variables are also acceptable, but such combinations are provided only when a compound is produced that is stable within the normal valence of the designated atom.

Chemical structures represented by dashed lines for chemical bonds are sometimes present. For example, the dotted line drawn next to the solid single bond means that the bond can be a single bond or a double bond.

When a bond to a substituent is shown as crossing the bond connecting two atoms in the ring, the substituent may be bonded to any atom on the ring. When a substituent is listed without the atoms to which such substituents will be attached to the remainder of the compound of the formula, the substituents may be attached via any atom in the substituent. Combinations of substituents and / or variables are acceptable, but only if such combinations produce stable compounds.

Where nitrogen atoms are present in the compounds of the invention, they may be converted to N -oxides by treatment with oxidizing agents (eg, MCPBA and / or hydrogen peroxide), as appropriate. Thus, the nitrogen atom shown and claimed is considered to include both the nitrogen shown and, if appropriate, its N -oxide (N → O) derivatives.

One approach to developing improved antiproliferative and antiinfective agents is to provide ribosome function modulators (eg, inhibitors).

Ribosomes are ribonucleoproteins, present in both prokaryotes and eukaryotes. Ribosomes are organelles of cells responsible for protein synthesis. During gene expression, ribosomes translate genetic information coated on messenger RNA into proteins (Garrett et al. (2000) " The Ribosome: Structure, Function, Antibiotics and Cellular Interactions," American Society for Microbiology, Washington, DC).

Ribosomes comprise two non-equivalent ribonucleoprotein subunits. Larger subunits (known as “giant ribosomal subunits”) are approximately twice the size of small subunits (known as “small ribosomal subunits”). Small ribosomal subunits bind to messenger RNA (mRNA) to mediate interactions between mRNA and delivery RNA (tRNA) anticodons that influence translation reliability. Large ribosomal subunits catalyze peptide bond formation, ie the peptidyl-transferase reaction of protein synthesis, and comprise at least three different tRNA binding sites, known as amino acyl, peptidyl, and exit sites. An amino acyl site or A-site receives an amino acyl-tRNA that enters to provide its amino acid to the growing peptide chain. Also, the A space at the A-site is important. The peptidyl site or P-site receives a peptidyl-tRNA complex, ie a tRNA with its amino acids that are part of a growing peptide chain. The exit or E-site provides its amino acid to the growing peptide chain and then receives deacylated tRNA.

1. Definition

"Isomerism" means compounds that have the same molecular formula but differ in the nature of their atomic bonds or in the alignment of their atoms in the sequence or space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are referred to as "diastereoisomers," and stereoisomers that are non-symmetrical mirror images are referred to as "enantiomers," or sometimes optical isomers. Carbon atoms bonded to four nonidentical substituents are referred to as "chiral centers".

"Chiral isomer" means a compound having one or more chiral centers. It has two enantiomeric forms of opposite chirality and can exist as individual enantiomers or as a mixture of enantiomers. A mixture containing the same amount of the individual enantiomeric forms of the opposite chirality is referred to as a "racemic mixture". Compounds with more than 1 chiral heavy heap have 2 ^n-1 enantiomeric pairs, where n is the number of chiral centers. Compounds having more than one chiral center may exist as a mixture of diastereomers or as individual diastereomers, referred to as “diastereomeric mixtures”. When there is one chiral center, the stereoisomer may be characterized by the absolute stereostructure (R or S) of that chiral center. Absolute conformation refers to the in-space alignment of substituents attached to the chiral center. Substituents attached to the chiral centers to be considered are described in 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 isomer" means a diastereomer that is present in a constrained rotation around a double bond. These conformations are distinguished by their names prefix cis and trans, or Z and E, which means that the groups are on the same side or on the opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rule.

In addition, the structures and other compounds described herein include all atropic isomers thereof. "Phase isomers" are stereoisomeric types in which the valences of the two isomers are arranged differently in the space. Phase isomers exist by limiting rotation caused by the constrained rotation of the macro group around the center bond. Such phase isomers generally exist as mixtures, but thanks to recent advances in chromatography technology, it is possible to separate mixtures of two phase isomers in selected cases.

By "tautomer" is meant a compound whose structure differs significantly in the arrangement of atoms, but which exists in an easy and rapid equilibrium. It is understood that the compounds of the present invention may be depicted as different tautomers. Where a compound has a tautomeric form, it is intended to include all tautomeric forms within the scope of the present invention and it is to be understood that the name of the compound does not exclude any tautomeric form.

Some compounds of the present invention may exist in tautomeric forms and are also intended to be included within the scope of the present invention.

The compounds, salts and prodrugs of the present invention may exist in several tautomeric forms, including enol and imine forms, and keto and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the present invention. Tautomers exist as a mixture of tautomer sets in solution. In solid form, generally one tautomer predominates. Although one tautomer has been described, the present invention includes all tautomers of the present invention.

Tautomers are one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. This reaction causes a regular shift of the hydrogen atoms accompanied by the switching of adjacent conjugated double bonds. In a solution capable of tautomerization, the chemical equilibrium of the tautomers can be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that can be interchanged with tautomerization is called tautomers.

Among the various types of tautomerism possible, two are commonly observed. In keto-enol tautomers, simultaneous migration of electrons and hydrogen atoms occurs. Ring-chain tautomers are represented by glucose. This occurs as a result of the reaction of the aldehyde group (-CHO) in the sugar chain molecule with the hydroxy group (-OH) in the same molecule to provide a cyclic (cyclic) form.

Tautomerization is performed by bases: 1. deprotonation; 2. formation of derailed anions (eg enolates); 3. both at different cation positions; Acid: 1. quantization; 2. formation of derailed cations; 3. Catalyzed by deprotonation at different positions adjacent to the cation.

Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, amide-imide acid tautomer, amine-enamine and enamine in heterocyclic rings (eg nucleobase guanine, thymine and cytosine) -It's enamine. The following examples are included for illustrative purposes and the invention is not limited to these examples:

The term “crystal polymorph” or “polymorph” or “crystal form” means a crystal structure in which a compound (or salt or solvate thereof) can all be crystallized in different crystal packing arrangements, all having the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystalline forms, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors can lead to one dominant crystalline form. Crystal polymorphs of compounds can be prepared through crystallization under different conditions.

As used herein, the term "substituted" means that any one or more hydrogens on a designated atom, generally carbon, oxygen or nitrogen atoms, are replaced with a selection from the indicated group, provided that it exceeds the normal valence of the designated atom. Instead, it is condition that a stable compound is produced as a result of substitution. If the substituent is keto (ie = 0), then two hydrogens on the atom are substituted. As used herein, a ring double bond refers to a double bond formed between two adjacent ring atoms (eg, C═C, C═N, N═N, etc.).

As used herein, the term "anomeric carbon" refers to the acetal carbon of glycosides.

As used herein, the term “glycoside” is a cyclic acetal.

As used herein, "alkyl" is intended to include branched and immediate chain saturated aliphatic hydrocarbon groups having a certain number of carbon atoms. For example, C _{1 -6} alkyl will want to include _{C 1, C 2, C 3} , C 4, C 5, and C ₆ alkyl groups. Some examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, n-heptyl, and n-octyl But it is not limited thereto.

As used herein, "alkenyl" is intended to include one or more unsaturated carbon-carbon bonds and straight or branched conformation hydrocarbon chains, ethenyl and propenyl which may be present at any stable point along the chain. For example, C _2-6 alkenyl is one containing C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkenyl groups.

As used herein, “alkynyl” is intended to include one or more triple carbon-carbon bonds and straight or branched conformational hydrocarbon chains such as ethynyl and propynyl, which may be present at any stable point along the chain. For example, C _2-6 alkynyl is one containing C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkynyl groups.

In addition, "alkyl", "alkenyl", and "alkynyl" are intended to include diradicals, ie, moieties having two points of attachment, for example in the present invention when D is selected from these chemical groups. Non-limiting examples of such alkyl moieties that are diradicals include -CH ₂ CH _2- , ie, a C ₂ alkyl group covalently bonded to the remainder of the molecule via each terminal carbon atom. Alkyl diradicals are also known as "alkylenyl" radicals. Alkenyl diradicals are also known as "alkenylenyl" radicals. Alkynyl diradicals are also known as "alkynylenyl" radicals.

As used herein, "cycloalkyl" is intended to include saturated ring groups such as cyclopropyl, cyclobutyl, or cyclopentyl. C _{3 -8} cycloalkyl is intended to include a group _{C 3, C 4, C 5} , C 6, C 7, and C ₈ cycloalkyl.

As used herein, “counter ion” is used to mean a positive or negative charged species present with ions of opposite charge. Non-limiting examples of counterions are the ions or ions present to balance the charge or charges on the organic compound. Non-limiting examples of counterions include chloride, bromide, hydroxides, acetates, sulfates, and ammonium.

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

As used herein, “haloalkyl” refers to branched and straight chain saturated aliphatic hydrocarbon groups having a certain 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 include, but are not limited to, trifluoromethyl, trichloro methyl, pentafluoroethyl, and pentachloroethyl.

As used herein, "alkoxy" means an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. C _{1 -6} alkoxy is intended to include a group _{C 1, C 2, C 3} , C 4, C 5, and C ₆ alkoxy. C _1-6 alkoxy 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 include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, n-heptoxy, And n-octoxy.

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

As used herein, “carbocyclic ring” or “carbocyclic ring” means any stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or As intended to mean tricyclic rings, any of them may be saturated, unsaturated (including partially and fully unsaturated) or aromatic. Examples of such carbocyclic rings include cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadiete Neyl, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane, [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, Adamantyl, and tetrahydronaphthyl, but are not limited to these. As shown above, bridged rings are also included in the definition of carbocycles (eg, [2.2.2] bicyclooctane). Bridged rings are created when one or more carbon atoms connects two nonadjacent carbon atoms. Preferred bridges are 1 or 2 carbon atoms. Note that the bridge always converts a monocyclic ring to a tricyclic ring. If the ring is bridged, the substituents mentioned for the ring may also be present on the bridge. Fusions (eg, naphthyl and tetrahydronaphthyl) and spiro rings are also included.

As used herein, the term “heterocycle”, unless stated otherwise, is saturated, unsaturated (including partially and fully unsaturated), or aromatic, and is a carbon atom and at least one ring heteroatom independently selected from nitrogen, oxygen and sulfur, e.g. Any bicyclic or tricyclic group consisting of 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, and wherein any of the above defined heterocyclic rings are fused or attached to the second ring Stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or tricyclic rings, including (eg, benzene rings). Nitrogen and sulfur heteroatoms may optionally be oxidized (ie, N → O and S (O) _p , where p = 1 or 2). When a nitrogen atom is included in a ring, it is either N or NH, depending on whether it is attached to a double bond in the ring (ie hydrogen is present if necessary to maintain the triple valence of the nitrogen atom). The nitrogen atom may be substituted or unsubstituted (ie, N or NR where R is H or another substituent as defined). The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that produces a stable structure. The heterocyclic rings described herein may be substituted on a carbon or nitrogen atom if the heterocycle is stable in the final compound. The nitrogen in the heterocycle may be quaternized in some cases. Bridged rings are also included in the definition of heterocycles. Bridged rings are formed when one or more atoms (ie, C, O, N, or S) connect two non-adjacent carbon or nitrogen atoms. Preferred bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. If the ring is bridged, the substituents mentioned for the ring may also be present on the bridge. Spiro and fused rings are also included.

As used herein, the term “aromatic heterocycle” or “heteroaryl” refers to a carbon atom and one or more heteroatoms independently selected from nitrogen, oxygen and sulfur, for example 1 or 1-2 or 1-3 or 1-4 or It is intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic aromatic ring consisting of 1-5 or 1-6 heteroatoms. In the case of bicyclic heterocyclic aromatic rings, both may be so (eg quinoline), but only one of the two rings needs to be aromatic (eg 2,3-dihydroindole). The second ring may also be fused or bridged as defined above for the heterocycle. The nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or another substituent as defined). Nitrogen and sulfur heteroatoms may optionally be oxidized (ie, N → O and S (O) _p , where p = 1 or 2). In certain compounds, the total number of S and O atoms in the aromatic heterocycle is no greater than one.

Examples of heterocycles include acridinyl, azabicyclooctanonyl, azepanyl, azetidinyl, azosinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzooxazolyl, benzooxazoli Neil, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisooxazolyl, benzisothiazolyl, benzimidazolinyl, benzodioxoyl, benzooxadiazolyl, carbazolyl, 4a H -carbazolyl , carboxylic Bolivar carbonyl, chromanyl, chroman-Mesnil sour fun carbonyl, cycloheptyl, decahydro-quinolinyl, benzo-dihydro-deoxy-carbonyl, 2 H, 6 H -1,5,2- di thiazinyl, dihydro-Pugh Ro [2,3- b ] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolidinylimine, imidazolinyl, imidazolyl, imidazolonyl, 1 H -indazolyl, Indolyl, indolinyl, indolinyl, indolyl, 3H-indolyl, istinoyl, isobenzofuranyl, isochromenyl, isodazolyl, iso Indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, methylbenztriazolyl, methylfuranyl, methylimidazolyl, methylthiazolyl, morpholinyl, naphthyridinyl , Octahydroisoquinolinyl, oxdiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadia Zolyl, oxazolidinyl, oxazolidinonyl, oxazolyl, oxindolyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxatinyl, phenoxazinyl, phthalazinyl, piperazinyl, phi Ferrazinyl, piperidinyl, piperidinyl, piperidonyl 4-piperidonyl piperonyl, putridinyl, furinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyrida Genyl pyridooxazolyl, pyridomidazolyl, pyridothiazolyl, pyridinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidionyl, pyrroly Carbonyl, pyrrolidino carbonyl, pyrrolinyl, 2H- pyrrolyl, pyrrolyl, quinazolinyl fun carbonyl, quinolinyl, quinolyl 4 H- possess fun, quinoxalinyl carbonyl, quinuclidine pyridinyl, tetrahydro-furanyl, tetrahydroisoquinoline quinolinyl, tetrahydro quinolinyl, tetrazolyl, 6 H -1,2,5- thiadiazol possess, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, thiomorpholinyldioxydyl , Triazinyl, triazolopyrimidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl This includes, but is not limited to.

As used herein, the phrase “pharmaceutically acceptable” refers to tissues of humans and animals without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the scope of sound medical judgment, corresponding to a reasonable benefit / risk ratio. A compound, material, composition, and / or formulation suitable for use in contact.

As used herein, “pharmaceutically acceptable salts” are derivatives of the disclosed compounds wherein the parent compound is modified by making its acid or base salts. Examples of pharmaceutically acceptable salts include mineral or organic acid salts of basic residues such as amines; Acidic residues such as alkali or organic salts of carboxylic acids, and the like. Pharmaceutically acceptable salts include, but are not limited to, for example, quaternary ammonium salts or parental non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts are 2-acetoxy benzoic acid, 2-hydroxyethane sulfonic acid, acetic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethane Sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycoliaricanilic acid, hexylesoric acid, hydramic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxymaleic acid, hydroxynap Tomic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methane sulfonic acid, naphsyl acid, nitric acid, oxalic acid, palmic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, But not limited to those derived from inorganic and organic acids selected from propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanic acid, sulfuric acid, tannic acid, tartaric acid, and toluene sulfonic acid. The.

Pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts may be prepared by reacting the stoichiometric appropriate base or acid with the free acid or base form of these compounds in water or an organic solvent, or a mixture of the two; Non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences , 18th ed., Mack Publishing Company, Easton, PA, USA, p. 1445 (1990).

Since prodrugs are known to enhance various desired qualities of a drug (eg, solubility, bioavailability, manufacturability, etc.), the compounds of the present invention can be delivered in the form of prodrugs. Accordingly, the present invention is intended to include prodrugs of the compounds claimed herein, methods of delivery thereof, and compositions comprising them. "Prodrugs" are intended to include any covalently bonded carriers that release the active parent drug of the invention in vivo when such prodrugs are administered to a mammalian subject. The prodrugs of the invention are prepared by modifying the functional groups present in the compound in such a way that the modifications are cleaved to the parent compound in a conventional manner or in vivo. Prodrugs are hydroxy, amino, or sulfhydryl groups, each of which is cleaved to form a free hydroxyl, free amino, or free sulfhydryl group, when the prodrug of the invention is administered to a mammalian subject, combined with any group Which include the compounds of the present invention. 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” refer to a compound that is sufficiently robust to be formulated as an effective therapeutic agent and to withstand isolation from the reaction mixture in useful purity.

As used herein, the term “patient” refers to a human or animal (in the case of an animal, more specifically a mammal) that is undergoing a surgical or invasive medical procedure. Such patients or subjects are considered to need a method of reducing the risk of infection due to surgical or invasive medical procedures or a method of preventing infection. Such patients may also be considered subjects requiring peri-operative prophylaxis.

As used herein, the term “treating” means providing a therapeutic intervention to treat or alleviate an infection.

As used herein, the term "preventing" means to completely or almost completely stop an infection from onset, for example, when a patient or subject is vulnerable to or at risk of becoming infected. Prevention may also include suppression of the infection, ie arrest of the onset.

As used herein, the term "reducing risk" means reducing the likelihood or probability of developing an infection, for example, when a patient or subject is vulnerable to or at risk of developing an infection.

As used herein, "unsaturated" means a compound having one or more degrees of unsaturation (eg, one or more multiple bonds) and includes partially and fully unsaturated compounds.

As used herein, the term “effective amount” means an amount of a compound of the present invention, or a combination of compounds, effective when administered alone or in combination as an antimicrobial agent. For example, an effective amount may be a composition given to a receiving patient or subject sufficient to cause a biological activity, such as an anti-infective activity such as antimicrobial activity, antibacterial activity, antifungal activity, antiviral activity or antiparasitic activity, The amount of compound present in the formulation or medical device.

The term “prophylactically effective amount” means an effective amount of a compound or compounds of the invention administered to prevent or alleviate the risk of human infection by surgical or invasive medical procedures.

Also, "hydrogen bond acceptor-hydrogen bond acceptor-hydrogen bond donor" and "hydrogen bond acceptor-hydrogen bond acceptor-hydrogen bond acceptor" are meant to indicate the relative orientation of hydrogen bond acceptor and donor and such groups It is understood that this is not meant to be linked directly together because of the consideration that additional atoms or groups of atoms may be included between these groups.

In the specification, the singular also includes the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of dispute, the present specification is adjusted. As used herein, "mammal" refers to humans and non-human patients.

As used herein, the term “therapeutically effective amount” refers to an amount of a recipient sufficient to cause a biological activity, such as antimicrobial activity, antifungal activity, antiviral activity, antiparasitic activity, antidiarrheal activity, and / or antiproliferative activity. Means a compound of the invention, or a combination of compounds, present on or on a recipient. The combination of compounds is preferably a synergistic combination. See, eg, Chou and Talalay, Adv . Enzyme Regul . vol. 22, pp. 27-55 (1984) occurs when the effect of the compound is greater when administered in combination than the additive effect of the compound when administered alone as a single active. In general, synergistic effects are most clearly verified below the optimal concentration of the compound. The synergistic effect may be in terms of low cytotoxicity, high antiproliferative and / or anti-infective effect, or some other beneficial effect of the combination compared to the individual compounds.

As used herein, the term "RNA microhelix binding site" refers to the ribofunctional position of the large ribosomal subunit occupied by the RNA microhelix of Formula III. RNA microhelix binding sites overlap or are defined as at least a portion of the E-site.

As used herein, the term "A-site" refers to a ribofunctional position occupied by an amino acyl-tRNA molecule immediately prior to participating in a peptide-binding reaction.

As used herein, the term "E-site" refers to a ribofunctional position occupied by a deacylated tRNA molecule after participating in a peptide-binding reaction.

As used herein, the term “P-site” refers to the ribofunctional position occupied by the peptidyl-tRNA when participating in a peptide bond formation reaction.

As used herein, the term "A-space" refers to the A-site portion within the peptidyl transferase core to which the amino acid portion of the amino acylated tRNA binds, or alternatively to which the oxazolidinone ring of linezolide binds. A-site part.

The terms "part of" or "part of the tertiary structure of" used in connection with a ribosomal or ribosomal subunit are three or more, more preferably at least three to ten, most preferred of the ribosome or ribosomal subunit. Is understood to mean a portion of the tertiary structure of a ribosome or ribosomal subunit, including charge distribution and hydrophilic / hydrophobic features, formed by at least 10 amino acid residues and / or nucleotide residues. The residues forming such moieties form, for example, (i) continuous moieties based on the primary sequence of ribosomal RNA or ribosomal protein, and (ii) continuous moieties of the tertiary structure of the ribosome or ribosomal subunit. Residues, or (c) combinations thereof. As used herein, the term "part of" or "part of tertiary structure of" as used in the context of RNA microhelix refers to at least three, more preferably at least three to ten, reactors of one or more core residues of Formula III. It is understood to mean a portion of the tertiary structure of RNA microhelix formed, including charge distribution and hydrophilic / hydrophobic features. The atoms forming this portion may be, for example, (i) solvent inaccessible atoms embedded in the core of the RNA microhelix, (ii) solvent accessible atoms of the RNA microhelix, or (iii) combinations thereof.

Unless otherwise indicated, all percentages and ratios used herein are by weight.

Throughout this application, when a composition is described as having, comprising, or containing a particular component, or when a process is described as having, comprising, or containing a particular process step, the composition of the present invention also It consists essentially of, or is considered to be made of, the components mentioned, and is also deemed to consist or consist essentially of the process steps mentioned. In addition, it is understood that the order of steps or performing the schedule activities is not critical as long as the present invention remains operable. In addition, two or more steps or activities may be performed simultaneously.

2. Compounds of the Invention

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

은 In this formula,

silver

또는

에서 선택되는 화학 부분이고, 여기서

or

Is the chemical moiety selected from

는 5 내지 7원 포화, 불포화, 또는 방향족 탄소환 또는 복소환 고리계이며,

Is a 5 to 7 membered saturated, unsaturated, or aromatic carbocyclic or heterocyclic ring system,

T ¹ is a carbon atom or N, so when T ¹ is N, -DEF is absent,

T ² is a carbon atom or N so that when T ² is N, -GHJ is absent,

T ¹ and T ² are not both N at the same time,

V is independently selected from -CR ^4a -or -N-,

W is O, NR ^1, NOR ^1, or S, alternatively W = are both a combination of both the H- and HO- attached to the same carbon atom or both attached to the same carbon atom (C _{1 -8} alkyl Is selected from a combination of O and H-,

X --- Y represents a single bond or a double bond, so when X --- Y is a single bond, X is selected from O, NR ² , and S (O) _n , Y is CR ³ , and X --- when Y is a double bond, X is N and Y is a carbon atom,

Z is selected from the group consisting of O, NR ⁴ , S (O) _n , or NH,

R ¹ is selected from H and C _{1 -8} alkyl,

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.

은 수소 결합 도너 부분 또는 추가의 수소 결합 억셉터 부분을 더 포함한다.In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein

Further comprises a hydrogen bond donor portion or an additional hydrogen bond acceptor portion.

은 2 이상의 수소 결합 억셉터 부분 및 1 이상의 수소 결합 도너 부분을 포함하는 화학 부분이다. In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein

Is a chemical moiety comprising at least two hydrogen bond acceptor moieties and at least one hydrogen bond donor moiety.

In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein the hydrogen bond acceptor portion and the hydrogen bond donor portion are hydrogen bond acceptor-hydrogen bond inhibitors. Is present in the orientation of the acceptor-hydrogen bond donor.

As used herein, the term "in the orientation of" does not necessarily mean that the hydrogen bond donor or acceptor moiety is directly connected together since there may be other intervening atoms or groups of atoms between the hydrogen bond donor or acceptor moiety.

In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein the hydrogen bond acceptor moieties are within 5 GPa of each other and the hydrogen bond donor moieties are hydrogen bond inhibitors. Within 5 5 of the acceptor portion.

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

In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein the hydrogen bond acceptor moiety is included in a ring structure, wherein the ring structure is a single ring structure Or fused plural ring structures.

은 3개 이상의 수소 결합 억셉터 부분을 포함하는 화학 부분이다. In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein

Is a chemical moiety comprising three or more hydrogen bond acceptor moieties.

In some embodiments, 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 inhibitor Present in the orientation of the acceptor.

As used herein, the term "in the orientation of" does not necessarily mean that the hydrogen bond donor or acceptor moiety is directly connected together because other intervening atoms or groups of atoms are present between the hydrogen bond acceptor moieties.

In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein each hydrogen bond acceptor portion is about 5 of one or more other hydrogen bond acceptor portions Å is within.

In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein each hydrogen bond acceptor portion is about 3 of one or more other hydrogen bond acceptor portions Å is within.

In some embodiments, 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 included in a ring structure, wherein the ring structure is It may be a single ring structure or a plurality of fused ring structures.

In some embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein the hydrogen bond acceptor moiety is independently a carbonyl group, a thiocarbonyl group, an imine group , Alkyl substituted imine groups, sulfoxide groups, sulfone groups, oxime groups, alkyl substituted oxime groups, hydrazone groups, monoalkyl or dialkyl substituted hydrazone groups, oxygen ether (-O-) groups, thioether groups It is selected from the group consisting of sulfides, hydroxy groups, alkoxy groups, amino groups, monoalkyl or dialkyl substituted amino groups, also known as (-S-), and nitro groups.

In some embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer compound, or prodrug thereof, wherein the hydrogen bond donor moiety is a hydroxy group, thiol group, amino group, and Monosubstituted amino groups.

은 하기의 구조적 부분을 포함한다; In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein

Includes the following structural moieties;

Wherein W is O, NR ¹ , NOR ¹ , or S, alternatively W = is a combination of HO— and H— both attached to the same carbon atom, or both attached to a carbon atom (C _{1 − 8} alkyl) O- and H-;

X --- Y will come on when represents a single bond or a double bond, X --- Y is a single bond, X is selected from O, NR ^2, and S (O) _n and Y is CR ^3, 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,

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,

n is 0, 1, or 2.

In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein W is O, NR ¹ , NOR ¹ , or S; R ⁴ is selected from hydrogen and C _{1 -6} alkyl.

은 하기 화학식의 구조적 부분을 포함한다; In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein

Includes structural parts of the formula:

Wherein Z is selected from the group consisting of O, NR ⁴ , or S (O) _n ;

R ⁴ is selected from hydrogen and C _{1 -6} alkyl,

n is 0, 1, and 2.

은 하기 화학식의 구조적 부분을 포함한다; In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein

Includes structural parts of the formula:

Wherein, R ⁴ is selected from H and C _{1 -6} alkyl.

In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein R ⁴ is hydrogen.

은 피롤로시토신 부분 또는 이의 유도체를 포함한다.In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein

Includes pyrrolocytosine moieties or derivatives thereof.

In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein R ⁴ is hydrogen.

은 하기 화학식의 구조적 부분을 포함한다;In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein

Includes structural parts of the formula:

또는

or

는 융합된 5 내지 7원 포화, 불포화, 또는 방향족 탄소환 또는 복소환 고리계이고, In this formula,

Is a fused 5- to 7-membered saturated, unsaturated, or aromatic carbocyclic or heterocyclic ring system,

V is selected from -CR ^4a -or -N-,

W is O, NR ^1, NOR ^1, or S, alternatively W = are both a combination of both the H- and HO- attached to the same carbon atom, or both, attached to the carbon atom (C _{1 -8} alkyl) Is selected from a combination of O- and H-,

X --- Y is selected from when the single bond or a double bond, then, X --- Y a single bond, X is O, NR ^2, and S (O) _n, Y is CR ^3, X - When Y is a double bond, X is N and Y is a carbon atom,

Z is selected from the group consisting of O, NR ⁴ , S (O) _n , or NH,

R ¹ is selected from H and C _{1 -8} alkyl,

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 embodiments, the present invention relates to a compound having a structure of formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof will be:

또는

or

는 융합된 5 내지 7원 포화, 불포화, 또는 방향족 탄소환 또는 복소환 고리계이고, In this formula,

Is a fused 5- to 7-membered saturated, unsaturated, or aromatic carbocyclic or heterocyclic ring system,

T ¹ is a carbon atom or N, so when T ¹ is N, -DEF is absent,

T ² is a carbon atom or N so that when T ² is N, -GHJ is absent,

T ¹ and T ² are not both N at the same time,

V is independently selected from -CR ^4a -or -N-,

W is O, NR ^1, NOR ^1, or S, alternatively W = are both a combination of both the H- and HO- attached to the same carbon atom or both attached to the same carbon atom (C _{1 -8} alkyl ) Is selected from a combination of O- and H-,

X --- Y represents a single bond or a double bond, so when X --- Y is a single bond, X is selected from O, NR ² , and S (O) _n , Y is CR ³ , and X --- when Y is a double bond, X is N and Y is a carbon atom,

Z is selected from the group consisting of O, NR ⁴ , S (O) _n , or NH,

R ¹ is selected from H and C _{1 -8} alkyl,

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;

에서 선택되고, 여기서Alternatively -GHJ

Selected from where

Each of H and J is independently selected;

C-B-A-, -D-E-F, and -G-H-J are chemical moieties, wherein

A, D and G are independently

(a) a single _{bond, (b) - (C 1} -8 -alkyl) -, (c) - (C _{2 -8} alkenyl) -, (d) - (C _{2 -8} alkynyl) (where, i In any of (b)-(d) directly above) 0-4 carbon atoms are -O-, S (O) _p , -NR ⁶ -,-(C = O)-, -S (O) optionally substituted with a moiety selected from the group consisting of _p NR ^6- , -NR ⁶ S (O) _p- , and -NR ⁶ S (O) _p NR ^6- ,

ii) any of (b)-(d) immediately above is at least one R ⁵ Optionally substituted with a group,

iii) any of (b)-(d) immediately above _is- (C _1-8 alkyl) -R ⁵ Optionally substituted with a 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) nitrogen, 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of oxygen, and sulfur,

(ee) 3-14 membered saturated, unsaturated, or aromatic carbocyclic rings, and

(ff)-(CR ⁶ R ⁶ ) _t-

Is selected, where

(Dd) or (ee) is optionally substituted with one or more R ⁵ groups;

B, E, and H are independently

(a) a single bond,

(b) a 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

(c) 3-14 membered saturated, unsaturated, or aromatic carbocyclic rings,

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) immediately above (d In any of)-(f) 0-4 carbon atoms are selected from -O-, -S (O) _p- , -NR ⁶ -,-(C = O)-, -C (= NR ⁶ )-, Optionally substituted with a moiety selected from the group consisting of -S (O) _p NR ^6- , -NR ⁶ S (O) _p- , and -NR ⁶ S (O) _p NR ^6- ,

ii) any of (d)-(f) immediately above is at least one R ⁵ Optionally substituted with a group,

iii) immediately above, (d) - Any of (f) - (C _{1 -8-alkyl)} -R ⁵ Optionally substituted with a group),

And (g)-(CR ⁶ R ⁶ ) _t-

It is selected from the group consisting of;

C, F, and J are independently

(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 group, ( mm) 3-14 membered saturated, unsaturated containing one or more heteroatoms selected from the group consisting of C _2-8 alkenyl groups, (nn) C _2-8 alkynyl groups, (oo) nitrogen, oxygen, and sulfur , Or aromatic heterocycle, (pp) 3-14 membered 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) -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

Is selected from the group consisting of

(Ll) to (pp) are optionally substituted with one or more R ⁷ groups;

R ⁵ is (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)} - (containing 1 or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle), (q)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (r) -haloalkyl, (s ) -SR ⁶ , (t)-a 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (u) -3-14 members Selected from saturated, unsaturated, or aromatic carbocyclic rings,

Alternatively, two R ⁵ groups together form a carbocycle, wherein

(M) to (r) and (t) to (u) are optionally substituted with one or more R ⁸ ;

R ⁶ is (a) hydrogen, (b) -C _{1 -8-alkyl} (or, alternatively, form a carbocyclic group with two R ^6), (c) - haloalkyl, (d) nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of: (e) -3-14 membered saturated, unsaturated, or aromatic carbocycles, wherein

(B) to (e) are optionally substituted with one or more R ⁸ ;

R ⁷ is (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 1 or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle), (q)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (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 ) 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (y) -3-14 membered saturated, unsaturated, or aromatic carbocyclic rings, (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) are optionally substituted with one or more R ⁹ ;

R ⁸ is (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)} - (containing 1 or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle), (q)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (r) nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of: (s) -3-14 membered saturated, unsaturated, or aromatic carbocycles, (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 with one or more R ⁹ ;

R ⁹ is (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) - consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group, (r) -3-14 membered saturated, unsaturated, or aromatic carbocycles, (s) -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) At least one heteroatom selected from the group consisting of -C (O) OR ¹⁰ , (y) -S (O) _p R ⁶ , (z)-(C _1-8 alkyl)-(nitrogen, oxygen, and sulfur) Containing 3-14 membered saturated, unsaturated, or aromatic heterocycle), (aa)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (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 with one or more R ¹⁰ ;

R ¹⁰ is (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) the group consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from (r) -3-14 membered saturated, unsaturated, or aromatic carbocycles, (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 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle), (aa)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (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, the group -D-E-F or group -G-H-J is absent, but neither -D-E-F and -G-H-J are absent at the same time;

p is 0, 1, or 2,

t is 0, 1, 2, or 3.

In some embodiments, the invention relates to a compound according to I, II, III, IV, Ia, IIa, IIIa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof

(a) a 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

(b) a 3-14 membered saturated, unsaturated, or aromatic carbocyclic ring, or

(c) single bond

Wherein (a) or (b) is optionally substituted with one or more R ⁵ groups.

In some embodiments, the invention relates to a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein B It is (a) - (C _1-8 alkyl) -, (b) - (C _2-8 alkenyl) -, (c) - (C _{2 -8} alkynyl) -, or (d) a single bond (wherein i) 0-4 carbon atoms in any of (a)-(c) immediately above are -O-, -S (O) _p- , -NR ⁶ -,-(C = O)-,- Substituted with a moiety selected from the group consisting of C (= NR ⁶ )-, -S (O) _p NR ^6- , and -NR ⁶ S (O) _p NR ^6- ,

ii) any of (a)-(c) immediately above is at least one R ⁵ Optionally substituted with a group, and / or

iii) any of (a)-(c) immediately above _is- (C _1-8 alkyl) -R ⁵ Optionally substituted with a group).

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

The present invention relates to pharmaceutically acceptable salts, esters, tautomers, or prodrugs of compounds according to formulas I, II, III, IV, Ia, IIa, IIIa, IVa.

In some embodiments, 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) a 4-7 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

(b) a 4-7 membered saturated, unsaturated, or aromatic carbocyclic ring, or

(c) is a single bond,

Wherein (a) or (b) is optionally substituted with one or more R ⁵ groups.

In some embodiments, 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 Azepanyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furanyl, tetrahydrofuranyl, tetrahydropyridyl, azetidinyl , Pyrrolidinyl, piperidinyl, or piperidenyl, wherein A is optionally substituted with one or more R ⁵ groups.

Alternatively, the present 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 single compound. It is a bond.

In some embodiments, the invention relates to a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein B It is - (C _{1 -8-alkyl)} -, and wherein

i) 0-4 carbon atoms are -O-, -S (O) _p- , -NR ⁶ -,-(C = O)-, -S (O) _p NR ^6- , or -NR ⁶ S ( O) optionally substituted with a moiety selected from _p NR ^6- ,

ii) (a) B is at least one R ⁵ Optionally substituted with a group, and / or

iii) B is - (C _{1 -8-alkyl)} -R ⁵ Optionally substituted with a 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 compound. It is a bond.

In some embodiments, 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 -NHC (= NH) NH ₂ .

In some embodiments, 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 the group DEF Represents hydrogen.

In some embodiments, 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 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

(b) a 3-14 membered saturated, unsaturated, or aromatic carbocyclic ring, or

(c) single bond

Wherein (a) or (b) is optionally substituted with one or more R ⁵ groups.

In some embodiments, 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 4-7 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

(b) a 4-7 membered saturated, unsaturated, or aromatic carbocyclic ring, or

(c) single bond

Wherein (a) or (b) is optionally substituted with one or more R ⁵ groups

In some embodiments, 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 Azepanyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furanyl, tetrahydrofuranyl, tetrahydropyridyl, azetidinyl , Pyrrolidinyl, piperidinyl, piperidenyl, or a single bond.

In some embodiments, the invention relates to a compound having a structure 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 embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A-, -D-E-F, -G-H-J, W, X, Y, Z, and V are as defined above.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A-, -D-E-F, and -G-H-J are as defined above.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A-,-G-H-J, W, X, Y, and Z are as defined above.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A-,-G-H-J, W, X, Y, Z, and V are as defined in formula (I).

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A-, -D-E-F, W, X, Y, Z, and V are as defined in formula (I).

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

C-B-A-, -D-E-F, -G-H-J, W, X, Y, Z, and V are as defined in formula (I).

In some embodiments, the invention relates to a compound having a structure 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 formula (II).

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A-, -D-E-F, -G-H-J, W, X, Y, Z, and V are as defined in formula (II).

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

In the above formula, it is as defined for C-B-A-, -D-E-F, and -G-H-J.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A-,-G-H-J, W, X, Y, and Z are as defined in formula (II).

In some embodiments, the present invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A-,-G-H-J, W, X, Y, Z, and V are as defined in formula (II).

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A-, -D-E-F, W, X, Y, Z, and V are as defined in formula (II).

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A-, -D-E-F, W, X, Y, Z, and V are as defined in formula (II).

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A-, -D-E-F, -G-H-J, W, X, Y, Z, V and K are as defined in formula III.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A-,-G-H-J, W, X, Y, Z, V and K are as defined in formula III.

는 융합된 6원 포화, 불포화 또는 방향족 탄소환 또는 복소환 고리계를 나타낸다. In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein

Represents a fused six-membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring system.

In some embodiments, the invention relates to a compound having a structure 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; Q ¹ , Q ² , Q ³ , and Q ⁴ are independently selected from a nitrogen atom, a carbon atom, a benzoto or CH, and -DEF, and -GHJ, if present, are attached to the carbon atom, respectively.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A-, D-E-F, and -G-H-J are as defined in Formula III.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A-,-D-E-F, -G-H-J, W, X, Y, Z, V and K are as defined in formula (IV).

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A-,-G-H-J, W, X, Y, Z, V and K are as defined in formula (IV).

는 융합된 6원 포화, 불포화 또는 방향족 탄소환 또는 복소환 고리계를 나타낸다. In some embodiments, the invention relates to a compound according to Formula IV, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein

Represents a fused six-membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring system.

In some embodiments, the invention relates to a compound having a structure 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; Q ¹ , Q ² , Q ³ , and Q ⁴ are independently selected from a nitrogen atom, a carbon atom, or CH, and -DEF, and -GHJ, when present, are each attached to a carbon atom.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A-, D-E-F, and -G-H-J are as defined in Formula IV.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Where A is

(a) a 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

(b) a 3-14 membered saturated, unsaturated, or aromatic carbocyclic ring, or

(c) 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) 0-4 carbon atoms in any of (a)-(c) immediately above are -O-, -S (O) _p- , -NR ⁶ -,-(C = O)-, Optionally substituted with a moiety selected from the group consisting of -C (= NR ⁶ )-, -S (O) _p NR ^6- , and -NR ⁶ S (O) _p NR ^6- ,

ii) any of (a)-(c) immediately above is at least one R ⁵ And / or substituted with a group

iii) any of (a)-(c) immediately above _is- (C _1-8 alkyl) -R ⁵ Substituted with a group)

ego;

C is selected from (a) NH ₂ , (b) -NHC (= NH) NH ₂ and (c) hydrogen.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

또는

or

Wherein C-B-A-, D-E-F, and -G-H-J are as defined in Formulas (I), (II), (III), and (IV).

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein A is azepanyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furanyl, tetrahydrofuranyl, tetrahydropyripy Dill, azetidinyl, pyrrolidinyl, piperidinyl, or piperidinyl, wherein A is optionally substituted with one or more R ⁵ groups; or

A is a single bond;

B is (a) - (C _{1 -8-alkyl)} - (where i) immediately 0-4 carbon atoms of (a) above is _{-O-, -S (O) p -} , -NR 6 -, - Optionally substituted with a moiety selected from the group consisting of (C═O) —, —S (O) _p NR ⁶ —, and —NR ⁶ S (O) _p NR ⁶ —,

ii) immediately above (a) is at least one R ⁵ Optionally substituted with a group, and / or

iii) immediately above (a) is - (C _{1 -8-alkyl)} -R ⁵ Optionally substituted with groups)

Or; or

B is a single bond;

C is (a) NH ₂ , (b) -NHC (= NH) NH ₂ or (c) hydrogen.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein C-B-A- is hydrogen,

Is selected.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein G is

(a) a 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

(b) a 3-14 membered saturated, unsaturated, or aromatic carbocyclic ring, or

(c) single bond

And (a) or (b) is optionally substituted with one or more R ⁵ groups.

In some embodiments, the invention relates to a compound having a structure 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, furanyl, tetrahydrofuranyl, tetrahydropyripy Dill, azetidinyl, pyrrolidinyl, piperidinyl, piperidenyl, or a single bond.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein -G-H-J is hydrogen,

및

And

Is selected.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein -G-H-J is hydrogen,

Where n is 0, 1, or 2.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

In the above formula, -G-H-J is

Is selected.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein, B is a C _{1 -8} alkyl, wherein is optionally substituted with 0-4 carbon atoms are NH,

Each -HJ is independently CF _3, OCF _3, and - (C _{1 -8)} alkyl is selected from -NH _2.

In some embodiments, the invention relates to a compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein each -HJ is independently CF _3, OCF _3, and - (C _{1 -8)} alkyl is selected from -NH _2.

In some embodiments, the invention relates to a compound comprising R ⁵ or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein R ⁵ is (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)} - (nitrogen, oxygen, and a 3-14 membered saturated containing 1 or more heteroatoms selected from the group consisting of sulfur, summon unsaturated, or aromatic heterocyclic), (q) - ( C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocyclic ring), (r) -haloalkyl, (s) -SR ⁶ , (t) -nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected, and (u) -3-14 membered saturated, unsaturated, or aromatic carbocycle; Alternatively, two R ⁵ groups together form a carbocycle.

In some embodiments, the invention relates to a compound comprising R ⁶ , or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein R ⁶ is (a) hydrogen, (b) -C _{1 -8-alkyl} (or alternatively alternatively form a carbocyclic group with two R ^6), (c) - haloalkyl, (d) - a nitrogen, oxygen, and at least one heteroatom selected from the group consisting of sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle containing atoms, and (e) -3-14 membered saturated, unsaturated, or aromatic carbocycles.

In some embodiments, the invention relates to a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein W Is O, NR ¹ , NOR ¹ , or S, if present.

In some embodiments, the invention relates to a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof X --- Y, if present, is a double bond, X is N and Y is a carbon atom.

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

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

In some embodiments, the invention relates to a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof

에서 선택되고, 이때 각각의 -H-J는 독립적으로 -O-CF₃ 및 -(C_{1 -8} 알킬)-NH₂에서 선택된다. Where -GHJ is

Selected, and wherein each -HJ is independently -O-CF ₃ and in - is selected from -NH ₂ (C _{1 -8-alkyl).}

In some embodiments, the invention relates to a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof R ^4a , when present, is hydrogen.

In some embodiments, the invention relates to a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof Z, if present, is NR ⁴ .

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

In some embodiments, the present invention provides a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or pro, which binds to ribosomes. It's about dragging.

In some embodiments, the present invention provides a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or pro, which binds to ribosomes. As for the drug, the ribosomes are bacterial ribosomes.

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

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

In some embodiments, the present invention relates to a method of treating or mitigating a risk of a disease state in a human or animal, which method is pharmaceutically acceptable to a compound of the present invention or a human or animal in need thereof. Administering an effective amount of a salt, ester, tautomer, or prodrug.

In some embodiments, the invention relates to a method of treating a microbial infection in a human or animal, wherein said human or animal is a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof Administering an effective amount.

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

In some embodiments, the invention provides a compound according to Formula (I), (II), (III), (IV), (Ia), (IIa), (IIIa), or (IVa), or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof to a human or animal. A method of treating, preventing or mitigating the risk of microbial infection in a human or animal comprising administering an effective amount of, or in the manufacture of a medicament for treating, preventing, or mitigating the risk of microbial infection in a human or animal. Regarding the use of a compound, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof,

Here, microbial infections include skin infections, Gram-positive bacteria infections, Gram-negative bacteria infections, pathogenic pneumonia, community-acquired pneumonia, post-viral pneumonia, hospital-acquired pneumonia / ventilator-related pneumonia, airway infections. Skin and soft tissue infections (SSTIs), including abdominal infections, including chronic airway infections (CRTIs), acute pelvic infections, complications of skin and skin structures, uncomplicated skin and soft tissue infections (uSSTI), and complications of skin and soft tissue infections , Complications of abdominal infection, urinary tract infection, bacteremia, sepsis, endocarditis, atrioventricular shunt infection, vascular access infection, meningitis, surgical prophylaxis, peritoneal infection, bone infection, joint infection, methi Staphylococcus aureus-resistant Staphylococcus aureus) infections, vancomycin-resistant Enterococcus (Enterococci) infection, linezolid-resistant organism infection, Bacillus anthraquinone system (Bacillus anthracis ) infection, Francisella tularensis ) infection, Yersinia pestis ) and infection, and tuberculosis.

In some embodiments, the invention provides a compound according to Formula (I), (II), (III), (IV), (Ia), (IIa), (IIIa), or (IVa), or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof to a human or animal. A method for treating, preventing or mitigating the risk of a complication of abdominal infection in humans or animals comprising administering an effective amount of, or a drug for treating, preventing or mitigating the risk of complications of abdominal infection in humans or animals. In the manufacture, it relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof,

The complication of abdominal infection here is a multiple microbial infection such as Escherichia. coli ), Clostridium Clostridium clostridioforme ), Eubacterium lentum , Peptostreptococcus spp .), Bacteroides fragilis), des night teroyi Di Star, Sony's (Bacteroides distasonis), night teroyi des Obama Charters (Bacteroides ovatus ), Bacteroides tetaotaomicron thetaiotaomicron ), Bacteroides uniformis), Streptococcus not Zino Saskatchewan (Streptococcus anginosus), Streptococcus cone Stella Charters (Streptococcus constellatus ), Enterococcus faecalis ), Proteus mirabilis , or Clostridium perfringens .

In some embodiments, the invention provides a compound according to Formula (I), (II), (III), (IV), (Ia), (IIa), (IIIa), or (IVa), or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof to a human or animal. A method for treating, preventing or mitigating the risk of a concomitant skin and skin structure infection in humans or animals comprising administering an effective amount of, or a drug for treating, preventing or mitigating the risk of a complication of skin and skin structure infections. Regarding the use of a compound of the present invention or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof in the manufacture,

The merger-prone skin and skin structure infections Staphylococcus aureus (methicillin-susceptible and resistant isolate weeks), Streptococcus Agar Rock Corsica (Streptococcus agalactiae), Streptococcus Pio jeneseu (Streptococcus pyogenes ), Escherichia coli ), Klebsiella pneumoniae), Proteus Billy's Mum (Proteus mirabilis ), Bacteroides fragilis ), Peptostreptococcus species , Porphyromonas Ascarolica asaccharolytica ), or premature foot infection without osteomyelitis due to Prevotella bivia .

In some embodiments, the present invention provides an effective amount of a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. Or a method for treating, preventing, or alleviating the risk of community-acquired pneumonia in a human or animal, comprising administering to the animal, or the manufacture of a drug for treating, preventing or alleviating the risk of community-acquired pneumonia. In regard to the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof,

Community-acquired pneumonia here includes Streptococcus pneumoniae (penicillin susceptible and resistant isolates), including Haemophilus influenzae (including beta-lactamase positive isolates), Morasella catarrhalis, including cases with concurrent bacteremia ( Moraxella catarrhalis ), or atypical bacteria such as Mycoplasma spp .

In some embodiments, the present invention provides an effective amount of a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. Or a method of treating, preventing or alleviating the risk of a complicated urinary tract infection in a human or animal comprising administering to the animal, or in the manufacture of a medicament for treating, preventing or alleviating the risk of a complicated urinary tract infection. Or to a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof,

The complication of urinary tract infection is here selected from pyelonephritis due to Escherichia coli , concurrent bacteremia, or pyelonephritis due to Klebsiella pneumoniae .

In some embodiments, the present invention provides an effective amount of a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. Or a method of treating, preventing, or mitigating the risk of an acute pelvic infection comprising administering to an animal, or a compound of the invention, or a pharmaceutical thereof, in the manufacture of a medicament for treating, preventing or alleviating the risk of an acute pelvic infection. Regarding the use of salts, esters, tautomers, or prodrugs that are acceptable as

Acute pelvic infections (including postpartum endometrial infection, septic abortion and postoperative gynecological infections) include Streptococcus agalactia, Escherichia coli, Bacteroides pragilis, Porphylomonas asacarolitica and pepto Streptococcus spp., Or Prevotella bivia .

In some embodiments, the present invention provides an effective amount of a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. Or a method of treating, preventing or reducing the risk of hospital-acquired pneumonia / ventilator-related pneumonia in a human or animal comprising administering to the animal, or treating, preventing or A method for the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, in the manufacture of a medicament for alleviating

Hospital-acquired pneumonia / ventilator-related pneumonia include Streptococcus pneumoniae (penicillin sensitive and resistant isolates), Staphylococcus aureus (methicillin susceptible and resistant isolates), Krebsiella pneumoniae, Pseudomonas aeruginosa Pseudomonas aeruginosa ), Acinetobacter species (Acinetobacter spp . ), Stenotrophomonas maltophilia ), Haemophilus influenza (including beta-lactamase positive isolates), or Legionella pneumophilia .

In some embodiments, the present invention provides an effective amount of a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. Or treating, preventing or alleviating the risk of human microbial infection with an aerobic or conditional Gram-positive microorganism in a human or animal, comprising administering to the animal, or treating a risk of microbial infection due to aerobic or conditional Gram-positive microorganisms In the manufacture of a medicament for the prevention, or alleviation, the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof,

Wherein the aerobic or conditional Gram-positive microorganisms are Staphylococcus aureus (methicillin susceptible and resistant isolate), Streptococcus pneumoniae (penicillin sensitive and resistant isolate), enterococcus species (vancomycin susceptible and resistant isolate) , Streptococcus agalactia, Streptococcus piogenes, or Staphylococcus epidermidis ) (methicillin susceptible and resistant isolates).

In some embodiments, the present invention provides an effective amount of a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. Or a method for treating, preventing, or alleviating the risk of microbial infection due to aerobic and conditional Gram-negative microorganisms in humans or animals, comprising administering to the animal, or risk of microbial infection due to aerobic or conditional Gram-negative microorganisms. A method for the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, in the manufacture of a medicament for the treatment, prevention or alleviation,

Where aerobic and conditional Gram-negative microorganisms are Escherichia coli (ESBL and KPC producing isolates), Haemophilus influenza (beta-lactamase positive isolates), Klebsiella pneumoniae (ESBL and KPC producing isolates) Citrobacter, Citrobacter freundii ), Enterobacter aerogenes ), Enterobacter cloacae ), Morganella morganii , Serratia marcescens ), Pseudomonas aeruginosa, Acinetobacter baumanni ), Moraxella catarrhalis), Proteus Billy's Mum (Proteus mirabilis ), Citrobacter koseri ), Haemophilus parainfluenzae , Klebsiella oxytoca) (produced ESBL and KPC isolating week), Proteus vulgaris (Proteus vulgaris ), Providencia Letgeri rettgeri ), and Providencia stuartii .

In some embodiments, the present invention provides an effective amount of a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. Or a method for treating, preventing or mitigating the risk of microbial infection due to anaerobic microorganisms in humans or animals comprising administering to the animal, or for the manufacture of a medicament for treating, preventing or mitigating the risk of microbial infection due to anaerobic microorganisms. In regard to the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof,

Anaerobic microorganisms include Bacteroides pragilis, Bacteroides distasonis distasonis ), Bacteroides ovatus ), Bacteroides tetaotaomicron thetaiotaomicron ), Bacteroides uniformis ), Clostridium Clostridioform, Eubacterium lentum ), Peptostreptococcus species ), Porphyromonas asacarolitica, Prebotella vivia, Bacteroides vulgares ( Bacteroides vulgates ), Clostridium perfringens, or Fusobacterium species spp . )to be.

In some embodiments, the present invention provides an effective amount of a compound according to Formula I, II, III, IV, Ia, IIa, IIIa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. Or a method of treating or lessening the risk of a microbial infection in a human or animal comprising administering to the animal, or in the manufacture of a medicament for treating, preventing or mitigating the risk of a microbial infection, or a pharmaceutical thereof Regarding the use of acceptable salts, esters, tautomers, or prodrugs, the microorganism is Legionella pneumophilia .

In some embodiments, the invention relates to a method or use of the compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, in which the ear, eye, nose, oral, parenteral, or topical administration is administered. It is about.

In some embodiments, the invention relates to a method of synthesizing a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

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

In some embodiments, the invention is directed to a medical device containing a compound of the invention, wherein the device is a stent.

3. Synthesis of Compounds of the Invention

The present invention provides a method for preparing the compound of the present invention. Schemes 1a-5a below depict general exemplary routes for synthesizing compounds of the present invention. More specific chemical content is provided in the Examples.

Scheme 1a- Pyrrolocytosine

Scheme 2a- Pyrroloisocytosine

Scheme 3a- Triazoleisocytosine

Scheme 4a-[6,5,6]- Pyrrolocytosine

Scheme 5a-[6,5,6]- Pyrroloisocytosine

4. Characterization of the Compounds of the Invention

Once a compound is designed, selected, and / or optimized by the methods described above, it can be characterized using a variety of assays known to those of skill in the art to determine whether the compound has biological activity. For example, molecules can be characterized via conventional assays, including but not limited to the assays described below, to determine whether they have expected activity, binding activity, and / or binding specificity.

In addition, high yield screening methods can be used to speed up analysis using such methods. As a result, the molecules described herein can be screened rapidly for activity, for example, as an anticancer, antibacterial, antifungal, antiparasitic or antiviral active agent. It may also be possible to analyze how a compound interacts with a ribosome or ribosomal subunit and / or is effective as a modulator (eg an inhibitor) of protein synthesis using techniques known in the art. General methodologies for performing high yield screening are described, for example, in Devlin (1998) High Throughput Screening , Marcel Dekker; And US Patent Application No. 5,763,263. High yield assays can use, but are not limited to, one or more different analytical techniques, including those described below.

(1) Surface Bonding Studies . Various binding assays may be useful for screening new molecules for their binding activity. One approach includes surface plasmon resonance (SPR), which can be used to assess the binding properties of the target molecule for ribosomes, ribosomal subunits or fragments thereof.

The SPR methodology measures the interaction between two or more macromolecules in real time through the production of quantum-mechanical surface plasmons. One device (BIAcore Biosensor RTM from Pharmacia Biosensor, Piscataway, N.J.) provides a multicolored focused light at the interface between a buffer fraction that can be adjusted by the user and the gold membrane (provided as a disposable biosensor "chip"). A 100 nm thick “hydrogel”, consisting of carboxylated dextran that provides a matrix for covalent fixation of the analyte of interest, is attached to the gold membrane. When the focused light interacts with the free electron cloud of the gold curtain, plasmon resonance is enhanced. The generated reflected light is spectrally diminished at a wavelength that optimally generates resonance. By separating the reflected polychromatic light into its component wavelengths (by prism) and measuring the decay frequency, BIAcore establishes an optical interface that accurately records the behavior of the generated surface plasmon resonance. When designed as described above, the plasmon resonance (and therefore the decay spectrum) is sensitive to mass in the dissipation field (approximately corresponding to the hydrogel thickness). If one component of the interaction pair is immobilized on the hydrogel so that an interaction partner is provided through the buffer compartment, the interaction between the two components provides the corresponding effect of plasmon resonance on the measurement of mass accumulation and depletion spectra in the evanescent field. You can measure in real time. Such a system enables rapid and sensitive real-time measurement of molecular interactions without the need to label components.

(2) fluorescence polarization . Fluorescence polarization (FP) is a measure that can be readily applied to protein-protein, protein-ligand or RNA-ligand interactions to derive IC ₅₀ and Kd of two-molecular light responses. In this method, one of the target molecules is conjugated to a fluorophore. It is usually a smaller molecule in the system (in this case the target compound). Sample mixtures containing ligand-probe conjugates and ribosomes, ribosomal subunits or fragments thereof are excited with vertically polarized light. Light is absorbed by the fluorophore and re-emitted after a short time. The polarization degree of the emitted light is measured. The polarization of the emitted light depends on several factors, but most importantly on the viscosity of the solution and the apparent molecular weight of the fluorophore. With proper control, the change in the degree of polarization of the emitted light depends only on the change in the apparent molecular weight of the fluorophore, and the apparent molecular weight of the fluorophore depends on whether the probe-ligand conjugate is free in solution or bound to the receptor. to be. FP-based binding assays have many important advantages and include the measurement of IC ₅₀ and Kd under true homogeneous equilibrium conditions, the convenience of assay speed and automation, and the ability to screen in turbid suspensions and colored solutions.

(3) protein synthesis . In addition to characterization by the biochemical assays described above, it is contemplated that the desired compound may be characterized as a modulator of the functional activity of the ribosome or ribosomal subunits (eg, inhibitors of protein synthesis).

In addition, more specific protein synthesis inhibition assays are directed to whole organisms, tissues, organs, organelles, cells, cells or subcellular extracts, or purified ribosome preparations, for example the inhibition constants that inhibit protein synthesis ( IC ₅₀ ) to determine the pharmacological and inhibitory properties.

Introduction of ³ H leucine or ³⁵ S methionine, or similar experiments can be performed to investigate protein synthesis activity. Changes in the amount or rate of intracellular protein synthesis in the presence of the molecule of interest mean that the molecule is a regulator of protein synthesis. Reduction in protein synthesis rate or amount means that the molecule is an inhibitor of protein synthesis.

(4) Antimicrobial Analysis and Other Assessment Methods . Compounds can also be analyzed for antiproliferative or antiinfective properties at the cellular level. For example, when the target organism is a microorganism, the activity of the target compound can be analyzed by growing the target microorganism in a medium containing the compound or in a medium free of the compound. Growth inhibition means that the molecule can act as a protein synthesis inhibitor. More specifically, the activity of the target compound against bacterial pathogens can be verified by the ability of the compound to inhibit the growth of designated human pathogen strains. For this purpose, a panel of bacterial strains can be aggregated to include various target pathogen species, some of which include defined resistance mechanisms. The use of such panels of organisms allows the determination of structure-activity relationships in terms of eliminating resistance mechanisms as well as titers and spectra.

Minimum inhibitory concentrations (MIC) are described in The Clinical and Laboratory Standards Institute [CLSI; According to a protocol previously outlined by the National Committee for Clinical Laboratory Standards (NCCLS), it is measured via microdilution, microdilution to a final volume of approximately 100 microliters. CLSI: Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard-fifth edition. Wayne, PA: NCCLS; 2000]. This assay can be performed in a microtiter tray according to the general methodology published by CLSI. 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 drug properties of the compounds can be further assessed in various 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 sepsis or long term infection models known to those skilled in the art. This efficacy model can be used as part of the assessment process and used as a guide of possible efficacy in humans. The endpoint may vary from reduced bacterial load to mortality. For the latter endpoint, the results are often expressed as a PD ₅₀ value or as a dose of drug that protects 50% of animals from death.

To further assess the drug-like properties of the compounds, measurements of inhibition of cytochrome P450 enzymes and stage II metabolic enzymes can also be measured using recombinant human enzyme systems or more complex systems such as human liver microsomes. In addition, compounds can also be assessed as substrates of these metabolic enzyme activities. Such activity is useful for determining the likelihood of a compound producing a drug-drug interaction or maintaining a useful antimicrobial activity or producing a metabolite without such activity.

Solubility and Caco-2 assays can also be performed to obtain a potential estimate of a compound that can be orally bioavailable. The latter is a human epithelial derived cell line that allows passage and drug measurements via Caco-2 cell monolayers normally grown in wells of 24-well microtiter plates equipped with 1 micron membranes. Free drug concentration can be measured on the side bottom of the monolayer and the amount of drug that can pass through the monolayer is measured. Appropriate control is required to ensure fault strength and tightness of the gap connections. This same system can be used to obtain an estimate of P-glycoprotein mediated influx. P-glycoproteins are pumps located in the apical membranes of cells that form polarized monolayers. The pump eliminates active or passive uptake through the Caco-2 cell membrane, resulting in less drug passing through the intestinal epithelial layer. These results are often done with solubility measurements and both of these factors are known to contribute to oral bioavailability in mammals. Oral bioavailability measurements in animals and traditional humans using traditional pharmacokinetic experiments will determine absolute oral bioavailability.

Experimental results can also be used to build models that help predict physico-chemical parameters that contribute to drug-like properties. If such a model is verified, the experimental methodology is reduced and confidence in model predictability is increased.

5. Formulation and Administration

The compounds of the present invention may be useful for the prevention or treatment of various human or other animals, including, for example, bacterial infections, fungal infections, viral infections, diarrhea, parasitic diseases, and cancers, mammals and non-mammals. have. Once identified, it is contemplated that the active molecules of the present invention may be incorporated into any suitable carrier prior to use. The dose, mode of administration, and use of appropriate carriers of the active molecule depend on the intended recipient and target organism. For veterinary and human medical use, the preparations of the compounds according to the invention generally comprise such compounds together with pharmaceutically acceptable carriers.

The carrier (s) must be one that is not detrimental to the recipient and is "acceptable" in terms of compatibility with the other ingredients of the formulation. In this regard, pharmaceutically acceptable carriers are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal actives, isotonic and absorption delaying agents, and the like, suitable for any pharmaceutical administration. The use of such media and actives for pharmaceutically active substances is known in the art. Except insofar as any conventional media or active agent is incompatible with the active compound, its use in the compositions is contemplated. Supplementary active compounds (identified or designed in the art and / or according to the invention) may also be incorporated into the compositions. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical / microbiological arts. As a rule, some formulations are prepared by mixing the compound with a liquid carrier or finely divided solid carrier or both and then molding the product into a suitable formulation if necessary.

The pharmaceutical composition of the present invention should be formulated to be suitable for the intended route of administration. Routes of administration include oral, ear, eye, nose, or parenteral, such as intravenous, intradermal, inhalation, transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may include the following components: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents ; Antibacterial agents such as benzyl alcohol or methyl parabens; Antioxidants such as ascorbic acid or sodium bisulfite; Chelating agents such as ethylenediaminetetraacetic acid; Buffers such as acetate, citrate or phosphate and tension regulators such as sodium chloride or dextrose, pH may be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide.

Solutions useful for oral or parenteral administration can be prepared by any method known in pharmaceutical embryos, for example, see Remington's Pharmaceutical. Sciences , (Gennaro, A., ed.), Mack Pub., (1990). Formulations for parenteral administration may also include glycocholate for oral administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration. Parenteral preparations may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Suppositories for rectal administration can also be prepared by mixing the drug with non-irritating excipients such as cocoa butter, other glycerides, or other compositions that are solid at room temperature and liquid at body temperature. The formulations may also include, for example, polyalkylene glycols such as polyethylene glycol, vegetable oils, and hydrogenated naphthalenes. Formulations for direct administration may include glycerol and other high viscosity compositions. Other parenteral carriers that may be useful for such drugs include ethylenevinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration may contain, for example, lactose as excipients, or are administered in the form of aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or nasal drops. Oily liquids, or gels applied in the nose. Retention enema can also be used for rectal delivery.

Formulations of the invention suitable for oral administration include discrete units such as capsules, gelatin capsules, cachets, tablets, troches, or lozenges, each containing a predetermined amount of drug; Powder or granule compositions; Solutions or suspensions in aqueous or non-aqueous liquids; Or in an oil-in-water emulsion or water-in-oil emulsion. The drug can also be administered in the form of a bolus, soft or paste. Tablets may be prepared by compressing or molding the drug, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, drugs in free flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersant. Molded tablets may be made by molding in a suitable machine a mixture of a suitable carrier and powdered drug moistened with an inert liquid diluent.

Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound may be incorporated with excipients. Oral compositions prepared using a fluid carrier for use as a mouthwash include compounds in the fluid carrier and are applied orally to beep, spit or swallow. Pharmaceutically suitable binders, and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, troches, and the like may contain any of the following components, or compounds of similar nature: binders such as microcrystalline cellulose, gum tragacanth or gelatin; Excipients such as starch or lactose; Disintegrants such as alginic acid, primogel, or corn starch; Lubricants such as magnesium stearate or steotes; Glidants such as colloidal silicon dioxide; Sweetening agents such as sucrose or saccharin; Or flavoring agents such as peppermint, methyl salicylate, or organic flavoring agents.

Pharmaceutical compositions suitable for injection include sterile aqueous solutions (if water soluble) or dispersions and sterile powders for the instant 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). It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycols), and appropriate mixtures thereof. Proper fluidity is maintained, for example, by the use of coatings such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. In many cases, it is preferable to include isotonic agents, such as sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be achieved by the addition of active agents which delay absorption to the composition, such as aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by introducing one or a combination of ingredients enumerated above and the required amount of the active compound in a suitable solvent, followed by filtration sterilization if necessary. Generally, dispersions are prepared by introducing the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation include vacuum drying and freeze drying, in which a powder of the active ingredient with which any additional desired ingredient is added is added from the previously sterilized solution.

Formulations suitable for intraarticular administration may be in the form of sterile aqueous preparations of the drug, which may be in microcrystalline form, for example in the form of an aqueous microcrystalline suspension. Liposomal preparations or biodegradable polymer systems can also be used to prepare drugs for both intraarticular and ocular administration.

Formulations suitable for topical administration, including eye treatment, include liquid or semi-liquid preparations such as stains, lotions, gels, coatings, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; Or solutions or suspensions such as drops. Formulations for topical administration to the skin surface are prepared by dispersing the drug in a dermatologically acceptable carrier such as lotion, cream, ointment or soap. Particularly useful are carriers that can form a film or layer on the skin for topical application and for inhibiting removal. For topical application to the internal tissue surface, the active agent may be dispersed in a liquid tissue adhesive or other material known to enhance adhesion to the tissue surface. For example, it is advantageous to use hydroxypropylcellulose or fibrinogen / thrombin solution. Alternatively, tissue coating solutions such as pectin-containing formulations can be used.

For inhalation treatment, the powder inhalation (self-propelled or spray formulation) dispensed into the spray may be a nebulizer or an automator may be used. Such formulations may be in powder form for pulmonary administration from a powder inhalation device or a self-propelled powder-dispensing formulation. For self-propelled solutions and spray formulations, the active ingredient may be introduced by the selection of a valve having the desired spray characteristics (i.e., the ability to produce a spray having the desired particle size) or as a suspended particle of controlled particle size. Effect can be achieved. For inhalation administration, the compound may also be delivered in the form of an aerosol spray from a pressurized vessel or dispenser containing a suitable propellant, for example a gas such as carbon dioxide, or a nebulizer.

Systemic administration may also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants suitable for the barrier to penetrate are used in the formulation. Such penetrants are generally known in the art and include, for example, detergents and bile salts for transmucosal administration. Transmucosal administration can be carried out through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are usually formulated into ointments, selvs, gels or creams as is known in the art.

The active compound may be prepared with a carrier that will protect the compound from rapid removal from the body, such as formulated in controlled release formulations including implants 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 preparing such formulations are known to those skilled in the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These are methods known to those skilled in the art, for example. It may be prepared according to the method described in US Pat. No. 4,522,811.

Oral or parenteral compositions may be formulated in unit dose formulations for ease of administration and dose uniformity. Unit dose formulation means a physically discrete unit adapted as an integrated dose for the subject to be treated; Each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect with the required pharmaceutical carrier. The details of the unit dosage form of the present invention are directly dependent on the inherent characteristics of the active compound and the particular therapeutic effect desired to be obtained, and the inherent limitations of the art in formulating such active compound with the treatment of the individual. Are instructed accordingly. In addition, administration can be by periodic injection of bolus, or more continuously via intravenous, intramuscular, or intraperitoneal administration from an external reservoir (eg, an intravenous bag).

The composition may comprise a drug dispersed in the fibrinogen-thrombin composition or other bioadhesive if desired to adhere to the tissue surface. The compound may also be painted, sprayed or otherwise applied to the desired tissue surface. Alternatively, the drug may be used in an ear, eye, nose, parenteral or human or other mammal, for example, in a therapeutically effective amount, such as in an amount that provides the concentration of the drug to the target tissue for a time sufficient to induce the desired effect. It may be formulated for oral administration.

If the active compound is used as part of a transplant procedure, it may be provided to the living tissue or organ to be transplanted prior to removal of the tissue or organ from the donor. The compound may be provided to the donor host. Alternatively, or in addition, once separated 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 is administered directly to the desired tissue by injecting it into the tissue, or using the ear, eye, nose, oral or the like, for example using any of the methods and agents known in the art and / or in the art. It may be given systemically by parenteral administration. If the drug is included as part of an organ or tissue preservation solution, it may be advantageous to use any commercially available preservation solution. For example, useful solutions known in the art include Collins solution, Wisconsin solution, Belzer solution, Eurocholine solution and Lactated Ringer's solution.

The compounds of the present invention can be administered directly to a tissue locus by applying the compound to a medical device positioned to be in contact with the tissue. An example of a medical device is a stent, which contains or is coated with one or more compounds of the present invention.

For example, the active compound can be applied to the stent at the site of vascular injury. Stents can be prepared by any method known in the pharmaceutical art. See, eg, Fattori, R. and Piva, T., "Drug Eluting Stents in Vascular Intervention," Lancet, 2003, 361, 247-249; Morice, M. C., "A New Era in the 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 can be made of stainless steel or other biocompatible metals or made of a biocompatible polymer. The active compound may be linked to the stent surface and inserted from the polymeric material coated on the stent, or may be released from and surrounded by a carrier that coats or spans the stent. Stents can be used to administer single or multiple active compounds to tissue adjacent to the stent.

Active compounds identified or designed by the methods described herein can be administered to an individual to treat (prophylactically or therapeutically) a disease. In conjunction with such treatment, genomic pharmacy (ie, a study of the association between an individual's genotype and the individual's response to a foreign compound or drug) may be considered. Therapeutic Metabolism Teeth can cause serious toxicity or treatment failure due to changes in dose- and blood concentration-related changes in pharmacologically active drugs. Thus, the attending physician or clinician may consider application knowledge gained from relevant genomic pharmaceutical studies in determining drug administration as well as tailoring the treatment plan and / or dose of treatment with the drug.

In therapeutic uses to treat, or prevent, bacterial infections in a mammal, the compound or pharmaceutical composition thereof has a concentration of active ingredient, i.e., amount or blood level or tissue level in an animal that is undergoing treatment with an antimicrobial effect. Ear, eye, nose, oral, parenteral and / or topical administration in doses to obtain and maintain. In general, the effective dose of the active ingredient ranges from about 0.1 to about 100, more preferably from about 1.0 to about 50 mg / kg body weight / day. The amount to be administered depends on such variables as the type and extent of the disease or indication to be treated, the general health of the particular patient, the relative biological efficacy of the delivered compound, the formulation of the drug, the presence and type of excipients in the formulation, the route of administration and the like. In addition, the initial dose administered may be increased to a higher or higher level to rapidly obtain superior blood or tissue levels, or the initial dose may be less than the optimal concentration and the daily dose may be progressive during the course of treatment, depending on the particular situation. Can be increased. If desired, the daily dose may also be divided into multiple doses for administration, for example twice to four times daily.

Various disease states or conditions in humans and other mammals are known to be caused or mediated by nonsense or missense mutations. Such mutations, for example, adversely affect protein synthesis, folding, tracking, and / or function to cause or mediate disease states or conditions. Examples of disease states or conditions in which noteworthy proportions of the disease or condition are believed to be caused by nonsense or missense mutations include hemophilia (factor VIII gene), neurofibromatosis (NF1 and NF2 genes), retinitis pigmentosa (human USH2A gene) , Bullous skin diseases such as bullous positive epidermal detachment (COL7A1 gene), cystic fibrosis (cystic fibrosis dura modulator gene), breast and ovarian cancer (BRCA1 and BRCA2 genes), Duchenne muscular dystrophy (dystrophin gene), colon cancer (miss) Matet repair genes, mainly in MLH1 and MSH2), and lysosomal storage diseases such as Neiman-Pick disease (acid spinomilinase gene). See, eg, 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: 101138560 ; and Rasko, Istvan; Downes, CS Genes in medicine : molecular biology and human genetic disorders 1st ed. London; New York: Chapman & Hall, 1995. NLM ID: 9502404. Compounds of the present invention are effective amounts of the present invention for inhibiting nonsense or missense mutations involved in such disease states in mammals in need of treatment or prevention of disease states caused or mediated by such nonsense or missense mutations. It can be used to treat or prevent a disease state in a mammal caused or mediated by nonsense or missense mutations by administering a.

6. Example

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

The compounds of the present invention can be prepared immediately using known chemical alternatives adapted to the particular situation.

Some terms used in the experimental details for the synthesis of the examples below are defined as follows: h or hr = time (s); min = minute (s); mol = mole (s); mmol = millimolar (s); M = molar; μM = micromolarity; g = gram (s); Μg = microgram (s); rt = room temperature; L = liter (s); mL = milliliter (s); Et ₂ O = diethyl ether; THF = tetrahydrofuran; DMSO = dimethyl sulfoxide; EtOAc = ethyl acetate; Et ₃ N = triethanolamine; i- Pr ₂ NEt or DIPEA = diisopropylethylamine; CH ₂ Cl ₂ = Methylene chloride; CHCl ₃ = Chloroform; CDCl ₃ = Deuterium containing chloroform; CCl ₄ = Carbon tetrachloride; MeOH = methanol; CD ₃ OD = deuterium containing methanol; EtOH = ethanol; DMF = dimethylformamide; BOC = t -butoxycarbonyl; CBZ = benzyloxycarbonyl; TBS = t -butyldimethylsilyl; TBSCl = t -butyldimethylsilyl chloride; TFA = trifluoroacetic acid; DBU = diazabicycloundecene; TBDPSCl = t -butyldiphenylchlorosilane; Hunig base = N, N -disopropylethylamine; DMAP = 4-dimethylaminopyridine; CuI = copper (I) iodide; MsCl = methanesulfonylchloride; 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 = Silica; Pd-C = palladium on carbon; Pd (dppf) Cl ₂ = large chloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II).

Exemplary compounds synthesized according to the invention are listed in Table 1 below. Thick or dotted bonds are shown to show specific stereochemistry at the chiral center, whereas wavy bonds mean that the substituents may be present in both orientations or the compound is a mixture thereof. In the conserved space of interest, it will be appreciated that the chemical structure of some compounds is divided into two parts, each with two connection points represented by crossed bonds. For example, compound 755, shown in two parts below,

However, it corresponds to the complete chemical structure below.

Compounds of the invention can be prepared, formulated, and delivered as salts, esters, and prodrugs. For convenience, compounds are generally shown without exhibiting specific salt, ester, or prodrug form.

The compounds of the present invention are shown in Table 1 below. LCMS (Liquid Chromatography Mass Spectrum) data are provided where available. If data is not available, it is labeled "NA". LCMS data are provided using the method for m / z , in the form [M + H] +, except where otherwise indicated.

In further embodiments, the compounds of the present invention do not include compounds having the structure:

Compounds of the invention can be prepared using synthetic chemistry techniques 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 to 3-amino-propyl) -carbamic acid tert- in toluene (200 mL). To a mixture of butyl ester (16.1 g, 92.51 mmol) and triethanolamine (29.6 ml, 213.5 mmol) was added dropwise at 80 ° C. for 30 minutes. The resulting mixture was heated at 80 ° C. for a further 2 h and then cooled to 0 ° C. Di- tert - butyl pyrocarbonate (23.5 g, 107.80 mmol) was added at 0 ° C. After 2 h, the mixture was warmed to rt and stirred overnight, then diluted with EtOAc (500 mL), washed with water (300 mL), brine (300 mL). The organic solution was concentrated and purified by flash chromatography (10% -25% EtOAc in heptanes) to give the desired product as a colorless oil (16.15 g, 51%). ¹ NMR (300 MHz, 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- [l, 3,2] dioxaborolan-2-yl) -benzyl] -carbamic Bamsan tert -butyl ester : {3-[(4-bromo-benzyl) -tert -butoxycarbonyl-amino] -propyl} -carbamic acid tert -butyl ester (16.15 g, 36.46 mmol), bispinolacate boronate (10.20, 40.11 mmol), a mixture of KOAc (10.72 g, 109.38 mmol), Pd (PPh ₃ ) ₄ (0) (2.03 g, 1.82 mmol) and DMF (80 mL) at 80 ° C. for 16 h under Argon atmosphere. Heated at. The reaction mixture was diluted with EtOAc (500 mL) and washed with water (300 mL) and brine (300 mL). The organic solution was concentrated and purified by flash chromatography (10% -30% EtOAc in heptanes) to afford the desired product as a colorless oil (14.15 g, 80%). ¹ NMR (300 MHz, 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-acrylic acid methyl ester: (3-tert -Butoxycarbonylamino-propyl)-[4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzyl] -carbamic acid tert -butyl Ester (6.00 g, 12.25 mmol), 2-iodo-3-methoxy-acrylic acid methyl ester (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), dioxane (60 mL) and water (12 mL) were degassed and heated at 80 ° C. for 20 h under argon atmosphere. The reaction mixture was diluted with EtOAc (500 mL) and washed with water (300 mL) and brine (300 mL). The organic solution was concentrated and purified by flash chromatography (0% -30% EtOAc in heptanes) to afford the desired product as a brown oil (5.35 g, 91%). ¹ NMR (300 MHz, 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-oxo-1,7-dihydro-imidazo [1,2-a] pyrimidin-6-yl) benzyl] -amino} -propyl ) -carbamic acid tert -butyl ester : 2- (4-{[tert-butoxycarbonyl- (3-tert-butoxycarbonylamino-propyl) -amino] -methyl} -phenyl) -3-methoxy-acrylic acid methyl ester (97 mg, 0.2 mmol), a solution of sodium methoxide (0.5 mL, 0.5 M in methanol, in a mixture of 1 H -imidazol-2-ylamine sulfate (29 mg, 0.223 mmol) and ethanol (10 mL), 0.25 mmol) was added. The resulting mixture was refluxed for 18 h, and additional 0.5 mL of sodium methoxide (0.5 M in methanol, 0.5 mmol) was added and the reflux continued for 20 h. The reaction was concentrated and diluted with EtOAc (30 mL), washed with water (20 mL), brine (20 mL). EtOAc solution was concentrated. The crude product was purified by flash chromatography (10% methanol in dichloromethane) to give the desired product as a white solid (48 mg, 48%). ¹ NMR (300 MHz, 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 (EI) m / z: 498.1 (M + H ⁺ ).

6- {4 - [(3-amino-propylamino) -methyl] -phenyl} -1H- imidazo [1,2-a] pyrimidin-7-one hydrochloride salt (the hydrochloride salt of compound 563): {(3- {tert-butoxycarbonyl- [4- (7-oxo-1,7-dihydro-imidazo [1,2-a] pyrimidin-6-yl) -benzyl] -amino}- Propyl) -carbamic acid tert-butyl ester (48 mg, 0.097 mmol) was dissolved in CH ₂ Cl ₂ (5 mL), TFA (1 mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated and 3 mL of 0.6 N HCl and 2 mL acetonitrile were added, stirred for 0.5 h, and ca. Concentrated to 3 mL and lyophilized to give the title compound (35 mg, 100%). ¹ NMR (300 MHz, 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, 1 H), 4.33 (s, 2 H), 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-oxo-1,7 -dihydro - imidazo [1,2-a] pyrimidin- 6-yl) -benzylamino ] -propyl} -guanidine hydrochloride salt ( Hydrochloride salt of compound 564 ) : N, N -bis-Boc-1-guanylpyrazole in a mixture of compound 563 (26 mg, 0.07 mmol), Hunig base (90 mg, 0.70 mmol) and DMF (10 mL) (22 mg, 0.07 mmol) was added. The reaction mixture was stirred at rt overnight, diluted with water (30 mL) and extracted with EtOAc (50 mL x 3). The organic solution was concentrated and purified by PTLC (2N NH ₃ / CH ₂ Cl ₂ , 1: 4) to give guandylated product (30 mg, 80%) as a white solid which gave 3 mL of CH ₂ Cl _2. Dissolved in and 1 mL of TFA was added. The resulting mixture was stirred overnight and concentrated. 3 mL of 0.6 N HCl and 2 mL acetonitrile were added and stirred for 0.5 h, ca. Concentrated to 3 mL and lyophilized to give the title compound (20 mg, 100%). ¹ NMR (300 MHz, 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 (EI) m / z: 339.7 (M + H ⁺ ).

N- (3-{(4-amino-butyl)-[4- (7-oxo-1,7 -dihydro - imidazo [1,2-a] pyrimidin -6-yl) -benzyl]- Amino} -propyl) -guanidine hydrochloride salt ( hydrochloride salt of compound 616) : N, N in a mixture of compound 563 (26 mg, 0.07 mmol), Hunig base (90 mg, 0.70 mmol) and DMF (10 mL) -Bis-Boc-1-guanylpyrazole (22 mg, 0.07 mmol) was added. The reaction mixture was stirred at rt overnight, diluted with water (30 mL) and extracted with EtOAc (50 mL × 3). The organic solution was concentrated and purified by PTLC (2N NH ₃ / CH ₂ Cl ₂ , 1: 4 in methanol) to give the guandylated product as a white solid (30 mg, 80%).

Guandylated compound (27 mg, 0.05 mmol), (3-oxo-propyl) -carbamic acid tert-butyl ester (9 mg, 0.05 mmol), acetic acid (6 mg, 0.1 mmol) and CH ₂ Cl ₂ (5 mL) was stirred at rt for 30 min before sodium cyanoborohydride (13 mg, 0.2 mmol) was added. The resulting mixture was stirred overnight, diluted with CH ₂ Cl ₂ (15 mL) and washed with saturated sodium bicarbonate solution. CH ₂ Cl ₂ The solution was concentrated and purified by PTLC (2N NH ₃ / CH ₂ Cl ₂ , 1: 9) to afford the desired tertiary amine as a white solid (13 mg, 37%).

Tertiary amine product (13 mg, 0.0187 mmol) was dissolved in 3 mL of CH ₂ Cl ₂ and 1 mL of TFA was added. The resulting mixture was stirred overnight and concentrated. 3 mL of 0.6 N HCl and 2 mL acetonitrile were added and stirred for 0.5 h, then ca. Concentrated to 3 mL and lyophilized to give the title compound (9.4 mg, 100%). ¹ NMR (300 MHz, 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 (EI) m / z: 396.9 (M + H ⁺ ).

{4- [2- (4-Bromo-phenyl) -7-oxo-1,7-dihydro-imidazo [1,2-a] pyrimidin-6-yl] -benzyl}-(3- tert -butoxycarbonylamino-propyl) -carbamic acid tert -butyl ester: 2- (4-{[tert-butoxycarbonyl- (3-tert-butoxycarbonylamino-propyl) -amino] -methyl} -phenyl) -3-methoxy-acrylic acid methyl ester (5.70 g, 11.92 mmol), sodium methoxide solution in a mixture of 5- (4-bromo-phenyl) -1 H -imidazol-2-ylamine (2.84 g, 11.92 mmol) and ethanol (60 mL) (12 mL, 0.5 M in methanol, 6 mmol) was added. The resulting mixture was refluxed for 18 h, an additional 12 mL of sodium methoxide (0.5 M in methanol, 6 mmol) was added and the reflux continued for 20 h. The reaction was concentrated and diluted with EtOAc (300 mL) and washed with water (200 mL), brine (200 mL). EtOAc solution was concentrated. The crude product was purified by flash chromatography (0% -8% methanol in dichloromethane) to give the desired product as a brown solid (4.05 g, 52%). ¹ NMR (300 MHz, 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) -1 H -imidazo [ 1,2-a] pyrimidin- 7-one hydrochloride salt (the hydrochloride salt of compound 617): {4- [2- (4-bromo-phenyl) -7-oxo-1,7-dihydro-imidazo [1,2-a] pyrimidine - 6-yl] -benzyl}-(3-tert-butoxycarbonylamino-propyl) -carbamic acid tert-butyl ester (100 mg, 0.153 mmol) is dissolved in CH ₂ Cl ₂ (5 mL) and TFA ( 1 mL) was added and stirred at room temperature for 2 h. The reaction mixture is concentrated and 3 mL of 0.6 N HCl and 2 mL acetonitrile are added and stirred for 0.5 h, ca. Concentrated to 3 mL and lyophilized to give the title compound (80 mg, 100%). ¹ NMR (300 MHz, 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-oxo-1,7-dihydro -imidazo [1,2-a] pyrimidin-2-yl] -benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester in a sealed tube {4- [2- (4-bromo- Phenyl) -7-oxo-1,7-dihydro-imidazo [1,2-a] pyrimidin-6-yl] -benzyl}-(3- tert -butoxycarbonylamino-propyl) -carbamic acid tert-butyl ester (1.50 g, 2.3 mmol), hydroxysuccinimide (0.40 g, 3.45 mmol), 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (67 mg, 0.115 mmol ), Palladium acetate (26 mg, 0.115 mmol), triethanolamine (700 mg, 6.9 mmol) and DMSO (3 mL) were degassed and backfilled with carbon monoxide (20 psi). The reaction mixture was heated at 80 ° C. for 16 h. After cooling to rt, the reaction mixture was diluted with water (30 mL) and extracted with CH ₂ Cl ₂ (50 mL × 3). The CH ₂ Cl ₂ solution was concentrated and purified by flash chromatography (0-10% methanol in CH ₂ Cl ₂ ) to give the activated ester as a brown solid (1.0 g, 61%). ¹ NMR (300 MHz, 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- (piperazin-1-carbonyl) -phenyl] -1 H -imidazo [1,2-a] pyrimidin-7-one hydrochloride salt (the hydrochloride salt of 682): 4- [6- (4 - {[tert - butoxycarbonyl - (3- tert-butoxycarbonylamino-propyl) amino] -Methyl} -phenyl) -7-oxo-1,7-dihydro-imidazo [1,2-a] pyrimidin-2-yl] -benzoic acid 2,5-dioxo-pyrrolidin-1-yl A mixture of ester, 1-boc-preperazine (229 mg, 1.23 mmol) and CH ₂ Cl ₂ (5 mL) was stirred at rt overnight, concentrated and flash chromatography (0-10% in CH ₂ Cl ₂ ). Methanol) to give the desired amide as a white solid (330 mg, 76%), ¹ NMR (300 MHz, 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, 0.5 H), 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) 44 (s, 9 H). LCMS (EI) m / z: 786 (M + H ⁺ ).

The amide product (330 mg) was dissolved in CH ₂ Cl ₂ (5 mL), TFA (1 mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated and 4 mL of 0.6 N HCl and 4 mL acetonitrile were added and stirred for 0.5 h, ca. Concentrated to 5 mL and lyophilized to give the title compound (250 mg, 100%). ¹ NMR (300 MHz, 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 (EI) m / z: 486.1 (M + H ⁺ ).

Example  2 - Pyrrolocytosine  synthesis

Synthesis of Compound 3 :

Compound 2 (65.0 g, 373 mmol) was dissolved in ethanol (150 mL). The flask was purged with argon. Compound 1 (55.93 g, 373 mmol) was then added and the mixture was stirred at rt for 2 h. The reaction mixture was then added to a suspension of NaBH ₄ (14.18 g, 373 mmol) in toluene (150 mL) at 0 ° C. for 20 minutes through an addition funnel. The ice bath was separated and the resulting mixture was stirred for 3 h at room temperature. 1 N HCl (750 mL) was added to the solution and the mixture was stirred at rt for 30 min. K ₂ CO ₃ (205.9 g, 1.49 mol), Boc ₂ O (81.41 g, 373 mmol), and THF (200 mL) were added to the solution and stirred at rt for 23 h. The reaction solution was partitioned between EtOAc and 1: 1 brine / H ₂ O. The aqueous layer was washed with EtOAc (2 x 300 mL). The combined organic layer was washed with brine (500 mL); Dried over Na ₂ SO ₄ ; Filtration and concentration. The crude product was purified in three portions via combi flash chromatography to give the product as a white solid (119.43 g, 78%); ¹ H-NMR (300 MHz, 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, 1 H), 7.34 (bs, 1 H), 7.78 (d: 8 Hz, 1 H), 8.19 (d: 8 Hz, 1 H).

Synthesis of Compound 5 :

Compound 3 (42.28 g, 103.5 mmol) And MeOH (3 L) and H ₂ O (750 mL) were added to a mixture of compound 4 (24.54 g, 103.5 mmol). The mixture was stirred vigorously at room temperature for 30 minutes. Cu (OAc) ₂ —H ₂ O (20.67 g, 103.5 mmol) was added followed by TMEDA (18.63 mL, 124.3 mmol). The solution was stirred in the atmosphere at room temperature for 5 h. Upon completion of the reaction, the solution was concentrated to 0.7 L and then partitioned between 20% NH ₄ OH / H ₂ O (500 mL) saturated with CH ₂ Cl ₂ (700 mL) and NH ₄ Cl. The aqueous layer was washed with CH ₂ Cl ₂ (500 mL, 200 mL). The combined organic layer was dried over MgSO ₄ , filtered and concentrated. The crude product was purified by Combi Flash _{chromatography: A: CH 2 Cl 2 B} : 15: 1 CH 2 Cl 2/2 N NH 3 / MeOH, 0-100% B 85 minutes (2 330 g column). The result was a product as a white solid (35.52 g, 58%); LCMS (ESI): m / e 600 (M + H) ⁺ .

Synthesis of Compound 6 :

Compound 5 (10.0 g, 16.68 mmol) was dissolved in THF (40 mL). The flask was purged with argon. Pyridine (40 mL) was added followed by BzCl (3.10 mL, 26.69 mmol). The solution was stirred for 3 h at room temperature under argon atmosphere. MeOH (4 mL) was added and the mixture was stirred at rt for 10 min, then partitioned between EtOAc (200 mL), heptane (100 mL), and 5% KHCO ₃ / H ₂ O (200 mL). The aqueous layer was washed red with EtOAc (100 mL, 50 mL). The combined organic layer was washed with 5% KHCO ₃ / H ₂ O (300 mL); Dried over Na ₂ SO ₄ ; Filtration and concentration. The crude product was purified by Combi flash chromatography: 0-100% EtOAc / heptanes, 55 min. (330 g column). Product was obtained as off-white powder (9.81 g, 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 DMF (30 mL). TBTU (5.38 g, 16.76 mmol) was added and the solution stirred at 22 ° C. for 5 minutes under argon. Diisopropylethyl amine (4.95 mL, 29.92 mmol) was added, followed by thiapiperazine S, S-dioxide (2.26 g, 16.76 mmol). The mixture was stirred at 22 ° C. for 24 h, then partitioned between EtOAc (200 mL) and 3% KHCO ₃ / H ₂ O (300 mL). The organic layer was washed with H ₂ O (200 mL), then brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by flash chromatography on silica gel (200 g) using 3% (2.5M NH ₃ / MeOH) / CH ₂ Cl ₂ . As a result, compound 8 (1.72 g; 36%) was obtained as a solid; ¹ H-NMR (300 MHz, DMSO-d6) δ 3.10-3.30 (m, 4H), 3.64 (m, 2H), 3.98 (m, 2H), 7.75 (d: 2.0 Hz, 2H), 7.97 (t: 2.0 Hz, 1H).

Synthesis of Compound 9 :

Compound 8 (1.72 g, 4.33 mmol), N-Boc-piperazine (931 mg, 5.0 mmol), K ₂ CO ₃ (1.26 g, 9.1 mmol), CuI (83 mg, 0.43 mmol), and L-proline ( 100 mg, 0.87 mmol) was suspended in dimethyl sulfoxide (15 mL). The mixture was purged with argon and then stirred at 85 ° C. for 20 h under argon. After cooling to ambient temperature, the mixture was partitioned between water (150 mL) and EtOAc (200 mL) and the organic layer was washed with water (100 mL), dried over Na ₂ SO ₄ and concentrated. The crude product was purified via flash chromatography on silica gel using 2% (2.5M NH ₃ / MeOH) / CH ₂ Cl ₂ . As a result, compound 9 (0.65 g; 30%) was obtained as a solid; ¹ H-NMR (300 MHz, DMSO-d6) crude product was purified by flash chromatography on silica gel (200 g) 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 THF (10 mL). The solution was placed in a pressure vessel and purged with argon, followed by CuI (60 mg, 0.313 mmol), Pd (PPh ₃ ) ₄ (145 mg, 0.125 mmol), Et ₃ N (1.40 mL, 10 mmol), and trimethylsilyl Acetylene (0.353 mL, 2.5 mmol) was added. The vessel was sealed and the mixture was stirred at 45-50 ° C. After 3 h, the mixture was diluted with EtOAc (30 mL), concentrated and purified by flash chromatography on silica gel (120 g) using 70% EtOAc-30% heptane. As a result, a semisolid (1.2 g) was obtained and dissolved in MeOH (70 mL). The solution was purged with argon, K ₂ CO ₃ (1.0 g) was added and the mixture was stirred at 45 ° C. for 30 minutes under argon. The mixture was filtered, concentrated and purified by flash chromatography on silica gel (120 g) using 75% EtOAc-25% heptane. The result was compound 10 (0.425 g, 76%) as a white, solid foam; 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 DMF (15 mL) was added. After purging the solution with argon, CuI (46 mg, 0.24 mmol), Pd (PPh ₃ ) ₄ (110 mg, 0.095 mmol), and Et ₃ N (1.06 mL, 7.6 mmol) were added and the vessel was sealed The mixture was then stirred at 22 ° C. for 15 minutes. Then the temperature was raised to 80-85 ° C. and the mixture was stirred for 14 h. Cool to ambient temperature, add MeOH (10 mL), seal the vessel and stir the mixture at 90 ° C. for 3 h. After cooling to ambient temperature, the mixture was sat. KH ₂ PO ₄ / H ₂ O (250 mL) and EtOAc (200 mL). The organic layer was washed with brine (150 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by flash chromatography on silica gel (150 g) using 5% (2.5M NH ₃ / MeOH) / CH ₂ Cl ₂ . Compound 11 (490 mg; 56%) was obtained as a yellow solid; LCMS (ESI): m / e 920 (M + H) ⁺ .

Synthesis of Compounds 12A and 12B:

Compound 11 (490 mg, 0.533 mmol) was dissolved in CH ₂ Cl ₂ (20 mL), trifluoroacetic acid (20 mL) was added, and the mixture was stirred at 22 ° C. for 40 minutes. CH ₂ Cl ₂ (30 mL) was added and the mixture was concentrated in vacuo to a viscous oil. Water (3 mL) and EtOH (70 mL) were added, the mixture was concentrated and crude compound 12A was obtained as a solid residue. This residue was dissolved in [(10% MeOH-90% H ₂ O) + 0.15% TFA] (40 mL). Aliquots (10 mL) are injected onto a Dynamax 41.4 mm, C-18 prep HPLC Unit (guard + column), and a solvent gradient of 10% -55% (MeOH / H ₂ O + 0.15% TFA) for 40 minutes. Eluted. Pure fractions were combined, concentrated with EtOH and dried. This sample was treated with 1 N HCl / H ₂ O (5 mL) and EtOH (70 mL) and concentrated. This operation was repeated; The solid thus obtained was lyophilized from H ₂ O-MeCN (4: 1) to give compound 12B (78 mg) as a yellow powder; LCMS (ESI): m / e 619 (M + H) ⁺ .

Synthesis of Compound 13 :

A solution of compound 12A (30 mL, 0.40 mmol) in a solvent mixture [(10% MeOH-90% H ₂ O) + 0.15% TFA], described above, was concentrated as a viscous oil, using EtOH. This sample was dissolved in a mixture of DMF (10 mL) and diisopropylethyl amine (0.53 mL, 3.20 mmol). N, N' -bis-Boc-1-guanylpyrazole (149 mg, 0.48 mmol) was added and the mixture was stirred at 22 ° C. for 15 h. EtOH (80 mL) was added and the mixture was concentrated in vacuo to a viscous oil (<1 mm Hg, 45 ° C.), which was dissolved in a mixture of CH ₂ Cl ₂ (25 mL) and trifluoroacetic acid (30 mL). . The mixture was stirred at 22 ° C. for 2 h, CH ₂ Cl ₂ (70 mL) was added, the solution was concentrated, the residue was dissolved in MeOH (30 mL) and Amberslyst A26 (OH) resin (10 g ). The mixture was stirred for 1 h and the filtrate was concentrated to semisolid. This sample was purified by preparative HPLC: Dynamax 41.4 mm, C-18 prep HPLC Unit (guard + column), eluted with a solvent gradient of 10% -55% (MeOH / H ₂ O + 0.15% TFA) for 40 minutes. . Pure fractions were combined and concentrated to dryness with EtOH. This sample was treated with 1 N HCl / H ₂ O (5 mL) and EtOH (70 mL) and concentrated. This operation was repeated; The solid thus obtained was lyophilized from H ₂ O-MeCN (4: 1) to give compound 13 (122 mg) as a yellow solid; LCMS (ESI): m / e 661 (M + H) ⁺ .

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

Synthesis of 2a and 2b:

Phosphonium salt 12 (5.24 g, 9.88 mmol), 1a (or 1b ) (2.65 g, 9.88 mmol), K ₂ CO ₃ (1.36 g, 9.88 mmol), and 18-crown-6 (in toluene (50 mL) The mixture of catalytic amount) was heated to reflux overnight under argon. Upon completion, the mixture was cooled to rt and water was added. The aqueous layer was extracted with ethyl acetate (3 × 75 mL) and the combined organics were dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography (2: 1 heptanes / ethyl acetate). Compound 2a was isolated cleanly as a mixture of E and Z isomers (3.78 g, 87% yield).

Synthesis of 3a and 3b:

To a flask containing phthalimide 2a (3.78 g, 8.58 mmol) (or 2b ) in ethyl acetate was added 10% Pd / C (0.76 g, 20% w / w). The flask was evacuated and charged with hydrogen through the balloon assembly. Stirring at rt was continued for 45 minutes while the contents were purged with argon. After filtration of the mixture through celite, the solvent was evaporated to afford the desired product 3a in quantitative yield (3.77 g).

Synthesis of 4a and 4b:

In a screwcap pressure tube, 3a (3.70 g, 8.37 mmol) (or 3b ) was dissolved in anhydrous ethanol. Hydrazine monohydrate (1.62 mL, 33.5 mmol) was added to the solution and heat was added at 65 ° C. for 8 h. After cooling to rt, the slurry was filtered to remove white solid by-products 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 NaSO ₄ . Evaporation of the solvent gave a clear, colorless oil (2.32 g, 89% yield) which was redissolved in dichloromethane (75 mL) and benzyl chloroformate (1.27 mL, 8.94 mmol) and triethanolamine (2.07 mL) at 0 ° C. , 14.9 mmol). After stirring for 1 hour, water was added and the organic layers were combined, dried over NaSO ₄ and concentrated. Purification of the crude residue by silica gel chromatography (2: 1 heptanes / ethyl acetate) gave 4a as a viscous oil (3.06 g, 92% yield).

Synthesis of 5a and 5b:

Compounds 5a (and 5b ) were prepared through the same two step Sonogashira-deprotection sequence used for the synthesis of alkyl 10 . Starting at 1.5 g of 4a , the desired product was obtained in 53% yield (0.69 g).

Synthesis of 7a and 7b:

Pyrrolocytosine 7a (and 7b ) was prepared by coupling of common intermediate 6 and alkyl 5a (and 5b , respectively) following the procedure described above for the synthesis of 11 . Starting from 690 mg 5a , 1.23 g of the desired compound were obtained as an orange-brown solid (81%); LCMS (ESI) m / e 863.4 (M + l) ⁺ .

Synthesis of 8a and 8b:

Boc-deprotection of 7a (0.60 g, 0.69 mmol) (and 7b ) was carried out using trifluoroacetic acid as described in the preparation of 12A (Patent Note: Provisional Application No.). Alternatively, this modification was performed by treating the starting material with 8 mL of 6 N HCl and anhydrous EtOH (30 mL) at 50 ° C. (2 h). After solvent evaporation, the crude residue (in each approach) was used in the next step without further purification. LCMS (ESI) m / e 663.3 (M + l) ⁺ .

Synthesis of 9a and 9b:

Guanidine formation is the protocol used to prepare compound 13 (Promoter Note: Provisional Application Number), except that starting material 8a (˜0.48 g, 0.65 mmol) (and 8b ) is used as a crude oil or semisolid rather than MeOH-water solution. It was performed according to. Removal of the Boc group was facilitated by dissolving the protected guanidine intermediate in 35 mL of anhydrous ethanol, followed by the addition of 10 mL of 6 N HCl. The solution was heated to 70 ° C. for 3 h. Upon cooling, the mixture was concentrated and further dried by azeotrope further anhydrous ethanol. A tan solid was used directly in the next step without further purification.

Synthesis of 11a and 11b:

Under argon, guanidine 9a (or 9b ) was dissolved in 30 mL of trifluoroacetic acid. Thioanisole (0.5 mL) was added dropwise and the solution was stirred at rt for 3-4 h. Upon completion, the solvent was evaporated to give an oil or semisolid. Diethyl ether was added and the liquid layer containing most of the remaining thioanisole was decanted. Crude 10 a was dissolved in [(20% MeOH-90% H 2 O) + 0.15% TFA] (20 mL). Aliquots (10 mL) were injected into a Dynamax 41.4 mm, C-18 prep HPLC Unit (guard + column) and eluted for 45 min with a solvent gradient of 10% -65% (MeOH / H 2 O + 0.15% TFA). Pure fractions were combined and concentrated to dryness with EtOH. This sample was treated with 1 N HCl / H ₂ O (5 mL) and EtOH (70 mL) and concentrated. This operation was repeated; The solid thus obtained was lyophilized from H ₂ O-MeCN (4: 1) to give compound 11a as a yellow powder (171 mg); LCMS (ESI) m / e 571.2 (M + l) ⁺ ; ¹ H NMR (300 MHz, 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)

Data for 11b : LCMS (ESI) m / e 555.3 (M + l) ⁺ ; ¹ H NMR (300 MHz, D ₂ O) δ 1.33-1.46 (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 - Triazolopyrimidinone  synthesis

Representative :

6- {4-[(3-amino- propylamino ) -methyl ] -phenyl } -2- (4- fluoro - phenyl ) -3H- [1,2,4] triazolo [1,5-a] Pyrimidin-5-one. 2- (4-{[tert-butoxycarbonyl- (3-tert-butoxycarbonylamino-propyl) -amino] -methyl} -phenyl) -3-methoxy-acrylic acid methyl ester in 10 mL of methanol To (1.13 g, 2.16 mmol), 5- (4-fluorophenyl) -3-amino-1,2,4-triazole (0.50 g, 2.81 mmol) was added. A 0.5 M solution of sodium methoxide in methanol (5.6 mL, 2.81 mmol) was added dropwise and the orange mixture was gradually heated to 50 ° C. and maintained overnight. Upon completion, methanol was removed in vacuo and the residue was partitioned between 100 mL of dichloromethane and 100 mL of water. The organic layer is collected, Na ₂ SO ₄ Dried over and concentrated to an orange-yellow precipitate. The crude material was loaded on a silica gel column and eluted as follows: 5 minutes at 40 mL / min with 100: 0 CH ₂ Cl ₂ / MeOH; 15 min at 40 mL / min with 95: 5 CH ₂ Cl ₂ / MeOH; 15 min at 40 mL / min with 90:10 CH ₂ Cl ₂ / MeOH, at this point the desired product was recovered from the column. Evaporation of the solvent gave a pale yellow precipitate which was triturated with ether to give 560 mg of a white solid (44% yield). Removal of the BOC-protecting group was then performed by dissolving the solid in 10 mL of dichloromethane followed by addition of 3 mL of trifluoroacetic acid. After 1 h at room temperature complete conversion was observed. After addition of dichloroethane (10 mL), the volatiles were removed under reduced pressure. The formation of HCl salt was approximately 3 mL of aq. 1 N HCl was added and then accelerated by evaporation of water. Lyophilization (aq. 1 N HCl / acetonitrile) gave 396 mg (90% from BOC-protected compound) of the desired product as a white powder: ¹ H NMR (300 MHz, DMSO) δ 1.99-2.09 (m, 2H, CH ₂ ), δ2.90-3.02 (m, 4H, NCH ₂ ), δ4.17 (bs, 2H, CH ₂ Ar), δ7.38 (t, J = 8.9 Hz, 2H, Ar), δ7 .66 (d, J = 8.4 Hz, 2H, Ar), δ7.76 (d, J = 8.4 Hz, 2H, Ar), δ8.07-8.12 (m, 3H, Ar, NH), δ8.99 ( s, 1H, CH = C), δ9.54 (bs, 2H, NH), δ13.4 (bs, 1H, NH); LCMS (ES ⁺ ) m / z 393.0 (MH ⁺ ).

N- (3- {4- [2- (4- fluoro - phenyl ) -5-oxo-3,5 -dihydro- [1,2,4] triazolo [1,5-a] pyrimidine- 6-yl] -benzylamino } -propyl) -guanidine. Triethanolamine (0.301 mL, 2.16 mmol) was added to HCl salt (250 mg, 0.54 mmol) suspended in DMF / THF (5: 1, 5.4 mL). N, N' -bis-BOC-1-guanylpyrazole (167 mg, 0.54 mmol) was then added to the solution and the reaction progress was monitored by LCMS. After 5 h, the solvent was evaporated by azeotroping with toluene / EtOH (small amount of DMF remaining). The crude material was classified into dichloromethane and water. The layers were separated and the aqueous layer was extracted twice with additional dichloromethane. The combined organics were washed with brine, dried over Na ₂ S0 ₄ and concentrated to give an oil as crude mixture. Purification was carried out via preparative TLC (2000 μm plate, 10% MeOH / CH ₂ Cl ₂ ) and after solvent removal, a white solid was obtained. Deprotection of the diamine and formation of the HCl salt were carried out as described above to give 145 mg (53% yield) after lyophilization: ¹ H NMR (300 MHz, DMSO) δ1.86-1.93 (m, 2H, CH _{2), δ2.89-2.95 (m, 2H} , NCH 2), δ3.20-3.27 (m, 2H, NCH 2), δ4.19 (bs, 2H, CH 2 Ar), δ7.35 (t, J = 9.0 Hz, 2H, Ar), δ7.63 (d, J = 7.8 Hz, 2H, Ar), δ7.68 (d, J = 7.8 Hz, 2H, Ar), δ8.07-8.12 (m, 2H, Ar), δ 8.99 (s, 1H, CH = C), 9.39.35 (bs, 2H, NH), δ13.4 (bs, 1H, NH); LCMS (ES ⁺ ) m / z 435.3 (MH ⁺ ).

Example  5-Synthesis of Compound 562

3- (2,4 -Dioxo- 3,4 -dihydro - 2H -pyrimidin-1-yl) -pyrrolidine- 1 -carboxylic acid tert -butyl ester (4): To a suspension of 1 (1 g, 5.3 mmol) and 2 (1.26 g, 5.87 mmol) in tetrahydrofuran, DIAD (1.16 ml, 5.87 mmol) was added dropwise and stirred at ambient temperature overnight. . The clear solution was concentrated to a thick liquid under reduced pressure. The crude mixture was purified by flash chromatography on silica gel (50-60% ethyl acetate-heptanes) to afford pure 3 . LCMS (EI) m / z 408.1 (M + Na ⁺ ). ¹ H NMR (300 MHz, CDCl ₃ ): δ7.94 (2H, d), 7.67 (1H, t), 7.50 (2H, t), 7.27 (1H, d), 5.87 (1H, d), 5.14 ( 1 H, m), 3.78 (1 H, dd), 3.54 (3 H. m), 2.34 (1 H, m), 2.11 (1 H, m), 1.49 (9 H, s). A solution of 3 (2 g) in 2N NH ₃ -MeOH (30 mL) was stirred at ambient temperature overnight. The solution was evaporated under reduced pressure and the crude mixture thus obtained was purified by flash chromatography on silica gel (70-100% ethyl acetate-dichloromethane) to give pure 4 as a white solid. LCMS (EI) m / z 281.1 (M + H) ^{+ 1} H NMR (300 MHz, CDCl ₃ ): δ9.41 (1H, bs), 7.18 (1H, d), 5.78 (1H, d), 5.17 ( 1 H, m), 3.76 (1 H, dd), 3.52 (3 H. m), 2.33 (1 H, m), 2.07 (1 H, m), 1.48 (9 H, s).

3- (5-Bromo-2, 4-dioxo-3,4-dihydro-2 H -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 DMF (15 mL) and stirred at ambient temperature for 3-4 h. The solution was partitioned between ethyl acetate (50 mL) and 10% Na ₂ S ₂ O ₃ (40 mL). The organic layer was separated, washed with brine (3 × 50 mL), dried (anhydrous Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude material was purified via flash chromatography on silica gel (70% ethyl acetate-dichloromethane) to give pure 5 .

¹ H NMR (300 MHz, 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 ( 1 H, m), 2.08 (1 H, m), 1.49 (9 H, s).

3- {5- (2- tert - butoxycarbonyl amine-phenyl) -2, 4-oxo-3, 4-dihydro -2 H-pyrimidin-1-yl} - pyrrolidin-1 Carboxylic acid tert -butyl ester (7). Dioxane in a mixture of 5 (0.515 g, 1.43 mmol), 6 (0.547 g, 1.72 mmol), Pd (PPh ₃ ) ₄ (0.165 g, 10 mol%) and K ₂ CO ₃ (0.592 g, 4.29 mmol) 8 mL) and water (2 mL) were added. The suspension was purged with argon under vacuum and heated at 90 ° C. in a sealed tube. After 15 h, the solution was concentrated and partitioned between ethyl acetate (50 mL) and brine (30 mL). The organic layer was separated, washed with brine (2 × 30 mL), dried (anhydrous Na ₂ SO ₄ ), evaporated and purified by flash chromatography on silica gel (50-70% ethyl acetate-dichloromethane) to give the title compound 7 Got it. LCMS (EI) m / z 495.1 (M + Na) ⁺ . ¹ H NMR (300 MHz, 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 - fluorene -2-one ( 9 ). To a mixture of 7 (0.3 g, 0.635 mmol) and 2-mesitylenesulfonyl chloride (0.278 g, 1.27 mmol) was added dichloromethane (5 mL), followed by triethylamine (0.176 mL, 1.27 mmol) and N , N Dimethylamino pyridine (0.039 g, 0.312 mmol) was added. The reaction solution was stirred under inert atmosphere for 3 h, then DBU (0.191 mL, 1.27 mmol) was added and stirred overnight at ambient temperature. Quenched with cold water and partitioned between ethyl acetate (50 mL) and brine (30 mL). The organic layer was separated, washed with brine (3 × 30 mL), dried (anhydrous Na ₂ SO ₄ ) and evaporated under reduced pressure. The crude product thus obtained was purified by flash chromatography on silica gel (70% ethyl acetate-dichloromethane) to give 8 . ¹ H NMR (300 MHz, 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 treated with TFA (3 mL) and stirred at ambient temperature for 2 h. The solution was evaporated under reduced pressure and vacuum dried to give 9 . LCMS (EI) m / z 276.3 (M + Na) ⁺ . The TFA salt of 9 was used in the next step without subsequent purification.

2- {4- [3- (2-oxo -2,9- dihydro -1,3,9- triaza-fluoren-3-yl) -pyrrolidin-1-yl]} - isoindole - The TFA salt of 1,3- dione (11) : 9 was neutralized with triethylamine (0.245 mL, 1.762 mmol) in CH ₃ CN (10 mL) and treated with bromide 10 (0.148 g, 0.528 mmol) and at ambient temperature Stirred. After 3 days, the solution was concentrated and the crude material was purified by flash chromatography on silica gel (10% methanol in dichloromethane) to give 11 (0.08 g). LCMS (EI) m / z 456.1 (M + H) ⁺ .

{4- [3- (2-Oxo-2,9-dihydro-1,3,9-triaza-fluoren-3-yl) -pyrrolidin-1-yl]}- carbamic acid tert -butyl ester (12): To the solution of 11 (0.08 g, 0.176 mmol) in ethanol (8 mL) was added excess hydrazine (0.1 mL) and stirred at ambient temperature for 3 h, followed by 50 for 3 h. Heated to ° C. The solution was concentrated and dissolved in tetrahydrofuran (3 mL) and water (3 mL). Next, Boc ₂ O (0.384 g, 1.76 mmol) and K ₂ CO ₃ (.1 g, 0.7 mmol) were added and stirred at ambient temperature overnight. The solution was concentrated under reduced pressure and partitioned between ethyl acetate (30 mL) and brine (30 mL). The organic layer was separated and the aqueous layer was extracted again with ethyl acetate (4 × 10 mL). All organic layers were combined together, dried (anhydrous Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by flash chromatography on silica gel (10% methanol in dichloromethane) to give 12 . LCMS (EI) m / z 426 (M + H) ⁺ . ¹ H NMR (300 MHz, 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).

Guanidine intermediate 13 : TFA (1 mL) was added to a solution of 12 (40 mg) in dichloromethane (4 mL) and stirred at ambient temperature for 1 h. The solution was evaporated under reduced pressure and coevaporated with dichloromethane (3x3 mL). This TFA salt was treated with 0.6 N HCl (2 mL). After 2 h this solution was lyophilized. LCMS (EI) m / z 325.8 (M + H) ⁺ . ¹ H NMR (300 MHz, 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). DMF in a mixture of hydrochloride salt (0.03 g, 0.0753 mmol) and ( tert -butoxycarbonylimino-pyrazol-1-yl-methyl) -carbamic acid tert -butyl ester, 15 (0.035 g, 0.113 mmol) (2 mL) was added followed by Hunig base (0.131 mL, 0.753 mmol). The solution was stirred at ambient temperature for 2 h and then diluted with ethyl acetate (30 mL). The ethyl acetate layer was washed with brine (3 × 20 mL), dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel (10% methanol in dichloromethane) to give 13 (30 mg) as a white solid. LCMS (EI) m / z 568.2 (M + H) ⁺ . ¹ H NMR (300 MHz, 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-oxo-2,9 -dihydro- 1,3,9 -triaza - fluorene- 3-yl) -pyrrolidin- 1 - yl] -butyl} -guanidine (14): TFA (2 mL) was added to a mixture of compound 13 (0.028 g) in dichloromethane (4 mL) and stirred at ambient temperature for 3 h. The solution was concentrated and co-evaporated with dichloromethane (3 × 4 mL), then vacuum dried, dissolved in 0.6 N HCl (2 mL) and lyophilized to give pure 14 (0.028 g) as a hydrochloride salt. LCMS (EI) m / z 368.2 (M + H) ⁺ . ¹ H NMR (300 MHz, 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-oxo -2,10- dihydro-benzo [4,5] imidazo already [1,2-a] pyrimidine-3 Yl) -benzyl] -carbamic acid tert -butyl ester (5). 2-iodo-3-methoxy-acrylic acid methyl ester (1, 1.21 g, 5 mmol ), 1 H - benzo-imidazo l-2-ylamine (2, 0.67 g, 5 mmol ) and ethanol (30 mL) To a mixture of was added a solution of sodium methoxide (10 mL, 0.5 M in methanol, 5 mmol). The resulting mixture was refluxed for 3 h and concentrated to afford 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] dioxaborolan-2-yl) -benzyl] -car Chest acid tert -butyl ester ( 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), ethanol (6 mL), dioxane (2 mL) and water (2 mL) were degassed and heated at 80 ° C. for 20 h under argon atmosphere. The reaction mixture was diluted with EtOAc (500 mL) and washed with water (300 mL) and brine (300 mL). The organic solution was concentrated and purified by flash chromatography (0% -6% MeOH in methanechloride) to afford the desired product 5 (170 mg, 31%) as a pale yellow solid. 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 salt (601) : Compound 5 (170 mg, 0.31 mmol) was dissolved in CH ₂ Cl ₂ (5 mL), TFA (1 mL) was added and stirred for 2 h at room temperature. The reaction mixture was concentrated and 3 mL of 0.6 N HCl and 2 mL acetonitrile were added, stirred for 0.5 h, and ca. Concentrated to 3 mL and lyophilized to give the title compound (150 mg, 100%). ¹ NMR (300 MHz, 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 (EI) m / z: 348.1 (M + H ⁺ ).

N- {3- [4- (2-oxo-2,10 -dihydro - benzo [4,5] imidazo [1,2-a] pyrimidin-3-yl) -benzylamino ] -propyl} Guanidine hydrochloride salt (602) : N, N -bis-Boc-1-sphere in a mixture of RX-6817 (110 mg, 0.16 mmol), Hunig base (720 mg, 5.8 mmol) and acetonitrile (10 mL) Anipyrazole (50 mg, 0.16 mmol) was added. The reaction mixture was stirred overnight at room temperature, diluted with water (30 mL) and then extracted with EtOAc (50 mL x 3). The organic solution was concentrated and purified by flash chromatography (2N NH ₃ / CH ₂ Cl _{2 in} methanol, 0-10%) to give guandylate product 7 (60 mg) as a white solid, which was 3 mL of CH ₂ Cl. Dissolved in ₂ and 1 mL of TFA was added. The resulting mixture was stirred overnight and concentrated. 3 mL of 0.6 N HCl and 2 mL acetonitrile were added and stirred for 0.5 h, ca. Concentrated to 3 mL and lyophilized to give the title compound (40 mg). ¹ NMR (300 MHz, 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 (EI) m / z: 390.1 (M + H ⁺ ).

Example  7 - Antimicrobial  activation

Compounds of the invention were tested for antimicrobial activity. These data are shown in Table 2. Compounds were processed against Escherichia coli strain ATCC25922 using standard microdilution assay to determine the minimum inhibitory concentration (MIC). "+" In the data means that the MIC value of the compound is 16 μg / mL or less and "-" means that the MIC value of the compound is higher than 16 μg / mL. "N / A" means that no data was available. Those skilled in the art will appreciate that compounds may be evaluated for other bacterial organisms and activity data results for Escherichia coli are exemplary and are not intended to limit the scope of the present invention. Compounds of the invention can be analyzed for different microbial ranges depending on the potency activity to be collected. In addition, selection of "+", "-", and "N / A" and cutoff values of 16 μg / mL are also illustrative and are not intended to limit the scope of the present invention. For example, "-" is not intended to mean that the compound is necessarily lacking in activity or utility, but rather that its MIC value for the indicated microorganism is higher than 16 μg / mL.

Bibliography

The entire contents of each of the patent and scientific literature cited herein are incorporated by reference for all purposes.

Equivalent

The invention may be embodied in other specific forms without departing from the scope or essential features of the invention. The foregoing embodiments should therefore be considered in all respects to be illustrative rather than to limit the invention described herein. Therefore, it is intended that the scope of the invention be defined by the appended claims rather than by the foregoing description, and that all changes fall within the equivalent scope and meaning of the claims herein.

Claims (25)

A compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

or

Wherein -GHJ is alternatively

Is selected, where
Each of H and J is independently selected;
CBA-, -DEF, and -GHJ are chemical moieties, where
A, D and G are independently
(a) a single _{bond, (b) - (C 1} -8 -alkyl) -, (c) - (C _{2 -8} alkenyl) -, (d) - (C _{2 -8} alkynyl) (where, i In any of (b)-(d) directly above) 0-4 carbon atoms are -O-, S (O) _p , -NR ⁶ -,-(C = O)-, -S (O) optionally substituted with a moiety selected from the group consisting of _p NR ^6- , -NR ⁶ S (O) _p- , and -NR ⁶ S (O) _p NR ^6- ,
ii) any of (b)-(d) immediately above is at least one R ⁵ Optionally substituted with a group,
iii) any of (b)-(d) immediately above _is- (C _1-8 alkyl) -R ⁵ Optionally substituted with a 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) nitrogen, 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of oxygen, and sulfur,
(ee) a 3-14 membered saturated, unsaturated, or aromatic carbocyclic ring, and
(ff)-(CR ⁶ R ⁶ ) _t-
Is selected from the group consisting of
(Dd) or (ee) is optionally substituted with one or more R ⁵ groups;
B, E, and H are independently
(a) a single bond,
(b) a 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
(c) 3-14 membered saturated, unsaturated, or aromatic carbocyclic rings,
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) immediately above (d In any of)-(f) 0-4 carbon atoms are selected from -O-, -S (O) _p- , -NR ⁶ -,-(C = O)-, -C (= NR ⁶ )-, Optionally substituted with a moiety selected from the group consisting of -S (O) _p NR ^6- , -NR ⁶ S (O) _p- , and -NR ⁶ S (O) _p NR ^6- ,
ii) any of (d)-(f) immediately above is at least one R ⁵ Optionally substituted with a group,
iii) immediately above, (d) - Any of (f) - (C _{1 -8-alkyl)} -R ⁵ Optionally substituted with a group), and
(g)-(CR ⁶ R ⁶ ) _t-
It is selected from the group consisting of;
C, F, and J are independently
(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 group, ( mm) C _{2 -8} alkenyl group, (nn) C _{2 - 8} alkynyl group, (oo) a nitrogen, oxygen, and a 3-14 membered saturated containing 1 or more heteroatoms selected from the group consisting of sulfur, an unsaturated , Or aromatic heterocycle, (pp) 3-14 membered 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) -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
Is selected from the group consisting of
(Ll) to (pp) are optionally substituted with one or more R ⁷ groups;
R ⁵ is (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)} - (containing 1 or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle), (q)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (r) -haloalkyl, (s ) -SR ⁶ , (t)-a 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (u) -3-14 members Selected from saturated, unsaturated, or aromatic carbocyclic rings,
Alternatively, two R ⁵ groups together form a carbocycle, wherein
(M) to (r) and (t) to (u) are optionally substituted with one or more R ⁸ ;
R ⁶ is (a) hydrogen, (b) -C _{1 -8-alkyl} (or alternatively to form a carbocyclic group with two R ^6), (c) - haloalkyl, (d) nitrogen, oxygen, and -3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of sulfur, and (e) -3-14 membered saturated, unsaturated, or aromatic carbocycles, wherein
(B) to (e) are optionally substituted with one or more R ⁸ ;
R ⁷ is (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 1 or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle), (q)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (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 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (y) -3-14 membered saturated, unsaturated, or aromatic carbocycles , (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) are optionally substituted with one or more R ⁹ ;
R ⁸ is (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)} - (containing 1 or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle), (q)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (r) -nitrogen, oxygen, and 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of sulfur, (s) -3-14 membered saturated, unsaturated, or aromatic carbocycles, (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 with one or more R ⁹ ;
R ⁹ is (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) - consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group, (r) -3-14 membered saturated, unsaturated, or aromatic carbocycles, (s) -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)} - (1 or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur containing 3-14 membered saturated, which, unsaturated, or aromatic heterocyclic ring), (aa) - (C _{1 -8-alkyl)} - (3-14 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 , wherein
(N) to (r) and (z) to (aa) are optionally substituted with one or more R ¹⁰ ;
R ¹⁰ is (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) - consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group, (r) -3-14 membered saturated, unsaturated, or aromatic carbocycles, (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)} - (1 or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur containing 3-14 membered saturated, which, unsaturated, or aromatic heterocyclic ring), (aa) - (C _{1 -8-alkyl)} - (3-14 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 ;
In some cases, groups -DEF or groups -GHJ are absent, but neither -DEF and -GHJ are absent at the same time;
p is 0, 1, or 2,
t is 0, 1, 2, or 3. The compound of claim 1, wherein the compound has a structure of formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

A compound according to claim 2, having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

Wherein D and E are single bonds and F is hydrogen. The method of claim 3, wherein A is
(a) a 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
(b) a 3-14 membered saturated, unsaturated, or aromatic carbocyclic ring, and
(c) 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) -, (d) selected from a single bond Where
i) In any of (a)-(c) immediately above, 0-4 carbon atoms are -O-, -S (O) _p- , -NR ⁶ -,-(C = O)-, -C Optionally substituted with a moiety selected from the group consisting of (= NR ⁶ )-, -S (O) _p NR ^6- , and -NR ⁶ S (O) _p NR ^6- ,
ii) any of (a)-(c) immediately above is at least one R ⁵ Optionally substituted with a group,
iii) any of (a)-(c) immediately above _is- (C _1-8 alkyl) -R ⁵ Optionally substituted with a group;
C is (a) NH ₂ , (b) -NHC (= NH) NH ₂ and (c) a compound selected from hydrogen, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. The compound of claim 4, wherein A is azepanyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furanyl, tetrahydrofuranyl, Tetrahydropyridyl, azetidinyl, pyrrolidinyl, piperidinyl, and piperidinyl,
Any A just above is 1 or more R⁵ Optionally substituted with a group,
Alternatively, A is a single bond;
B is (a)-(C_{One -8} Alkyl)-, wherein
i) In (a) just above, 0-4 carbon atoms are -O-, -S (O)_p-, -NR⁶-,-(C = O)-, -S (O)_pNR⁶-, And -NR⁶S (O)_pNR⁶Optionally substituted with a moiety selected from the group consisting of
ii) immediately above (a) is at least one R;⁵ Optionally substituted with a group,
iii) immediately above (a) is-(C_{One -8} Alkyl) -R⁵ Optionally substituted with a group;
Alternatively, B is a single bond;
C is (a) NH₂, (b) -NHC (= NH) NH₂ And (c) a compound selected from hydrogen, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. The compound of claim 5, wherein CBA- is hydrogen,

A compound selected from the group consisting of, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. The compound of claim 3, wherein G is
(a) a 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and
(b) 3-14 membered saturated, unsaturated, or aromatic carbocyclic rings,
(c) single bond
Wherein (a) or (b) is optionally substituted with one or more R ⁵ groups, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. The compound of claim 4, wherein R ⁵ is (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 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur 3-14-membered saturated, unsaturated recalled, or the aromatic heterocyclic), (q) - (C _{1 -8-alkyl)} - (3-14 membered saturated, unsaturated, or aromatic carbocyclic ring), (r) - haloalkyl, ( s) a 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of -SR ⁶ , (t) -nitrogen, oxygen, and sulfur, and (u) -3-14 Selected from circle saturated, unsaturated, or aromatic carbocycles; Alternatively, two R ⁵ groups together form a carbocycle, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. The method of claim 4 wherein, R ⁶ is (a) hydrogen, (b) -C _{1 -8-alkyl} (or also alternatively, to form a carbocyclic group with two R ^6), (c) - haloalkyl, (d 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (e) -3-14 membered saturated, unsaturated, or aromatic carbon A compound selected from the summons, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. The compound of claim 7, wherein G is azepanyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furanyl, tetrahydrofuranyl, Tetrahydropyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperidinyl, and a compound selected from a single bond, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. The method of claim 10, wherein -GHJ is hydrogen,

And

A compound selected from the group, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. The compound of claim 11, wherein each -GHJ is hydrogen,

Wherein n is 0, 1, or 2, and R ⁵ is as defined in claim 8, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. The compound according to any one of claims 1 to 12, which binds to ribosomes. The compound of claim 13, wherein the ribosomes are bacterial ribosomes. A compound according to any compound of Table 1, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, and a pharmaceutically acceptable carrier. A method of treating, preventing or mitigating a risk of a disease state in a human or animal, comprising: a compound according to any one of claims 1 to 15, or a pharmaceutical thereof, in a human or animal in need of such treatment, prevention or alleviation. A method of treatment, prophylaxis or alleviation comprising administering an effective amount of a salt, ester, tautomer, or prodrug that is acceptable. A method of treating a microbial infection in a human or animal, the effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, in said human or animal. Method of treatment comprising administering. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, in the manufacture of a medicament for the treatment of a microbial infection in a human or animal. A method for the treatment, prevention or alleviation of the risk of microbial infection in a human or animal, comprising the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, ester, tautomer thereof , Or administering an effective amount of a prodrug to a human or animal, wherein the microbial infection is
Skin infection, Gram-positive bacteria infection, Gram-negative bacteria infection, pathogenic pneumonia, community-acquired pneumonia, post-viral pneumonia, hospital-acquired pneumonia / ventilator-related pneumonia, airway infections such as chronic airway infection (CRTI), skin and soft tissue infections (SSTI), including acute pelvic infections, complications of skin and skin structure infections, uncomplicated skin and soft tissue infections (uSSTI), and complications of skin and soft tissues, abdominal infections, complications of the abdomen Internal infections, urinary tract infections, bacteremia, sepsis, endocarditis, atrioventricular shunt infection, vascular access infection, meningitis, surgical prophylaxis, peritoneal infection, bone infection, joint infection, methicillin resistant staphylo Caucasus aureus ( Staphylococcus) aureus) infections, vancomycin-resistant enterococci (Enterococci) infection, linezolid-resistant organism infection, Bacillus anthraquinone system (Bacillus anthracis ) infection, Francisella tularensis ) infection, Yersinia pestis ) The method of treatment, prevention or alleviation of infection and tuberculosis. The compound of claim 17, wherein the compound, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, is ear, eye, nose, oral, parenteral, topical, or intravenous. Method or use. 16. A method for the synthesis of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. A medical device comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof. The medical device of claim 23, wherein the device is a stent. A compound having a structure of the formula: or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof:

or

In this formula,

Represents a fused 5- to 7-membered saturated, unsaturated, or aromatic carbocyclic or heterocyclic ring system,
T ¹ is a carbon atom or N, so when T ¹ is N, -DEF is absent,
T ² is a carbon atom or N so that when T ² is N, -GHJ is absent,
T ¹ and T ² are not both N at the same time,
V is independently selected from -CR ^4a -or -N-,
W is O, NR ^1, NOR ^1, or S, alternatively W = are both a combination of both the H- and HO- attached to the same carbon atom or both attached to the same carbon atom (C _{1 -8} alkyl Is selected from a combination of O- and H-,
X --- Y represents a single bond or a double bond, so when X --- Y is a single bond, X is selected from O, NR ² , and S (O) _n , Y is CR ³ , and X --- when Y is a double bond, X is N, Y is a carbon atom,
Z is selected from the group consisting of O, NR ⁴ , S (O) _n , or NH,
R ¹ is selected from H and C _{1 -8} alkyl,
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;
Alternatively -GHJ

Selected from where
Each of H and J is independently selected;
CBA-, -DEF, and -GHJ are chemical moieties, where
A, D and G are independently
(a) a single _{bond, (b) - (C 1} -8 -alkyl) -, (c) - (C _{2 -8} alkenyl) -, (d) - (C _{2 -8} alkynyl) (where, i In any of (b)-(d) immediately above) 0-4 carbon atoms are -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 -optionally substituted with a moiety selected from the group consisting of
ii) any of (b)-(d) immediately above is at least one R ⁵ Optionally substituted with a group,
iii) any of (b)-(d) immediately above _is- (C _1-8 alkyl) -R ⁵ Optionally substituted with a 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) nitrogen, 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of oxygen, and sulfur,
(ee) a 3-14 membered saturated, unsaturated, or aromatic carbocyclic ring, and
(ff)-(CR ⁶ R ⁶ ) _t-
Selected from the group consisting of
(Dd) or (ee) is optionally substituted with one or more R ⁵ groups;
B, E, and H are independently
(a) a single bond,
(b) a 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
(c) 3-14 membered saturated, unsaturated, or aromatic carbocycles
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) immediately above (d In any of)-(f) 0-4 carbon atoms are selected from -O-, -S (O) _p- , -NR ⁶ -,-(C = O)-, -C (= NR ⁶ )-, Optionally substituted with a moiety selected from the group consisting of -S (O) _p NR ^6- , -NR ⁶ S (O) _p- , and -NR ⁶ S (O) _p NR ^6- ,
ii) any of (d)-(f) immediately above is at least one R ⁵ Optionally substituted with a group,
iii) immediately above, (d) - Any of (f) - (C _{1 -8-alkyl)} -R ⁵ Optionally substituted with a group), and
(g)-(CR ⁶ R ⁶ ) _t-
It is selected from the group consisting of;
C, F, and J are independently
(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 group, ( mm) C _{2 -8} alkenyl group, (nn) C _{2 - 8} alkynyl group, (oo) a nitrogen, oxygen, and a 3-14 membered saturated containing 1 or more heteroatoms selected from the group consisting of sulfur, an unsaturated , Or aromatic heterocycle, (pp) 3-14 membered 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) -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
Selected from the group consisting of
(Ll) to (pp) are optionally substituted with one or more R ⁷ groups;
R ⁵ is (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)} - (containing 1 or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle), (q)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (r) -haloalkyl, (s ) -SR ⁶ , (t)-a 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (u) -3-14 members Selected from saturated, unsaturated, or aromatic carbocyclic rings,
Alternatively, two R ⁵ groups together form a carbocycle, wherein
(M) to (r) and (t) to (u) are optionally substituted with one or more R ⁸ ;
R ⁶ is (a) hydrogen, (b) -C _{1 -8-alkyl} (or alternatively to form a carbocyclic group with two R ^6), (c) - haloalkyl, (d) - a nitrogen, oxygen, And 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of sulfur, and (e) -3-14 membered saturated, unsaturated, or aromatic carbocycles, wherein
(B) to (e) are optionally substituted with one or more R ⁸ ;
R ⁷ is (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 1 or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle), (q)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (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 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (y) -3-14 membered saturated, unsaturated, or aromatic carbocycles , (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) are optionally substituted with one or more R ⁹ ;
R ⁸ is (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)} - (containing 1 or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle), (q)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (r) -nitrogen, oxygen, and 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of sulfur, (s) -3-14 membered saturated, unsaturated, or aromatic carbocycles, (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 with one or more R ⁹ ;
R ⁹ is (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) - consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group, (r) -3-14 membered saturated, unsaturated, or aromatic carbocycles, (s) -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) At least one heteroatom selected from the group consisting of -C (O) OR ¹⁰ , (y) -S (O) _p R ⁶ , (z)-(C _1-8 alkyl)-(nitrogen, oxygen, and sulfur) Containing 3-14 membered saturated, unsaturated, or aromatic heterocycle), (aa)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (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 with one or more R ¹⁰ ;
R ¹⁰ is (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) - consisting of nitrogen, oxygen, and sulfur 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group, (r) -3-14 membered saturated, unsaturated, or aromatic carbocycles, (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) At least one heteroatom selected from the group consisting of -C (O) OR ⁶ , (y) -S (O) _p R ⁶ , (z)-(C _1-8 alkyl)-(nitrogen, oxygen, and sulfur) Containing 3-14 membered saturated, unsaturated, or aromatic heterocycle), (aa)-(C _1-8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (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 ;
In some cases, groups -DEF or groups -GHJ are absent, but neither -DEF and -GHJ are absent at the same time,
p is 0, 1, or 2,
t is 0, 1, 2, or 3.