Compounds for the treatment of inflammatory disorders and microbial diseases

• US 20070167426A1
• Filed: 11/15/2006
• Published: 07/19/2007
• Est. Priority Date: 06/02/2004
• Status: Abandoned Application

• Current Assignee: Schering Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Madison, Vincent, Reddy, Panduranga, Siddiqui, M., Mansoor, Umar
• Application Number:
  US11/599,784
• Publication Number:
  US 20070167426A1
• Time in Patent Office: Days
• US Class Current: 514/210.170
• CPC Class Codes: C07C 235/06 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 235/08 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07D 207/06 with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/08 with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/14 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/44 Iso-indoles; Hydrogenated iso-indoles
• CPC Class Codes: C07D 211/16 with acylated ring nitrogen atom
• CPC Class Codes: C07D 211/18 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 211/26 with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 211/46 having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 211/54 Sulfur atoms
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 211/64 having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 213/30 Oxygen atoms
• CPC Class Codes: C07D 215/14 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 217/06 with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/22 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 235/26 : Oxygen atoms
• CPC Class Codes: C07D 239/26 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 249/06 : with aryl radicals directly attached to ring atoms
• CPC Class Codes: C07D 263/32 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 265/30 : not condensed with other rings
• CPC Class Codes: C07D 277/24 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 277/28 : Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 295/135 : with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/185 : from aliphatic carboxylic acids
• CPC Class Codes: C07D 307/52 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 317/64 : Oxygen atoms
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/08 : Bridged systems
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 471/18 : Bridged systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/08 : Bridged systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

This invention relates to compounds of the Formula (I): or a pharmaceutically acceptable salt, solvate or isomer thereof, which can be useful for the treatment of diseases or conditions mediated by MMPs, aggrecanase, ADMP, LpxC, ADAMs, TACE, TNF-α or combinations thereof.

Claims

1. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate or ester thereof.

2. The compound of claim 1, wherein said compound is selected from the group consisting of

or a pharmaceutically acceptable salt, solvate or ester thereof.

3. A pharmaceutical composition comprising as an active ingredient at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

4. The pharmaceutical composition of claim 3, additionally comprising at least one pharmaceutically acceptable carrier.

5. A method of treating disorders associated with tumor necrosis factor-alpha-converting enzyme (TACE), aggrecanase, aggrecan degrading metallo protease (ADMP), UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC), tumor necrosis factor-alpha (TNF-α

), matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs) or any combination thereof, said method comprising administering to a patient in need of such treatment a pharmaceutical composition which comprises therapeutically effective amounts of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

6. A method of preparing a pharmaceutical composition for treating the disorders associated with TACE, LpxC, aggrecanase, ADMP, TNF-α

, MMPs, ADAMs or any combination thereof, said method comprising bringing into intimate contact at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, and at least one pharmaceutically acceptable carrier.

7. A pharmaceutical composition for treating disorders associated with TACE, aggrecanase, ADMP, TNF-α

, MMP, ADAM or any combination thereof in a subject comprising, administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

8. A compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof in purified form.

9. A method of treating a condition or disease mediated by TACE, LpxC, MMPs, ADMP, TNF-α

, aggrecanase, or any combination thereof in a subject comprising;

administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

10. The method of claim 9, wherein said aggrecanase is aggrecanase 1, aggrecanase 2, aggrecanase 3, or aggrecanase 4.

11. A method of treating a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and psoriasis in a subject, comprising:

administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

12. A method of treating a condition or disease selected from the group consisting of fever, cardiovascular conditions, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease and HIV infection in a subject comprising administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

13. A method of treating a condition or disease selected from the group consisting of septic shock, haemodynamic shock, sepsis syndrome, post ischaemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, inflammatory bowel diseases such as Crohn'"'"'s disease and colitis, osteo and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, adult Still'"'"'s disease, ureitis, Wegener'"'"'s granulomatosis, Behcehe disease, Sjogren'"'"'s syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, non-insulin dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) and bronchitis in a subject comprising administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

14. A method of treating a condition or disease associated with COPD, comprising:

administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

15. A method of treating a condition or disease associated with rheumatoid arthritis, comprising:

administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

16. A method of treating a condition or disease associated with Crohn'"'"'s disease, comprising:

administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

17. A method of treating a condition or disease associated with psoriasis, comprising:

administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

18. A method of treating a condition or disease associated with ankylosing spondylitis, comprising:

administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

19. A method of treating a condition or disease associated with sciatica, comprising:

administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

20. A method of treating a condition or disease associated with complex regional pain syndrome, comprising:

administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

21. A method of treating a condition or disease associated with psoriatic arthritis, comprising:

administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

22. A method of treating a condition or disease associated with multiple sclerosis, comprising:

administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof, in combination with a compound selected from the group consisting of Avonex®

, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis.

23. The method of claim 11 further comprising administering to said subject a therapeutically effective amount of at least one medicament selected from the group consisting of disease modifying anti-rheumatic drugs (DMARDS), NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, biological response modifiers (BRMs), anti-infammatory agents and H1 antagonists.

24. A method of claim 12, further comprising administering to said subject a therapeutically effective amount of at least one medicament selected from the group consisting of DMARDS, NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, BRMs, anti-infammatory agents and H1 antagonists.

25. A method of claim 13, further comprising administering to said subject a therapeutically effective amount of at least one medicament selected from the group consisting of DMARDS, NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, BRMs, anti-infammatory agents and H1 antagonists.

26. A method for the treatment of a microbial infection in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

27. The method of claim 26, wherein said infection is a gram negative infection.

28. The method of claim 26, wherein said infection is a gram positive infection.

29. The method of claim 26, further comprising administering one or more additional antibacterial agents.

30. The method of claim 29, wherein said antibacterial agent is active against gram negative bacteria.

31. The method of claim 29, wherein said antibacterial agent is active against gram positive bacteria.

32. The method of claim 26, wherein said microbial infection is caused by at least one organism selected from the group consisting of Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Acinetobacter hydrophila, Actinobacillus actinomycetemcomitans, Aeromonas hydrophila, Alcaligenes xylosoxidans, Bacteroides distasonis, Bacteroides fragilis, Bacteroides melaninogenicus, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bartonella henselae, Bordetella pertussis, Branhamella catarrhalis, Brucella melitensis, Brucella abortus, Brucella canis, Burkholderia cepacia, Burkholderia mallei, Burkholderia pseudomallei, Campylobacter coli, Campylobacter fetus, Campylobacter jejuni, Citrobacter diversus, Citrobacter freundii, Citrobacter koseri, Coxiella burnetli, Edwarsiella tarda, Ehrlichia chafeenis, Eikenella corrondens, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Escherichia coli, Flavobacterium meningosepticum, Francisella tularensis, Fusobacterium spp., Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Helicobacter pylori, Kingella kingae, Klebsiella oxytoca, Klebsiella ozaenae, Klebsiella pneumoniae, Klebsiella rhinoscleromatis, Legionella pneumophila, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitides, Pasteurella multocida, Plesiomonas shigelloides, Porphyromonas asaccharolytica, Porphyromonas gingivalis, Prevotella bivia, Prevotella buccae, Prevotella corporis, Prevotella endodontalis, Prevotella intermedia, Prevotella melaninogenica, Prevotella oralis, Proteus mirabilis, Proteus myxofaciens, Proteus penner, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuafli, Pseudomonas aeruginosa, Pseudomonas fluorescens, Ricketsia prowozekii, Salmonella enterica, Serratia marcescens, Shigella boydii, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Stenotrophomonas maltophilia, Streptobacillus moniliformis, Vibrio alginolyticus, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vuluificus, Yersinia enterocolitica, Yersinia pestis, and Yersinia pseudotuberculosis.

33. The method of claim 26, wherein the organism is selected from the group consisting of Acinetobacter baumannii, Acinetobacter spp., Aeromonas hydrophila, Bacteroides fragilis, Bacteroides spp., Bordetella pertussis, Campylobacter jejuni, Campylobacter spp., Citrobacter freundii, Citrobacter spp., Enterobacter cloacae, Enterobacter spp., Escherichia coli, Fusobacterium spp., Haemophilus influenzae, Haemophilus parainfluenzae, Helicobacter pylori, Klebsiella pneumoniae, Klebsiella spp., Legionella pneumophila, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitides, Pasteurella multocida, Prevotella spp., Proteus mirabilis, Proteus spp., Providencia stuartii, Pseudomonas aeruginosa, Pseudomonas spp., Salmonella enterica, Salmonella typhi, Serratia marcescens, Shigella spp., Stenotrophomonas maltophilia, Vibrio cholerae, Vibrio spp., and Yersinia spp.

34. The method of claim 26, wherein said microbial infection is a fungal infection.

35. A method of treating a disorder associated with UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC), said method comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein;

A is selected from the group consisting of;

d is 0 to 4;

J is selected from the group consisting of O, S, and NR⁵;

E is selected from the group consisting of;

O, S, and NR⁵;

T is O or S;

R¹ and R² are the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl, and heteroaryl;

or alternatively R¹ and R², taken together with the N to which R¹ and R² are shown attached, represent a 4-8 membered heterocyclic ring having 1-3 heteroatoms including said N, said heterocyclic ring being optionally fused with aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaralkyl, heteroaryl and 4-8 membered heterocyclic ring can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group of R⁷⁰ moieties below;

R¹⁰ is selected from the group consisting of H, alkyl, and fluoroalkyl;

R²⁰ is selected from the group consisting of H, alkyl, and fluoroalkyl;

R³⁰ is H or alkyl, or alternatively R³⁰ and R⁴⁰ taken together with the N to which R⁴⁰ is shown attached to in Formula I, are joined to form a 4-7 membered heterocylic ring, wherein said heterocylic ring is unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group of R⁷⁰ moieties below;

R⁴⁰ is H or alkyl;

R⁵⁰ is H or alkyl;

W is —

(CR¹³₂)_n—

, wherein n is 0 to 5 or a covalent bond, or alternatively two R¹³ groups can fuse to form a 3-8 membered cycloalkyl, wherein said 3-8 membered cycloalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group of R⁶ moieties below;

X is absent or present, and if present X is selected from the group consisting of a covalent bond, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group of R⁷⁰ moieties below;

Y is absent or present, and if present Y is selected from the group consisting of a covalent bond, —

[C(R⁶)₂]_n—

wherein n is 1 or 2, —

O—

, —

S—

, —

NR¹—

, —

SO_v—

wherein v is 1 to 2, —

SO_n(CR⁶₂)_p—

wherein n is 1 or 2 and p is 1 to 4, —

O(CR⁶₂)_q—

or —

(CR⁶²)_qO—

wherein q is 1 to 4, —

N(R⁷)S(O)_n—

or —

S(O)_nN(R⁷)—

;

wherein n is 1 or 2, and —

N(R⁷)C(O)—

or —

C(O)N(R⁷)—

;

Z is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, said cycloalkyl, heterocyclyl, aryl, and heteroaryl being optionally fused with aryl, heterocyclyl, heteroaryl or cycloalky;

wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group of R⁷⁰ moieties below;

R⁵ is selected from the group consisting of hydrogen, alkyl, and alkylaryl;

each R⁶ is the same or different and is independently selected from the group consisting of hydrogen, halogen, —

SR¹⁵, —

S(O)_qR¹⁵ wherein q is 1 to 2, alkyl, cycloalkyl, heterocyclyl, alkoxyl, hydroxy, nitro, cyano, amino, alkenyl, alkynyl, arylalkyl, aminocarbonyl, alkylcarbonyl, and alkoxycarbonyl;

each R⁷ is the same or different and is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, alkenyl, alkynyl, arylalkyl, alkylcarbonyl, and alkoxycarbonyl, wherein each of the aryl, heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group of R⁷⁰ moieties below;

R¹³ is the same or different and is independently selected from the group consisting of hydrogen, halogen, —

OH, —

OR¹⁴, alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylaryl, alkylamino, and alkylcarbonyl;

R¹⁴ is alkyl;

each R⁷⁰ is a substituent for H where indicated and is the same or different and is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —

CN, —

CF₃, —

OCF₃, —

OR¹⁵, —

C(O)R¹⁵, —

C(O)OR¹⁵, —

C(O)N(R¹⁵)(R¹⁶), —

SR¹⁵, —

S(O)_qN(R¹⁵)(R¹⁶) wherein q is 1 to 2, —

C(═

NOR¹⁵)R¹⁶, —

N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —

N(R¹⁵)C(O)R¹⁶, —

CH₂—

N(R¹⁵)C(O)R¹⁶, —

N(R¹⁵)S(O)R¹⁶, —

N(R¹⁵)S(O)₂R¹⁶, —

CH₂—

N(R¹⁵)S(O)₂R¹⁶, —

N(R¹⁷)S(O)₂N(R¹⁶)(R¹⁵), N(R¹⁷)S(O)N(R¹⁶)(R¹⁵), —

N(R¹⁷)C(O)N(R¹⁶)(R¹⁵), —

CH₂—

N(R¹⁷)C(O)N(R¹⁶)(R¹⁵), —

N(R¹⁵)C(O)OR¹⁶, —

CH₂—

N(R¹⁵)C(O)OR¹⁶, and —

S(O)_qR¹⁵ wherein q is 1 to 2; and

wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl are independently unsubstituted or substituted by 1 to 5 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, —

CF₃, —

CN, —

OR¹⁵, —

N(R¹⁵)(R¹⁶), —

C(O)OR¹⁵, —

C(O)N(R¹⁵)(R¹⁶), and —

N(R¹⁵)S(O)R¹⁶; and

each R¹⁵, R¹⁶ and R¹⁷ are independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or alternatively R¹⁵ and R¹⁶ taken together with the N to which they are shown attached, are joined to form a 4-8 membered heterocylic ring, wherein said 4-8 membered cycloalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group of R⁷⁵ moieties below;

each R⁷⁵ is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl, and wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl are independently unsubstituted or substituted by 1 to 5 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, —

CF₃, —

CN, —

OR¹⁹, —

N(R¹⁹)₂, —

C(O)OR¹⁹, —

C(O)N(R¹⁹)₂, and —

N(R¹⁹)S(O)R¹⁹; and

each R¹⁹ is independently selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

36. The method of claim 35, wherein said disorder is a microbial infection.

37. The method of claim 36, wherein said microbial infection is a bacterial or fungal infection.

38. The method of claim 37, wherein said bacterial infection is a gram negative infection.

39. The method of claim 37, wherein said bacterial infection is a gram positive infection.