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Title:
ANTIFUNGAL COMPOUNDS AND METHODS
Document Type and Number:
WIPO Patent Application WO/2017/100171
Kind Code:
A1
Abstract:
Compounds of the Formula (I) and (II) as described herein, or pharmaceutically acceptable salts thereof, are described, along with pharmaceutical compositions comprising such compounds, salts or combinations thereof, and methods for making them. Such compounds, salts and compositions are useful for inhibiting fungal growth. For example, in an embodiment, fungal infections can be treated by administering effective amounts of such compounds, salts and/or compositions to a subject in need thereof.

Inventors:
PINCHMAN JOSEPH ROBERT (US)
BUNKER KEVIN DUANE (US)
HUANG PETER QINHUA (US)
SLEE DEBORAH HELEN (US)
HOPKINS CHAD DANIEL (US)
KAHRAMAN MEHMET (US)
Application Number:
PCT/US2016/065097
Publication Date:
June 15, 2017
Filing Date:
December 06, 2016
Export Citation:
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Assignee:
KALYRA PHARMACEUTICALS INC (US)
International Classes:
C07H17/08; A61K31/7048; A61P31/10
Domestic Patent References:
WO2015054148A12015-04-16
WO2016112243A12016-07-14
WO2016168568A12016-10-20
Foreign References:
CA2951516A12015-12-17
Other References:
CARMODY, M. ET AL.: "Biosynthesis of Amphotericin Derivatives Lacking Exocyclic Carboxyl Groups", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 280, no. 41, 2005, pages 34420 - 34426, XP055390733
Attorney, Agent or Firm:
MALLON, Joseph J. (US)
Download PDF:
Claims:
WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Formula (I) has the structure:

wherein:

R1 is selected from e group consisting of -R\ -C(0)R 34 -C(=S)NR5AR5B, and

2 τ«?-° ,·

R2 is selected from the group consisting of -NRSARSB; -(NR9AR9BR9C)+ and - NHC(0)R10;

R3, R4, R5A, R5B and R6 are each independently selected from the group consisting of hydrogen, an unsubstituted Ci -f, alkyl, a substituted Ci-6 aikyl, an optionally substituted C3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl; or

R5A and R5B, together with the N to which they are attached, form an optionally substituted monocyclic heterocyclyl;

R8A, R8B, R9A, R9B and R9C are each independently selected from the group consisting of hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C3..6 cycloalkyl, -

13AR i3BR13C)+ j 11, -(C2..6 alkyl)-NR12AR12B, -(C2.6 a R " is selected from the group consisting of an optionally substituted C1-6 alkyl, an optionally substituted C3-6 cycloalk -(C2-6 alkyl)-()R1 !, -(C2-6 alkyl)-NRi2ARi2B, -(C2-6

alkyl)-(NR13AR13BRf 3C)+, and

R , R ' \ Rl " ~", R i , R1' "' and are each independently selected from the group consisting of hydrogen and an unsubstituted Cj-6 alkyl; and

n is zero or an integer in the range of 1 to about 40;

provided that when R1 is -C(0)R4 and Rz is NH2, then R1* is not selected from substituents A, B, C, D, E, F, G, H, I or J, as follows:

and provided that when R1 is -C(0)R4 and R'' is NH2, then R4 is not an N-linked optionally substituted monocyclic heterocyclyl.

2. The compound of Claim 1 , provided that when R is ~C(0)R4 and R is NH2, then R4 is not selected from the group consisting of methyl, ethyl, propyl, isopropyl,

propenyl,

3. The compound of any one of Claims 1 to 2, wherein R1 is -R3, or a pharmaceutically acceptable salt thereof,

4. The compound of any one of Claims 1 to 2, wherein R1 is -C(0)R4, or a pharmaceutically acceptable salt thereof,

5. The compound of any one of Claims 1 to 2, wherein R1 is -C(==S)NR:'AR:'B, or a pharmaceutically acceptable salt thereof.

6. The compound of Claim 5, wherein R^ is H and R5r5 is ethyl, hydroxy ethyl or aminoethyl, or a pharmaceutically acceptable salt thereof.

7. The compound of any one of Claims 1 to 6, wherein R2 is -NR8AR8B, or a pharmaceutically acceptable salt thereof.

8. The compound of any one of Claims 1 to 6, wherein R2 is -(NR9AR9BR9C)T , or a pharmaceutically acceptable salt thereof.

9. The compound of any one of Claims 1 to 6, wherein R' is NHC(0)R , or a pharmaceutically acceptable salt thereof.

10. The compound of any one of Claims 1 to 9, wherein R', R4, R3A, R5B and R6 are each independently selected from the group consisting of an unsubstituted C1-6 alkyl, a substituted Ci _6 alkyl, and an optionally substituted C -7 cycloalkyl, or a pharmaceutically acceptable salt thereof.

1 1. The compound of Claim 10, wherein the substituted C1-6 alkyl is substituted with a moiety selected from the group consisting of hydroxy, halogen, alkoxy, amino, C3-? cycloalkyl, halogen, a mono-substituted amine, a di -substituted amine, an optionally substituted N-linked monocyclic heteroaryl, an optionally substituted aryl, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, and an optionally substituted N-linked monocyclic heterocyclyl, or a pharmaceutically acceptable salt thereof.

12. The compound of Claim 10, wherein the substituted C1-6 aikyl is a C1-6 haloalkyl, or a pharmaceutically acceptable salt thereof.

13. The compound of Claim 10, wherein the optionally substituted C3.7 cycloalkyl is selected from the group consisting of optionally substituted cyclopropane, optionally substituted cyclobutane, optionally substituted bicyclobutane, optionally substituted cyclopentane, optionally substituted bicyclopentane, and optionally substituted cyclohexane, or a pharmaceutically acceptable salt thereof.

14. The compound of any one of Claims 1 to 9, wherein R , R , R"' , R and RJ are each independently selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclvl, or a pharmaceutically acceptable salt thereof.

15. The compound of any one of Claims 1 to 9, wherein R3A and R5B, together with the N to which they are attached, form an optionally substituted monocyclic heterocyclvl selected from the group consisting of pvrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, and piperazinyl, or a pharmaceutically acceptable salt thereof.

16. A compound selected from the group consisting of:

WO 2017/100171

pharmaceutically acceptable sail of the foregoing.

17. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt of the foregoing.

18. The compound of Claim 1, selected from the group consisting of:

or a pharmaceutically acceptable salt of the foregoing.

19. A pharmaceutical composition comprising an effective amount of the compound of any one of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner, diluent, excipient or combination thereof.

20. A method of inhibiting the growth of a fungus, comprising contacting the fungus with an effective amount of the compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 19.

21. A method of treating a fungal infection, comprising identifying a subject in need thereof and administering to said subject an effective amount of the compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 19.

22. The method of Claim 21, wherein said administering to said subject comprises an intravenous administration.

23. The method of Claim 21 , wherein said administering to said subject comprises an oral administration.

24. The method of Claim 21, wherein said administering to said subject comprises an intramuscular administration.

25. The method of Claim 21, wherein said administering to said subject comprises a topical administration.

26. The method of Claim 21, wherein said administering to said subject comprises a systemic administration.

27. The method of any one of Claims 21 to 26, wherein said pharmaceutical composition comprises a pharmaceutically acceptable carrier.

28. The compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 19, for use in the treatment and/or diagnosis of a fungal infection.

29. An acylation process, comprising reacting a compound of Formula (II) with a carboxylic acid of formula R4-('0.->l ! under conditions selected to form a compound of Formula (la), as follows:

wherein:

R3A is hydrogen;

R3B is an unsubstituted C1- alkyl;

R3C is a protecting group;

R3D is a protecting group; and

R4 is selected from the group consisting of an unsubstituted C1-6 alkyl, a substituted Cj.e alkyl, an optionally substituted C3..7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocy cly 1.

30. The acylation process of Claim 29, wherein the conditions selected to form the compound of Formula (la) comprise reacting the compound of Formula (Π) with the carboxylic acid of formula R4-C02H in the presence of an organic solvent,

31. The acylation process of any one of Claims 29 to 30, wherein the conditions selected to form the compound of Formula (la) comprise reacting the compound of Formula (II) with the carboxylic acid of formula R4-C02H in the presence of an acylating agent selected from the group consisting of, l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxidhexafluorophosphate) (HATU), diisopropylcarbodiimide (DIC), dicyclohexylcarbodumide (DCC), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide HC1 (EDC · HC1), Ι,Γ-Carbonyldiimidazole, benzotriazol-l-yloxy-tripyrrolidino- phosphonium hexafluorophosphate (PyBOP®), 7-Aza-benzotriazol-l-yloxy- tripyrrolidinophosphonium hexafluorophosphate (PyAOP), 2-(l H-Benzotriazol- 1 -yl)- Ν,Ν,Ν',Ν'- tetramethylaminium tetrafluoroborate (TBTU), 2-(lH-Benzotriazol-l -yl)- Ν,Ν,Ν',Ν'- tetramethylaminium hexafluorophosphate HBTU), 2-Propanephosphonic acid anhydride (T3P), thionyl chloride, and oxalyl chloride.

32. The acylation process of any one of Claims 29 to 31, wherein the conditions selected to form the compound of Formula (la) comprise reacting the compound of Formula (II) with the carboxylic acid of formula R -('() >! I in the presence of an organic base.

33. The acylation process of any one of Claims 29 to 31, wherein the conditions selected to form the compound of Formula (la) comprise reacting the compound of Formula (II) with the carboxylic acid of formula R4-C02H in the presence of an inorganic base.

34. A reductive amination process, comprising reacting a compound of Formula (II) with an aldehyde of formula R4-COH under conditions selected to form a compound of Formula (lb), as follows:

wherein:

R A is hydrogen;

R,B is an unsubsiituted Ci-3 atkyl;

R3C is a protecting group;

R,D is a protecting group; and

R4 is selected from the group consisting of an unsubsiituted C1-6 alkyl, a substituted C1-6 alkyl, an optionally substituted C3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.

35. The reductive amination process of Claim 34, wherein the conditions selected to form the compound of Formula (lb) comprise reactmg the compound of Formula (II) with the aldehyde of formula R -COH in the presence of a reducing agent.

36. The reductive amination process of Claim 34, wherein the reducing agent is selected from the group consisting of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, triethylsilane, and phenyl silane.

37. An alkylation process, comprising reacting a compound of Formula (11) with a compound of formula R4-C¾-X under conditions selected to form a compound of Formula (lb), as follows:

wherein:

RiA is hydrogen;

R ,E is an unsubstituted C1..3 alky 3;

R3C is a protecting group;

R3D is a protecting group;

RJ is selected from the group consisting of an unsubstituted Cj -6 alkyl, a substituted Ci..6 alkyl, an optionally substituted C3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl; and

X is a halide or pseudohalide.

38. The alkylation process of Claim 37 wherein the conditions selected to form the compound of Formula (lb) comprise reacting the compound of Formula (II) with the compound of formula RJ-('I {.<-X in the presence of an organic solvent.

39. The alkyation process of any one of Claims 37 to 38, wherein the conditions selected to form the compound of Formula (lb) comprise reacting the compound of Formula (II) with the compound of formula R*-CH2-X in the presence of an organic base.

40. The alkyation process of any one of Claims 37 to 38, wherein the conditions selected to form the compound of Formula (lb) comprise reacting the compound of Formula (II) with a compound of formula R4-CH2-X in the presence of an inorganic base.

Description:
ANTIFUNGAL COMPOUNDS AND METHODS

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] Any and ail applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application are hereby incorporated by reference under 37 CFR 1.57.

Field

[0002] The present application relates to antifungal compounds and methods of using them to treat fungal infections.

Description

[0003] Amphotericin B (AmB) is a potent anti-fungal compound having the following chemical structure:

[0004] AmB has been used for treating severe fungal infections for over half a century. AmB is an especially valuable treatment for severe fungal infections because it is effective against a wide variety of fungi, and fungal pathogens have been relatively unsuccessful at developing resistance to it. However, despite its potency and ability to evade the development of resistance, the use of AmB is often precluded due to its highly toxic side effects including nephrotoxicity, hepatoxieity, and anemia-related symptoms. There have been many attempts to reduce toxicity while retaining therapeutic effectiveness. See WO 2014165676, WO 2015054148, WO 201 5190587, W 2016168568 and Stephen A. Davis et al , "Nontoxic antimicrobials that evade drug resistance," Nature Chemical Biology (June 1 2015). Thus, there remains a need for better tolerated compounds and methods of treatment for fungal infections that are therapeutically effective.

SUMMARY

[0005] A first embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Formula (I) has the structure:

[0006] In an aspect of the first embodiment, R 1 is selected from the group consisting of -R 3 , -C(0)R 4 , -C(=X 1 )NR 5A R 5B , and ~S(G) 2 R 6

[0007] In an aspect of the first embodiment, R 2 is selected from the group consisting of - R 8A R 8B ; -(NR 9A R 9B R 9C ) + and -NHC(0)R 10 .

[0008] In an aspect of the first embodiment, R\ R 4 , R ~ A , R "B and R b are each independently selected from the group consisting of hydrogen, an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, an optionally substituted C3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocvclyi; or, in another embodiment, R JA and R 38 , together with the N to which they are attached, form an optionally substituted monocyclic heterocvclyi.

[0009] In an aspect of the first embodiment, R A , R 8r5 , R 9A , R 9B and R 9C are each independently selected from the group consisting of hydrogen, an optionally substituted Ci_6 alkyl, an optionally substituted C3-6 cycloalkyl, -{C 2 - 6 alkyl)-OR n , -(C 2 6 alkyl)-NR 12A R 12B , -

(C 2 -6 alkyl)-(NR 13A R 13B R 13C ) + , and \ 0010] aspect of the first embodiment, R 1 is selected from the group consisting of an optionally substituted C 1-6 alkyl, an optionally substituted C 3 _6 cycloalkyl, - -OR J J , -(C 2-6 alkyl)-NR f 2A R f 2B , -(C 2 6 alky!)-^ 3A R i3B R 33C ) + , and

[0011] In an aspect of the first embodiment, R f f , R 12A , R f 2B , R 13A R ¾3B and R i3C are each independently selected from the group consisting of hydrogen and an unsubstituted Ci_6 alkyl; and X ! is O or S.

0012 In an aspect of the first embodiment, when R is -C(0)NR"' R" , R " is

Ni l * and one or the other of R 5A and R 5B is H, then the other of R 5A and R 5B is not -CH 3 , - CH 2 CH 2 NH 2 , or -CH 2 CH 2 C(0)OH.

[0013] A second embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of -R 3 , -C(0)R 4 , -C(=S) R 5A R 5B , and -S(0) 2 R 6

[0014] In an aspect of the second embodiment, R is selected from the group consisting of ----NR 8A R 8B ; -(NR 9A R 9B R 9C ) + and -NHC(0)R 10 .

[0015] In an aspect of the second embodiment, R J , R 4 , R iA , R "B and R b are each independently selected from the group consisting of hydrogen, an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, an optionally substituted C 3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocvclyi; or, in another embodiment, " and R "" , together with the N to which they are attached, form an optionally substituted monocyclic heterocvclyi.

[0016] In an aspect of the second embodiment, R 8A R B , R 9A , R 9B and R 9C are each independently selected from the group consisting of hydrogen, an optionally substituted Ci-6 alkyl, an optionally substituted C 3-6 cycloalkyl, -(C 2-6 alkyl)-OR n , -(C 2- 6 alk l)-

NR ! A R ! B , -fC 2 . 6 alkyl)-(NR l A R l3B R 13C r, and

[0017] In an aspect of the second embodiment, R " is selected from the group consisting of an optionally substituted C 1-6 alkyl, an optionally substituted C 3-6 cycloalkyl, - ! ; A R ' ; | : R ! ! } . and

[0018] In an aspect of the second embodiment, R N , R 12A , R 12B , R f 3A , R ! 3B and

R ! ,c are each independently selected from the group consisting of hydrogen and an unsubstituted Ci„6 alkyl.

[ 0019] In an aspect of the second embodiment, n is zero or an integer in the range of 1 to about 40.

[0020] In an embodiment, when R 1 is -C(0)R 4 and R 2 is NH 2 , then R 4 is not an N-linked optionally substituted monocyclic heterocvclyl.

[0021] In an embodiment, when R 1 is -C(0)R 4 and R 2 is NH 2 , then R " is not selected from substituents A, B, C, D, E, F, G, H, I or J, as follows:

[0022] In an embodiment, when R ¾ is -C(0)R 4 and R 2 is NH 2 , then R 4 is not selected from the group consisting of methyl, ethyl, propyl, isopropyl, propenyl,

[0023] In an embodiment, when R 1 is -C(0)NR 5A R 5B , R is -NH 2 and one or the other of R 5A and R 5b is H, then the other of R 5A and R 5si is not -CH 3 , -CH 2 CH 2 NH 2 , or - CH 2 CH 2 C(0)OH.

[0024] In an embodiment, when R is -C(0)NR" ~ R " and R" is -NH 2 , then - NR 5A R 5B }s not i l )C j | ; -N(H)CH 2 CH -N(! I)( I !^C -N(CH 3 ) 2 , -

N(CH 2 CH 3 )2, -N(CH(CH 3 ) 2 ) 2 , , or

[0025] An embodiment provides a pharmaceutical composition comprising an effective amount of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0026] An embodiment provides a method of inhibiting the growth of a fungus, comprising contacting the fungus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0027] An embodiment provides a method of inhibiting the growth of a fungus, comprising contacting the fungus with an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0028] An embodiment provides a method of treating a fungal infection, comprising identifying a subject in need thereof and administering to said subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0029] An embodiment provides a method of treating a fungal infection, comprising contacting the fungus with an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0030] An embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment and/or diagnosis of a fungal infection.

[0031] An embodiment provides a pharmaceutical composition for use in the treatment and/or diagnosis of a fungal infection, wherein the pharmaceutical composition comprises an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0032] An embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt thereof, as described below. Embodiments of such compounds of Formula (II) and/or salts thereof are useful in the methods and/or uses summarized above and described elsewhere herein.

[0033] An embodiment provides a pharmaceutical composition comprising an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. Embodiments of such pharmaceutical compositions containing such compounds of Formula (II) and/or salts thereof are useful in the methods and/or uses summarized above and described elsewhere herein.

[0034] Embodiments of compounds of Formula (II) and/or salts thereof are useful as starting materials or intermediates for the preparation of other compounds, such as compounds of Formula (I), (la) and/or (lb), and/or pharmaceutically acceptable salts thereof, as described below. An embodiment provides a process of making a compound of Formula (la) and/or (lb) using a compound of Formula (II) as a starting material or intermediate. In various embodiments, the process is an acylation process, a reductive animation process or an alleviation process.

[0035] These and other embodiments are described in greater detail below. DRAWINGS

[0036] FIG. 1A illustrates General Scheme 1.

[0037] FIG. IB illustrates the chemical structure of Compound 1.

[0038] FIG. 1C illustrates a reaction scheme for making Compound 1.

[0039] FIG. ID illustrates another reaction scheme for making Compound 1

[0040] FIG. IE illustrates another reaction scheme for making Compound 1.

[0041] FIG. IF illustrates another reaction scheme for making Compound 1.

[0042] FIG. 2A illustrates the chemical structure of Compound 2.

[0043] FIG. 2B illustrates a reaction scheme for making Compound 2.

[0044] FIG. 3 illustrates the chemical structure of Compound 3.

[0045] FIG. 4 illustrates the chemical structure of Compound 4.

[0046] FIG. 5 illustrates the chemical structure of Compound 5.

[0047] FIG. 6 illustrates the chemical structure of Compound 6.

[0048] FIG. 7 illustrates the chemical structure of Compound 7.

[0049] FIG. 8 illustrates the chemical structure of Compound 8.

[0050] FIG. 9 illustrates the chemical structure of Compound 9.

[0051] FIG. 10 illustrates the chemical structure of Compound 10.

[0052] FIG. 11 illustrates the chemical structure of Compound 11.

[0053] FIG. 12 illustrates the chemical structure of Compound 12,

[0054] FIG. 13 illustrates the chemical structure of Compound 13.

[0055] FIG. 14 illustrates the chemical structure of Compound 14.

[0056] FIG 15 illustrates the chemical structure of Compound 15.

[0057] FIG. 16 illustrates the chemical structure of Compound 16.

[0058] FIG 17 illustrates the chemical structure of Compound 17.

[0059] FIG. 18A illustrates the chemical structure of Compound 18.

[0060] FIG 18B illustrates a reaction scheme for making Compound 18.

[0061] FIG. 19 illustrates the chemical structure of Compound 19.

[0062] FIG 20A illustrates the chemical structure of Compound 20.

[0063] FIG. 20B illustrates a reaction scheme for making Compound 20.

[0064] FIG. 21 illustrates the chemical structure of Compound 21.

[0065] FIG. 22A illustrates the chemical structure of Compound 22. [0066] FIG 22B illustrates a reaction scheme for making Compound 22.

[0067] FIG. 23 illustrates the chemical structure of Compound 23.

[0068] FIG. 24A illustrates the chemical structure of Compound 24.

[0069] FIG. 24B illustrates a reaction scheme for making Compound 24.

[0070] FIG. 24C illustrates another reaction scheme for making Compound 24.

[0071] FIG. 24D illustrates another reaction scheme for making Compound 24.

[0072] FIG. 25 illustrates the chemical structure of Compound 25.

[0073] FIG. 26A illustrates the chemical structure of Compound 26.

[0074] FIG. 26B illustrates a reaction scheme for making Compound 26.

[0075] FIG. 27A illustrates the chemical structure of Compound 27.

[0076] FIG. 27B illustrates a reaction scheme for making Compound 27.

[0077] FIG. 27C illustrates another reaction scheme for making Compound 27.

[0078] FIG. 28 illustrates the chemical structure of Compound 28.

[0079] FIG. 29 illustrates the chemical structure of Compound 29.

[0080] FIG. 30 illustrates the chemical structure of Compound 30.

[0081] FIG. 31 A illustrates the chemical structure of Compound 31.

[0082] FIG. 31 B illustrates a reaction scheme for making Compound 31.

[0083] FIG 32 illustrates the chemical structure of Compound 32.

[0084] FIG. 33 illustrates the chemical structure of Compound 33.

[0085] FIG 34 illustrates the chemical structure of Compound 34.

[0086] FIG. 35A illustrates the chemical structure of Compound 35.

[0087] FIG 35B illustrates a reaction scheme for making Compound 35.

[0088] FIG. 36 illustrates the chemical structure of Compound 36.

[0089] FIG 37 illustrates the chemical structure of Compound 37.

[0090] FIG. 38 illustrates an acylation process for making a compound of

Formula (la) using a compound of Formula (II).

[0091] FIG. 39 illustrates a reductive amination process for making a compound of Formula (lb) using a compound of Formula (II).

[0092] FIG. 40 illustrates an alkylation process for making a compound of Formula (lb) using a compound of Formula (II). DETAILED DESCRIPTION

Definitions

[0093] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. Reference herein to a compound of Formula (I) or (II) shall be understood as a reference to any of the embodiments of Formula (I) or (II), respectively, described herein unless the context indicates otherwise.

[0094] Whenever a group is described as being "optionally substituted" that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being "unsubstituted or substituted" if substituted, the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated "optionally substituted" or "substituted" group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-armdo, S-sulfonaraido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, an ammo, a mono-substituted ammo group and a di-substituted amino group.

[0095] As used herein, "C a to Ct > " in which "a" and "b" are integers refer to the number of carbon atoms in a group. The indicated group can contain from "a" to "b", inclusive, carbon atoms. Thus, for example, a "Cj to C 4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (Ci h bC! i-. (Ί ! -,(Ί Ι .<Ί 1 Ί Ι ·. CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-. If no "a" and "b" are designated, the broadest range described in these definitions is to be assumed.

[0096] If two "R" groups are described as being "taken together" the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. For example, without limitation, if R a and R b of an NR a R group are indicated to be "taken together," it means that they are covalently bonded to one another to form a ring:

[0097] As used herein, the term "alk l" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like. The alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as "1 to 30" refers to each integer in the given range; e.g., "1 to 30 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 12 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. An alkyl group may be substituted or unsubstituted.

[0098] The term "alkenyi" used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon double bond(s) including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1- butenyl, 2-butenyl and the like. An alkenyi group may be unsubstituted or substituted.

[0099] The term "alkynyl" used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond(s) including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl and the like. An alkynyl group may be unsubstituted or substituted.

[0100] As used herein, "cycloalkyl" refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the nng(s) or 3 to 6 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. As used herein, the term "fused" refers to a connectivity between two rings in which two adjacent atoms sharing at least one bond (saturated or unsaturated) are common to the rings. For example, in the following structure, rings A and B are fused Examples of fused ring structures include, but are not limited to, decahydronaphthalene, lH-indole, quinolone, chromane, bicyclo[2.1.0]pentane and 6,7,8,9- tetrahydro-5H-benzo[7]annulene.

As used herein, the term "bridged" refers to a connectivity wherein three

or more atoms are shared between two rings. The following structures and

are examples of "bridged" rings because the indicated atoms are shared between at least two rings. Examples of bridged ring structures include, but are not limited to, bicyclo[l . l . l ]pentane, 2-oxabicyclo[l.. l . l]pentane, 5-azabicyclo[2.1.1 ]hexane, 6- azabicyclo[3.1. ljheptane, adamantane and norbornane.

As used herein, the term "spiro" refers to a connectivity betwe rings

wherein the rings have only one atom in common. For example, in the structure rings C and D are joined by a spiro connection. Examples of spiro connected ring structures include, but are not limited to, spiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxa-6- azaspiro[3.3]heptane, spiro[4.5]decane and 2,6-dioxaspiro[3.3]heptane.

[0104] As used herein, "cycloalkenyl" refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocahzed pi- electron system throughout all the rings (otherwise the group would be "aryl," as defined herein). Cycloalkenyl groups can contain 3 to 30 atoms in the rmg(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the rmg(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro fashion. A cycloalkenyl group may be unsubstituted or substituted.

[0105] As used herein, "cycloalkynyi" refers to a mono- or muiti- cyclic hydrocarbon ring system that contains one or more triple bonds in at least one ring. If there is more than one triple bond, the triple bonds cannot form a fully delocalized pi-electron system throughout all the rings. Cycloalkynyi groups can contain 8 to 30 atoms in the ring(s), 8 to 20 atoms in the ring(s) or 8 to 10 atoms in the ring(s). When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. A cycloalkynyi group may be unsubstituted or substituted.

[0106] As used herein, "aryl" refers to a carboeyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carboeyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C 6 -C 14 aryl group, a ( Cio aryl group, or a C 6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.

[0107] As used herein, "heteroaryl" refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2, 3, 4 or 5 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the rmg(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term "heteroaryl" includes fused ring systems. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazme, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, ,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, mdazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazoie, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, ptendine, quinolme, isoquinoline, quinazoline, quinoxaline, cmnoline and triazine. A heteroaryf group may be substituted or unsubstituted.

[0108] As used herein, "heterocyclyl" or "heteroalicyclyl" refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicychc and tricyclic ring systems wherein carbon atoms together with from 1 to 5 heteroatonis constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio- systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. Additionally, any nitrogens in a heteroalicyclic may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such "heterocyclyl" or "heteroalicyclyl" groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1 ,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4- oxathiin, 1 ,3-oxathiolane, 1 ,3-dithiole, 1 ,3-dithiolane, 1 ,4-oxathiane, tetrahydro-l ,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazme, hydantoin, dihydrouracil, tnoxane, hexahydro-l,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine, piperazme, pyrrolidine, pyrrolidone, pyrrolidine, 4-piperidone, pyrazoime, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline and/or 3,4-methylenedioxyphenyl). Examples of bridged heterocyclic compounds include, but are not limited to, l,4-diazabicyclo[2.2.2]octane and 1 ,4- diazabicyclo[3.1.1]heptane. Examples of spiro-connected heterocyclic compounds include, but are not limited to, 2-azaspiro[3,3]heptane, 2,6-diazaspiro[3,3]heptane, and 2-oxa-6- azaspiro [3 , 3 ]heptane.

[0109] As used herein, "araikyl" and "aryl(alkyl)" refer to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkyiene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.

[0110] As used herein, "heteroaralkvl" and "heteroaryl(alkyl)" refer to a heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaralkvl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl and imidazolylalkyl and their benzo-fused analogs.

[0111] A "heteroalicyclyl(alkyl)" and "heterocyclyl(alkyl)" refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group. The lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-y] (ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl) and 1 ,3- thiazinan-4-y 1 (methyl) .

[0112] As used herein, "lower alkylene groups" are straight-chained -CH 2 - tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -) and butylene (-CH 2 CH 2 CH 2 CH 2 -). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group and/or b - substituting both hydrogens on the same carbon with a cycloalkyl group (e.g.,

[0113] As used herein, the term "hydroxy" refers to a -OH group.

[0114] As used herein, "aikoxy" refers to the Formula -OR wherein R is an alkyl, an aikenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An aikoxy may be substituted or unsubstituted.

[0115] As used herein, "acyl" refers to a hydrogen, alkyl, aikenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) and heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include forniyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted. [0116] A "cyano" group refers to a "-CN" group.

[0117] The term "halogen atom" or "halogen" as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.

[0118] A "thiocarbonyl" group refers to a "-C(=S)R" group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.

[0119] An "O-carbamyl" group refers to a "-OC(=0)N(R A R B )" group in which R A and R B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl (alkyl) or heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted.

[0120] An "N-carbamyl" group refers to an "ROC(=0)N(R A )-" group in which R and A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl (alkyl) or heterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted.

[0121] An "O-thiocarbamyl" group refers to a "-OC(=S)-N(RARB)" group in which R A and B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-thiocarbamyl may be substituted or unsubstituted.

[0122] An "N-thiocarbamyl" group refers to an "ROC(=S)N(R A )-" group in which R and A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(aikyl), aryl (alkyl), heteroaryl (alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or unsubstituted.

[0123] A "C-amido" group refers to a "-C(=0)N(R A R B )" group in which R A and R B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, eycloalkyi(alkyl), aryl(alkyl), heteroaryli alkyl) or heterocyclyl(alkyl). A C-amido may be substituted or unsubstituted.

[0124] An "N-amido" group refers to a "RC(=0)N(R A )-" group in which R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, eycloalkyi(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-amido may be substituted or unsubstituted.

[0125] An "S-sulfonaniido" group refers to a "-S0 2 N(R A ¾)" group in which R A and R B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyi, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(aikyl). An S-sulfonamido may be substituted or unsubstituted.

[0126] An "N-sulfonamido" group refers to a "RS0 2 N(R A )-" group in which R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyi, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyi), heteroaryl(alkyl) or heterocyclyl (alkyl). An N-sulfonamido may be substituted or unsubstituted.

[0127] An "O-carboxy" group refers to a "RC(=0)0-" group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyi, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. An O-carboxy may be substituted or unsubstituted.

[0128] The terms "ester" and "C-carboxy" refer to a "~C(=0)OR" group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted.

[0129] An "isocyanato" group refers to a "-NCO" group.

[0130] A "thiocyanato" group refers to a "-CNS" group.

[0131] An "isothiocyanato" group refers to an " -NCS" group.

[0132] A "nitro" group refers to an " -N0 2 " group.

[0133] A "suifenyi" group refers to an "-SR" group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyi, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cydoalkyl(alkyf), aryl(alkyl), heteroaryl(alkyf) or heterocyciylfalkyi). A suifenyi may be substituted or unsubstituted.

[0134] A "sulfinyl" group refers to an "-S(=0)-R" group in which R can be the same as defined with respect to suifenyi. A sulfinyl may be substituted or unsubstituted.

[0135] A "sulfonyl" group refers to an "S0 2 R" group in which R can be the same as defined with respect to suifenyi. A sulfonyl may be substituted or unsubstituted.

[0136] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haioaikyl, di-haloalkyi and tri- haioalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, l-chloro-2-fluoromethyl and 2-fluoroisobutyl. A haioalkyl may be substituted or unsubstituted.

[0137] As used herein, "haloalkoxy" refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difiuoromethoxy, trifluoromethoxy, l-chloro-2-fluoromethoxy and 2- fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

[0138] The term "ammo" as used herein refers to a -NH 2 group.

[0139] A "mono-substituted amino" group refers to a " -ΝΊ IK " group in which R can be an alkyl, an aikenyl, an alkynyi, a cycloaikyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl (alkyl), as defined herein. A mono-substituted ammo may be substituted or unsubstituted. Examples of mono- substituted amino groups include, but are not limited to, -NH(methyl), -NH(phenyl) and the like.

[0140] A "di~substituted ammo" group refers to a "-NR A R B " group in which R A and R B can be independently an alkyl, an aikenyl, an alkynyi, a cycloaikyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. A di-substituted ammo may be substituted or unsubstituted. Examples of di-substituted amino groups include, but are not limited to, -N(methyl) 2 , -N(phenyl)(methyl), -N(ethyl)(methyl) and the like.

[0141] Where the number of substituents is not specified (e.g. haioalkyl), there may be one or more substituents present. For example "haioalkyl" may include one or more of the same or different halogens. As another example, "C-.-Cj alkoxyphenyl" may include one or more of the same or different alkoxy groups containing one, two or three atoms.

[0142] As used herein, a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species. Hence, in this context, a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule. The term "radical" can be used interchangeably with the term "group." [0143] As used herein, when a chemical group or unit includes an asterisk (*), that asterisk indicates a point of attachment of the group or unit to another structure.

[0144] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3- dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, trifluoroaeetie, benzoic, salicylic, 2- oxopentanedioic, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, eyclohexylarmne, triethanol amine, ethylenediamine, and salts with amino acids such as arginine and lysine. For compounds of Formula (I), those skilled in the art understand that when a salt is formed by protonation of a nitrogen-based group (for example, NH 2 ), the nitrogen-based group can be associated with a positive charge (for example, NH 2 can become NH3 "1 and the positive charge can be balanced by a negatively charged counterion (such as CI " ).

[0145] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomericafly pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomencally enriched, or a stereoisomeric mixture. In addition, it is understood that in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, ail tautomeric forms are also intended to be included.

[0146] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).

[0147] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0148] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may ¬ be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0149] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments. [0150] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term 'including' should be read to mean 'including, without limitation,' 'including but not limited to,' or the like; the term 'comprising' as used herein is synonymous with 'including,' 'containing,' or 'characterized by,' and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term 'having' should be interpreted as 'having at least;' the term 'includes' should be interpreted as 'includes but is not limited to;' the term 'example' is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like 'preferably,' 'preferred,' 'desired,' or 'desirable,' and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term "comprising" is to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, the term "comprising" means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. Likewise, a group of items linked with the conjunction 'and' should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as 'and/or' unless the context indicates otherwise. Similarly, a group of items linked with the conjunction Or' should not be read as requiring mutual exclusivity among that group, but rather should be read as 'and/or' unless the context indicates otherwise.

[0151] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article "a" or "an" does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

Compounds

[0152] Some embodiments disclosed herein relate to compounds of the Formula (I), or pharmaceutically acceptable salts thereof.

Formula (I)

[0153] In various embodiments, the compounds of Formula (I) are useful for ameliorating, treating and/or diagnosing a fungal infection. Additional details regarding various uses and methods of treatment are described elsewhere herein.

[0154] In various embodiments the variable R 1 in Formula (I) is selected from the group consisting of ~R 3 , -C(0)R 4 , ~C(=X')NR 5A R 5b , and -S(0)2R 6 In some embodiments the variable R 1 in Formula (I) is selected from the group consisting of -R J , -C(0)R 4 , - C(=S)NR 5A R 5B , and -S(0) 2 R 6 For example, in some embodiments the variable R 1 in Formula (I) is -R or -C(0)R + . In various embodiments the variable R " in Formula (I) is selected from the group consisting of — NR 8A R 8B ; -(NR 9A R 9B R 9C ) + and - HC(0)R 10 . The variables R J , R 4 , R 5 i , R sb , R 6 , and X 1 in the description of the variable R 1 and the variables R 8A , R 8ci , R 9A , R 9B , R 9C and R l0 in the description of the variable R " are as described elsewhere herein. Examples of compounds of the Formula (I) thus include those having the general structures summarized in Table 1 . TABLE 1 : General structures of compounds of the Formula (I)

[0155] In various embodiments, the variable R 3 is selected from the group consisting of hydrogen, an unsubstituted C¾ .6 a iky I. a substituted C 1-6 alkyl, an optionally substituted C3..7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl. In an embodiment, the variable R 3 is not hydrogen. In an embodiment, R 3 is not an unsubstituted C 1-6 alkyl. In an embodiment R 3 is not a substituted Ci-e alkyl In an embodiment, R 3 is not an optionally- substituted C3-7 cycloalkyl. In an embodiment, R 3 is not an optionally substituted aryl. In an embodiment R 3 is not an optionally substituted heteroaryl. In an embodiment, 5 is not an optionally substituted monocyclic heterocyclyl.

[0156] In an embodiment, R 3 is selected from the group consisting of an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, and an optionally substituted C3-7 cycloalkyl. In an embodiment, R 3 is a substituted C 1 -6 alkyl that is substituted with a moiety selected from the group consisting of hydroxy, alkoxy, amino, C3-7 cycloalkyl, halogen, a mono- substituted amine, a di-substituted amine, an optionally substituted N-linked monocyclic heteroaryl, an optionally substituted aryl, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, and an optionally substituted N-linked monocyclic heterocyclyl. In an embodiment, R is a C 1-6 haloalkyl. In an embodiment, R is an optionally substituted C 3-7 cycloalkyl that is selected from the group consisting of optionally substituted cyclopropane, optionally substituted cyclobutane, optionally substituted bicyciobutane, optionally substituted eyeiopentane, optionally substituted bicvclopentane, and optionally substituted cyclohexane. In an embodiment, R 3 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.

[0157] Examples of include hydrogen, methyl, ethyl, benzyl, hydroxyethyl, aminoethyl, cyclopropyl, cyclobutyi, cyclopentyl, aminocyclopentyl, hydroxycyclopentyl, bicyclobutyl, bi cyclopentyl, hydroxymethyl bic clopentyl, amino bicyclopentyl, aminomethyl bicyclopentyl, imidazolyl, amino imidazolyl, phenyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.

[0158] In various embodiments, the variable R 4 is selected from, the group consisting of hydrogen, an unsubstituted C¾ .6 alkyl, a substituted C 1-6 alkyl, an optionally substituted C3..7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl. In an embodiment, R is not hydrogen. In an embodiment, R * is not an unsubstituted C 1-6 alkyl. In an embodiment, R 4 is not a substituted Ci-e alkyl. In an embodiment, R 4 is not an optionally substituted C 3-7 cycloalkyl. In an embodiment, R 4 is not an optionally substituted aryl. In an embodiment, R 4 is not an optionally substituted heteroaryl. In an embodiment, R " is not an optionally substituted monocyclic heterocyclyl.

[0159] In an embodiment, R 4 is selected from the group consisting of an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, and an optionally substituted C 3-7 cycloalkyl. In an embodiment, R 4 is a substituted C 1-6 alkyl that is substituted with a moiety selected from the group consisting of hydroxy, alkoxy, amino, C 3-7 cycloalkyl, halogen, a mono- substituted amine, a di-substituted amine, an optionally substituted N-linked monocyclic heteroaryl, an optionally substituted aryl, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, and an optionally substituted N-linked monocyclic heterocyclyl. In an embodiment, R 4 is a C 1-6 haloalkyl. In an embodiment, R 4 is an optionally substituted C -7 cycloalkyl that is selected from the group consisting of optionally substituted cyclopropane, optionally substituted cyclobutane, optionally substituted bicyclobutane, optionally substituted cyclopentane, optionally substituted bicyclopentane, and optionally substituted cyclohexane. In an embodiment, R * is selected from the group consisting of an optionally substituted aryi, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.

[0160] Examples of R 4 include methyl, ethyl, benzyl, hydroxyethyl, aminoethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminocyclopentyl, hydroxycyclopentyl, bicyclobutyl, bicyclopentyl, hydroxymethyl bicyciopentyl, amino bicyclopentyl, aminomethyl bicyclopentyl, imidazolyi, amino imidazolyl, phenyl, morpholinyl, piperazinyl, piperidmyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.

[0161] In various embodiments, the variable R 5A is selected from the group consisting of hydrogen, an unsubstituted C e alkyl, a substituted C 1-6 alkyl, an optionally substituted C 3-7 cycloalkyl, an optionally substituted aryi, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl. In an embodiment, R 5A is not hydrogen. In an embodiment, R 5A is not an unsubstituted C 1-6 alkyl. In an embodiment, R sA is not a substituted C 1-6 alkyl. In an embodiment, R ~ A is not an optionally substituted C3.7 cycloalkyl. In an embodiment, R " A is not an optionally substituted aryi. In an embodiment, R sA is not an optionally substituted heteroaryl. In an embodiment, R sA is not an optionally substituted monocyclic heterocyclyl.

[0162] In an embodiment, R 5 i is selected from the group consisting of an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, and an optionally substituted C 3-7 cycloalkyl. In an embodiment, R^ is a substituted C 1-6 alkyl that is substituted with a moiety selected from the group consisting of hydroxy, alkoxy, ammo, C 3-7 cycloalkyl, halogen, a mono- substituted amine, a di-substituted amine, an optionally substituted N-linked monocyclic heteroaryl, an optionally substituted aryi, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, and an optionally substituted N-linked monocyclic heterocyclyl. In an embodiment, R JA is a C 1-6 haloalkyl. In an embodiment, R 5A is an optionally substituted C 3-7 cycloalkyl that is selected from the group consisting of optionally substituted cyclopropane, optionally substituted cvclobutane, optionally substituted bicyclobutane, optionally substituted cyclopentane, optionally substituted bicyclopentane, and optionally substituted cyclohexane. In an embodiment, R 5A is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.

[0163] Examples of R 5A include methyl, ethyl, benzyl, hydroxyethyl, ammoethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminocyclopentyl, hydroxycyclopentyl, bicyclobutyl, bicyclopentyl, hydroxymethyl bicyciopentyl, amino bicyclopentyl, aminomethyl bicyclopentyl, imidazolyl, amino imidazolyl, phenyl, morpholinyl, piperazinyl, piperidmyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.

[0164] In various embodiments, the variable R " is selected from the group consisting of hydrogen, an unsubstituted C , alkyl, a substituted Ci„6 alkyi, an optionally substituted C 3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl In an embodiment, R 5B is not hydrogen. In an embodiment, R 5B is not an unsubstituted C 1-6 alkyl. In an embodiment R 5B is not a substituted Cj.e alkyl. In an embodiment, R 5B is not an optionally substituted C3.7 cycloalkyl. In an embodiment, R 5B is not an optionally substituted aryl. In an embodiment, R 5B is not an optionally substituted heteroaryl. In an embodiment, R sb is not an optionally substituted monocyclic heterocyclyl.

[0165] In an embodiment, R 5B is selected from the group consisting of an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, and an optionally substituted C 3-7 cycloalkyl. In an embodiment, R sb is a substituted C 1-6 alkyl that is substituted with a moiety selected from the group consisting of hydroxy, alkoxy, amino, C 3-7 cycloalkyl, halogen, a mono- substituted amine, a di-substituted amine, an optionally substituted N-linked monocyclic heteroaryl, an optionally substituted aryl, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, and an optionally substituted N-linked monocyclic heterocyclyl. In an embodiment, R 5B is a Cj-6 haloalkyl. In an embodiment, R 5B is an optionally substituted C 3- cycloalkyl that is selected from the group consisting of optionally substituted cyclopropane, optionally substituted cvclobutane, optionally substituted bicyclobutane, optionally substituted cyclopentane, optionally substituted bicyclopentane, and optionally substituted cyclohexane. In an embodiment, R 5B is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl. [0166] Examples of R " include methyl, ethyl, benzyl, hydroxyethyl, aminoethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminocyclopentyl, hydroxycyclopentyl, bicyclobutyl, bicyclopentyl, hydroxymethyl bicyclopentyl, amino bicyclopentyl, aminomethyl bicyclopentyl, imidazolyi, amino imidazolyl, phenyl, morpholinyl, piperazinyl, piperidmyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.

[0167] In other embodiments, R 5A and R 5B , together with the N to which they are attached, form an optionally substituted monocyclic heterocyclyl. Examples of such optionally substituted monocyclic heterocyciyls include pyrrolidinyl, imidazolidmyl, pyrazolidinyl, piperidinyi, morpholinyl, and piperazinyl. The formed monocyclic heterocyciyls may be optionally substituted by one or more groups selected from alkyl, halogen, amino, hydroxy, alkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, aryl, and heteroaryi.

[0168] In various embodiments, X 1 is O or S. Thus, in some embodiments R 1 is - C(=0)NR 5A R 5B In other embodiments, R 1 is -C(=S)NR 5A R 5B .

[0169] In various embodiments, the variable R b is selected from the group consisting of hydrogen, an unsubstituted C e alkyl, a substituted C 1-6 alkyl, an optionally substituted C 3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryi, and an optionally substituted monocyclic heterocyclyl. In an embodiment, R° is not hydrogen.

[0170] In an embodiment, R 6 is selected from the group consisting of an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, and an optionally substituted C 3-7 cycloalkyl. In an embodiment, R 6 is a substituted C 1-6 alkyl that is substituted with a moiety selected from the group consisting of hydroxy, alkoxy, ammo, C 3-7 cycloalkyl, halogen, a mono- substituted amine, a di-substituted amine, an optionally substituted N-linked monocyclic heteroaryi, an optionally substituted aryl, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryi, and an optionally substituted N-linked monocyclic heterocyclyl. In an embodiment, R° is a C 1-6 haloalkyl. In an embodiment, R 6 is an optionally substituted C 3-7 cycloalkyl that is selected from the group consisting of optionally substituted cyclopropane, optionally substituted cyclobutane, optionally substituted bicyclobutane, optionally substituted cyclopentane, optionally substituted bicvclopentane, and optionally substituted cyclohexane. In an embodiment, R 6 is selected from the group consisting of an optionally substituted aryi, an optionally substituted heteroaiyl, and an optionally substituted monocyclic heterocyclyl.

[0171] Examples of R 6 include methyl, ethyl, benzyl, hydroxyethvl, aminoethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminocyclopentyl, hydroxycyclopentyl, bicyelobutyl, bicyclopentyl, hydroxymethyl bicyciopentyl, amino bicyclopentyl, aminomethyl bicyclopentyl, imidazolyi, amino imidazolyl, phenyl, morpholinyl, piperazinyl, piperidmyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.

8 A.

[0172] In various embodiments, R " is selected from the group consisting of hydrogen, an optionally substituted Cj-6 alkyi, an optionally substituted C3.6 cycloalkyl, -(C 2-6 aikyl)-OR H , ~(C 2-6 alkyl)-NR l2A R l2B , -(C 2 . 6 alkyl)-(NR 13A R 13B R !3C ) + , and

. In an embodiment, R 8A is not hydrogen. In an embodiment, R 8A is not alkyl. In an embodiment, R 8A is not optionally substituted alkyl. In an embodiment, R 8A is methyl. In another embodiment, R SA is ethyl or aminoethyl, for example -(CH 2 ) 2 -NH 2 .

[0173] In various embodiments, R 8B is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C3-6 cycloalkyl, -(C 2-6 alkyl)-OR n , -(C 2-6 alkyl)-NR 12A R 12B , -(C 2 _ 6 alkyl)~(NR 13A R 13B R I3C ) + , and

. In an embodiment, R is not hydrogen. In an embodiment, R is not alkyl. In an embodiment, R ' is not optionally substituted alkyl. In an embodiment, R 1 is methyl. In another embodiment, R 8B is ethyl or aminoethyl, for example -(CH 2 ) 2 -NH 2 . In an embodiment, R 8A is hydrogen.

[0174] In various embodiments, R" is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C3-6 cycloalkyl, -(C 2-6 alkyl)-OR j j , -(C 2-6 alkyl)- R. 12A R 12B , ~(C 2 _ 6 alkyl)-(NR 13A R 13B R i3C ) + , and

. In an embodiment, R ' is not hydrogen. In an embodiment, R" is not alkyl. In an embodiment, R A is not optionally substituted alkyl. In an embodiment, R ' is methyl. In another embodiment, R 9A is ethyl or aminoethyl, for example -(CH 2 ) 2 ~NH 2 . [0175] In various embodiments, R 9B is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-6 cycloalkyl, -(C 2-6 alky! -OR ; ; . -(C 2 - 6 alkyl)-NR f 2A R f 2B , ~(C 2 . 6 aikyl)~(NR 13A R 13B R i3C ) + , and

-(C 2 .. 6

. In an embodiment, R 9B is not hydrogen. In an embodiment, R 9B is not alkyl. In an embodiment, R "" is not optionally substituted alkyl. In an embodiment, is methyl. In another embodiment, R 9B is ethyl or aminoethyl, for example -(CH 2 ) 2 -NH 2 .

[0176] In various embodiments, R 9C is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-6 cycloalkyl, -(C 2-6 alkyl )-OR ". ·-(( -, alkyl)-NR l2A R l2B , -(C 2 . 6 alkyl)-(NR 13A R 13B R 13C ) + , and

In an embodiment, R 9C is not hydrogen. In an embodiment, R 9C is not alkyl. In an embodiment, R l is not optionally substituted alkyl. In an embodiment, R " is methyl. In another embodiment, R 9C is ethyl or aminoethyl, for example -(CH 2 ) 2 -NH 2 .

[0177] In various embodiments, R 10 is selected from the group consisting of an optionally substituted C 1-6 alkyl, an optionally substituted C 3 - 6 cycloalkyl, -(C 2-6 aikyl)-OR H ,

~(C 2-6 alkyl)-NR 12A R 12B , -(C 2 _ 6 alkyl)-(NR 13A R 13B R 13C ) + , and . In an embodiment, R 1G is ethyl, methyl, propyl or butyl.

[0178] As discussed elsewhere herein, when R 8A , R 8B , R 9A , R 9B , R 9C and/or R 10 are positively charged, the positive charge can be balanced by association with a negatively- charged counterion (such as CI " ) to form a salt, which may be a pharmaceutically acceptable salt.

[0179] In various embodiments, R 11 , R 12A , R i2B , R i3A , R 13B and R 5 C are each independently selected from the group consisting of hydrogen and an unsubstituted C 1-6 alkyl. In some embodiments, one or more of R 11 , R ¾ A , R i2B , R 1 A , R ¾ 3B and/or R r3C are not hydrogen. In some embodiments, one or more of R ! ! , R l A , R |2B , ~ R i iA , R i B and/or R J jC are selected from the group consisting of ethyl, methyl, propyl and butyl.

[0180] In various embodiments, each n is independently zero or an integer in the range of 1 to about 40. In an embodiment, each n is independently zero or an integer in the range of 1 to about 10. For example, in an embodiment each n is independently zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0181] In some embodiments, when R 1 is -C(G)NR 5A R 5B , R 2 is -NH 2 and one or the other of R 3A and R 5B is H, then the other of R 5ft and R 3B is not -C¾. In some embodiments, when R 1 is -QC NR^R 36 , R 2 is -Nil?, and one or the other of R 5A and R 5B is H, then the other of R 5A and R 5B is not -O S -C ' HAl k In some embodiments, when R 1 is - C(0)NR 5A R 5B , R is -NH 2 and one or the other of R 5A and R 5B is H, then the other of R 5A and R 5B is not -CH 2 CH 2 C(0)OH. In an embodiment, when R 1 is ~C(0)NR 5A R 5B and R 2 is Ni k then -M R cannot be -N(H) -N(H)CH 2

-N(CH 2 CH 3 ) 2 , -N(CH(CH 3 ) 2 ) 2 , , or . In some embodiments, when R l is -C(0)NR 5A R 5B , then R 2 is selected from -NR 8A R 8B and - HC(O)R ¾0 .

1 4 2 %

[0182] In some embodiments, when R is -C(0)R and R is NH 2 , then R " is not an N-linked optionally substituted monocyclic heterocyclyl.

[0183] In some embodiments, when R is -C(0)R , then R " is not selected from substituents A, B, C, D, E, F, G, H, I or J, as follows;

[0184] For example, in some embodiments, when R l is -C(0)R 4 and R is Ni¾, then R 4 is not selected from substituents A, B, C, D, E, F, G, FI, I or J.

[0185] In some embodiments, when R ! is -C(0)R 4 and R 2 is NH 2 , then R 4 is not selected from the group consisting of methyl, ethyl, propyl, isopropyl, propenyl,

[0186] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is not a compound that is disclosed in any of the following publications: WO 201 6/168568, WO 201 5/190587, WO 2015/054148, and WO 2014/165676, each of which is incorporated herein by reference in its entirety and for the express purpose of describing particular compounds that are not, in various embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0187] The Examples and Figures of U.S. Serial No. 62/264,497, filed December 8, 2015, to which this application claims priority, describe a genus of the Formula (II), or a pharmaceutically acceptable salt thereof, wherein R 3A can be hydrogen or unsubstituted C 1 -3 alkyl; R 30 can be unsubstituted C 1 -3 alkyl (e.g., methyl); R 3 can be hydrogen or a protecting group; and R jD can be hydrogen or a protecting group. The disclosure of U.S. Serial No. 62/264,497 is hereby incorporated herein by reference, and particularly for the purpose of describing such a genus of the Formula (II), or a pharmaceutically acceptable salt thereof.

Formula (II)

[0188] The present disclosure describes various additional embodiments of Formula (II). In an embodiment, R 3A is hydrogen, an unsubstituted Cj-6 alkyl, a substituted Ci-6 alkyl, an optionally substituted C3-7 cycioalkyl, an optionally substituted CH 2 -aryl, an optionally substituted -CH 2 -heteroaryl, or an optionally substituted monocyclic heterocyclyl. In an embodiment, R A is a substituted C 1-6 alkyl that is substituted with a moiety selected from the group consisting of hydroxy, alkoxy, amino, C3-7 cycioalkyl, halogen, a mono- substituted amine, a di-substituted amine, an optionally substituted N-linked monocyclic heteroaryl, an optionally substituted aryl, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, and an optionally substituted N-lmked monocyclic heterocyclyl. In an embodiment, R A is hydrogen. In another embodiment, R 3A is methyl. In another embodiment, R 3A is ethyl or propyl. In another embodiment, R 3B is methyl. In another embodiment, R B is ethyl or propyl. In another embodiment, R 3C is hydrogen. In another embodiment, R jC is a protecting group. For example, R jC can be allyloxycarbonyl (Alloc), fluorenylmethyloxycarbonyl (Fmoc) or carboxybenzyl (Cbz). In an embodiment, R 3C is not a silyl protecting group. In another embodiment, R D is hydrogen. In another embodiment, R 3D is a protecting group. For example, R 3D can be allyloxycarbonyl (Alloc), fluorenylmethyloxycarbonyl (Fmoc), or carboxybenzyl (Cbz). In an embodiment, R jD is not a silyl protecting group. Those skilled in the art understand how to make and use a wide variety of protecting groups suitable for R jC and R 3D , including selecting suitable protecting groups from among those described in Kocienski, P.J. Protecting Groups (3 rd Ed., Theme, 2004), and/or Wuts, P. G. M. and Greene, T.W., Greene's Protective Groups in Organic Synthesis, (4 th Ed., Wiley, 2006), which are hereby incorporated herein by reference and particularly for the purpose of describing protective groups.

Methods of Making

[0189] Compounds of the Formula (I) or (II), or pharmaceutically acceptable salts thereof, can be made in various ways by those skilled using known techniques as guided by the detailed teachings provided herein. For example, in an embodiment, compounds of the Formula (I) are prepared in accordance with General Scheme 1 as shown in FIGURE 1A. The variables in General Scheme I are as described elsewhere herein with respect to the Formula (I). Examples of methods of making compounds of the Formula (I) are described in Examples 1-37 below, which are exemplar}' and can be used as a starting point to prepare a large number of additional compounds beyond those specifically described. Compounds of Formula (II) can also be prepared in accordance with the methods provided in General Scheme 1 and Examples 1 -37 below. For example, Figure 24C and Example 24 describe the preparation of compound 24- 1 , which is a compound of Formula (II) in which R J " is hydrogen, R jB is -CH 3 , and R jC and R 3D are both Alloc protecting groups. In addition, compounds of Formula (II) can be used as starting materials or intermediates to prepare other compounds. For example, in an embodiment, compounds of Formula (II) can be used to prepare compounds of Formula (I). For example. Figure 27C and Example 27 describe the preparation of compound 27, a compound of Formula (I) in which R f is -C(0)CH 3 and R 2 is -NH , using a process in which compound 24-1 is a starting material and compounds 27-1 and 27-2 are intermediates.

[0190] An embodiment provides an acylation process, comprising reacting a compound of Formula (II) with a carboxylic acid of formula R -C0 2 H under acylation conditions selected to form a compound of Formula (la), as illustrated in FIG. 38.

Formula (la)

[0191] In various embodiraents of the acylation process, R jA , R 3b , R 3C and R jD in Formula (II) and (la) are defined as described elsewhere herein for Formula (II). In various

4 4

embodiments, R in Formula (la) and in the formula R -C0 2 H are defined as described elsewhere herein for Formula (I). For example, in an embodiment of the acylation process, R 3A is hydrogen, R iB is an unsubstituted C-. -3 alkyi, R iC is a protecting group, R' 0 is a protecting group, and R 4 is selected from the group consisting of an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, an optionally substituted C3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl. Compound 27-1 is an example of a compound of the Formula (la).

[0192] In various embodiments, acylation conditions selected to form a compound of Formula (la) include conducting the reaction of the compound of Formula (II) with the carboxylic acid of formula 4 -C0 2 PI in the presence of an organic solvent suitable for acylation reactions, such as a polar organic solvent or a non-polar organic solvent. Such organic solvents are known to those skilled in the art, and include, for example, dichloromethane (DCM), tetrahydrofuran (THF), and dimethylformamide (DMF). In various embodiments, acylation conditions selected to form a compound of Formula (la) include conducting the reaction of the compound of Formula (II) with the carboxylic acid of formula R 4 -C0 2 H in the presence of an acylating agent that promotes acylation reactions. Such acylating agents are known to those skilled in the art and include, for example, 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridi nium 3- oxidhexafluorophosphate) (HATU), diisopropylcarbodiimide (DIG), dicyclohexylcarbodiimide (DCC), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide · HC1 (EDC · HC1), Ι, -Car bony ldiimidazole, benzotriazol-l-yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyBOP ¾ ), 7- Aza-benzotriazol- 1 -yloxy-tripyrrolidinophosphonium hexafluorophosphate (Py AOP), 2~( 1 H-Benzotriazol- 1 -yl)-N,N,N' ,Ν' - tetramethylaminium tetrafluoroborate (TBTU), 2-(l H-Benzotriazol- 1 -yl)-N,N,N',N'- tetramethylaminium hexafluorophosphate (HBTU), 2-Propanephosphonic acid anhydride (T3P), thionyl chloride, and oxalyi chloride. In various embodiments, acylation conditions selected to form a compound of Formula (la) include conducting the reaction of the compound of Formula (II) with the carboxylie acid of formula R 4 -C0 2 H in the presence of a base that promotes acylation reactions. Such bases are known to those skilled in the art. In an embodiment, the base is an inorganic base. Such inorganic bases are known to those skilled in the art and include, for example, Na 2 C0 3 , K 2 C0 3 , Li 2 C0 3 , Cs 2 C0 3 , KOtBu, K2HPO4, Na 2 HP04, Na 3 P0 4 , :!·'().:. NaOAc, KOAc, CsOAe, LiOAc, NaHCG 3 , KHC0 3 , CsHC0 3 and ! i! !( () . In an embodiment, the base is an organic base. Such organic bases are known to those skilled in the art and include, for example, triethylamine (TEA), pyridine, N,N- diisopropylethylamine (DIPEA), piperidine, morpholine, Proton Sponge™, 4- (Dimethylamino)pyridine, and 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).

[0193] An embodiment provides a reductive amination process, comprising reacting a compound of Formula (II) with an aldehyde of formula R 4 -COH under conditions selected to form a compound of Formuia (lb), as illustrated in FIG. 39.

Formula (lb)

[0194] In various embodiments of the reductive animation process, R , R , R and R ,D in Formula (II) and (lb) are defined as described elsewhere herein for Formula (II). In various embodiments, R 4 in Formula (lb) and in the formula R 4 -CQH are defined as described elsewhere herein for Formula (I). For example, in an embodiment of the reductive animation process, R ,A is hydrogen, R' B is an unsubstituted Cj_3 alkyl, R C is a protecting group, R ,D is a protecting group, and R 4 is selected from the group consisting of an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, an optionally substituted C3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.

[0195] In various embodiments, reductive amination conditions selected to form a compound of Formula (lb) include conducting the reaction of the compound of Formula (II) with the aldehyde of formula R 4 ~COH in the presence of a solvent suitable for reductive ammation reactions, such as a polar aprotic solvent. Such solvents are known to those skilled in the art, and include, for example, chloroform, ,2-dichloroethane (DCE), tetrahydrofuran (THF), N,N-dimethyiformamide (DMF), and acetonitrile. In various embodiments, reductive amination conditions selected to form a compound of Formula (lb) include conducting the reaction of the compound of Formula (II) with the aldehyde of formula R 4 -COH in the presence of a solvent suitable for reductive ammation reactions, such as a polar protic solvent. Such solvents are known to those skilled in the art, and include, for example, methanol (MeOH). In various embodiments, reductive amination conditions selected to form a compound of Formula (lb) include conducting the reaction of the compound of Formula (II) with the aldehyde of formula R 4 -COH in the presence of an acid that promotes reductive ammation reactions. Such acids are known to those skilled in the art and include, for example, acetic acid and hydrochloric acid. In various embodiments, reductive amination conditions selected to form a compound of Formula (lb) include conducting the reaction of the compound of Formula (II) with the aldehyde of formula R 4 -COH in the presence of a reducing agent that promotes reductive ammation reactions. Such reducing agents are known to those skilled in the art and include, for example, sodium borohydnde, sodium cyaiioborohydride, sodium triacetoxyborohydride, trietliylsilane, and phenyl silane. [0196] A compound of formula (lb) can also be prepared from a compound of Formula (II) via an alkylation process as illustrated in FIG. 40. For example, an embodiment provides an alkylation process, comprising reacting a compound of Formula (II) with a compound of formula R' t -CH 2 -X under conditions selected to form a compound of Formula (lb). In various embodiments, R' A , K iB , R 3C and R' D in Formula (II) and (lb) are defined as described elsewhere herein for Formula (II). In various embodiments, R 4 in Formula (lb) and in the formula R 4 -CH 2 -X are defined as described elsewhere herein for Formula (I). In various embodiments, X in the formula R 4 -CH 2 -X is a halide or pseudohalide. For example, in an embodiment of the alkylation process, X is a halide (such as chloride, bromide or iodide) or a pseudohalide (such as triflate, mesylate, tosylate, nitrophenyl sulfonate, bromophenyl sulfonate, benzene sulfonate or phosphate), R 3A is hydrogen, R 3B is an unsubstituted Ci- 3 alkyl, R 3C is a protecting group, R 3D is a protecting group, and R 4 is selected from the group consisting of an unsubstituted C 1-6 alkyl, a substituted C¾ .6 alkyl, an optionally substituted C 3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.

[0197] In various embodiments, alkylation conditions selected to form a compound of Formula (lb) include conducting the reaction of the compound of Formula (II) with the compound of formula R 4 -CH 2 -X in the presence of a solvent suitable for alkylation reactions, such as an organic solvent. Such solvents are known to those skilled in the art, and include, for example, N,N-dimethylformamide (DMF), N-methyl pyrrolidinone, tetrahydrofuran, methylene chloride, and 1,2-dichloroethane. In various embodiments, alkylation conditions selected to form a compound of Formula (lb) include conducting the reaction of the compound of Formula (II) with the compound of formula R 4 -CH 2 -X in the presence of a base that promotes alkylation reactions. Such bases are known to those skilled in the art. In an embodiment, the base is an inorganic base, for example, Na 2 C0 3 , K ··< ' ()-.. Li 2 C0 3 , Cs 2 C0 3 , KOtBu, K2HPO4, Na 2 HP0 4 , Na 3 P0 4 , K3PO4, NaOAc, OAc, CsOAc, LiOAc, NaHC€>3, HCO3, CsHC0 3 and i.il ICO-.. In an embodiment, the base is an organic base. Such organic bases are known to those skilled in the art and include, for example, triethylamine (TEA), pyridine, Ν,Ν-diisopropylethylamiiie (DIPEA), piperidine, morpholine, Proton Sponge™, 4~(Dimethylamino)pyridine, and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU). Uses and Methods of Treatment

[0198] As described herein, one or more compounds of Formula (I), (la), (lb) and/or (II), or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as described herein, can be used to inhibit the growth of a fungus. Growth of a fungus can be inhibited by contacting the fungus with an effective amount of at least one of the compounds described herein, or pharmaceutically acceptable salts thereof. Such contacting of the one or more compounds, or pharmaceutically acceptable salts thereof, can take place in various ways and locations, including without limitation away from a living subject (e.g., in a laboratory, diagnostic and/or analytical setting) or in proximity to a living subject (e.g., within or on an exterior portion of an animal, e.g., a human). For example, an embodiment provides a method of treating a fungal infection, comprising identifying a subject in need thereof and administering to said subject an effective amount of one or more compounds of Formula (I), (la), (lb) and/or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, as described elsewhere herein.

[0199] As described herein, compounds of Formula (I), (la), (lb) and/or (II), or a pharmaceutically acceptable salt thereof!, can be administered to such subjects by a variety of methods. In any of the methods described herein, administration can be by various routes known to those skilled in the art, including without limitation oral, intravenous, intramuscular, topical, systemic, and/or intraperitoneal administration to a subject in need thereof.

[0200] As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily mean total cure or abolition of the fungal infection. Any alleviation of any undesired signs or symptoms of the fungal infection, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject's overall feeling of well-being or appearance.

[0201] The terms "therapeutically effective amount" and "effective amount" are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, a therapeutically effective amount of compound can be the amount needed to prevent, alleviate or ameliorate symptoms of the fungal infection or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the fungal infection being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

[0202] The amount of the compound of Formula (I), (la), (lb) and/or (II), or a pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature and/or symptoms of the fungal infection being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges described herein in order to effectively and aggressively treat particularly aggressive fungal infections.

[0203] In general, however, a suitable dose will often be in the range of from about 0.05 mg/kg to about 10 mg/kg. For example, a suitable dose may be in the range from about 0.10 mg/kg to about 7.5 mg/kg of body weight per day, such as about 0.15 mg/kg to about 5.0 mg/kg of body weight of the recipient per day, about 0.2 mg/kg to 4.00 mg/kg of body weight of the recipient per day. The compound may be administered in unit dosage form; for example, containing 1 to 200 mg, 10 to 100 mg or 5 to 50 mg of active ingredient per unit dosage form.

[0204] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. [0205] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies and in vitro studies. For example, useful dosages of a compound of Formula (I), (la), (lb) and/or (II), or pharmaceutically acceptable salts thereof, can be determined by comparing their in vitro activity and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as Amphotericin B.

[0206] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and/or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0207] It should be noted that the attending physician would know how to and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the fungal infection to be treated and to the route of administration. The seventy of the fungal infection may, for example, be evaluated, in pari, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine. [0208] Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.

Pharmaceutical Compositions

[0209] Some embodiments described herein relate to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (e.g., a compound of Formula (I), (la), (lb) and/or (II), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0210] The term "pharmaceutical composition" refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanes ulfonic acid, ethanesulfomc acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.

[0211] The term "physiologically acceptable" defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound nor cause appreciable damage or injury to an animal to which delivery of the composition is intended. [0212] As used herein, a "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0213] As used herem, a "diluent" refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.

[0214] As used herein, an "excipient" refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A "diluent" is a type of excipient.

[0215] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0216] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0217] Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.

[0218] One may also administer the compound in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory infection may be desirable.

[0219] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

EXAMPLES

[0220] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.

COMPOUNDS

[0221] The compounds of Formula (1) and (II) illustrated in FIGURES 1-37 can be prepared in various ways, using techniques known to those skilled in the art as guided by the detailed teachings provided herein. For example, the compounds of Formula (I) illustrated in FIGURES 1-37 can be prepared in accordance with General Scheme 1 as described in Examples 1-37 below, winch are exemplary and can be used as a starting point to prepare a large number of additional compounds beyond those specifically described. Compounds of Formula (II) can also be prepared in accordance with the methods provided in General Scheme 1 and Examples 1-37 below. In addition, compounds of Formula (II) can be used as starting materials or intermediates to prepare other compounds. For example, in an embodiment, compounds of Formula (II) can be used to prepare compounds of Formula (la) and/or (lb), e.g., via a process that includes an acylation as illustrated in FIG. 38, a reductive animation as illustrated in FIG. 39, and/or an alkylation as illustrated in FIG. 40. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise routes based on the disclosures herein; all such modifications and alternate routes are contemplated.

EXAMPLE 1

[0222] Compound 1 (FIGURE IB) is prepared by Method I, Method 2, Method 3 and/or Method 4, as follows:

[0223] Method 1 (FIGURE 1C): Step 1 : A suspension of Amphotericin B (1 eq.) in DMF:MeOH(2: l ) is treated with pyridine (5 eq.) and Frnoc-Succ (1.5 equi .) at room temperature. After 3 h the reaction mixture is poured into Et 2 0 at 0 °C to precipitate out the product. The crude product is collected using a Buchner funnel, and is washed with additional Et 2 0. The crude product is dried under vacuum and then dissolved in a solution of THF:MeOH (1 : 1) at 0 °C. The solution is treated with CSA (0.5 eq.). After I h, the reaction is quenched at 0 °C with triethylamme (1 eq.) and filtered. The filtrate is concentrated and the desired product is crashed out using hexanes:Et 2 0 (1 : 1). Following filtration, the collected crude product is washed with EtOAc:Et 2 0 (1 : 1) to provide Int-1.

[0224] Step 2: A solution of Int-1 and 2,6-lutidine (25 eq.) in DCM at 0 °C is treated with a triethylsilyltrifiate (20 eq.) After the reaction is complete, the reaction is quenched with saturated aqueous sodium bicarbonate solution, and diluted with Et 2 0. The organic layer is washed with saturated aqueous sodium bicarbonate solution, and brine. The organic layer is then dried over sodium sulfate, filtered and concentrated under vacuum to provide the crude product. Purification by column chromatography provides Int-2. [0225] Step 3: A solution of Int-2 in THF is treated with triethylamine (1.1 eq. ) followed by diphenyl phosphoryl azide (3 eq.). The reaction is heated to 50 °C overnight and then treated with ethylamine (2.0M in THF, 8 eq.). After an additional 4 hours at 50 °C the reaction mixture is cooled to room temperature, concentrated under vacuum and purified by column chromatography to provide Int-3.

[0226] Step 4: A solution of Int-3 in THF:H 2 0 (9: 1) is treated with CSA (5 eq.) and stirred until completion, at which point the reaction is quenched with E N, and concentrated under vacuum to provide the crude product. The crude product is purified by RP-HPLC to provide Compound 1.

[0227] Method 2 (Figure ID): Compound 1 is synthesized as illustrated in FIGURE ID utilizing Int~l in a manner analogous to that described in Davis, S.A., et al. Nat. Chem. Biol. 2015, 11, 481-487,

[0228] Method 3 (Figure IE): Compound 1 is synthesized as illustrated in FIGURE IE in a manner analogous to that described in Davis, S.A, et al. Nat. Chem. Biol. 2015, 1 1 , 481-487, With respect to the structures illustrated in FIGURE IE, R and R" represent any suitable protecting group such as those described in Kocienski, PJ. Protecting Groups (3 rd Ed., Theme, 2004), and/or Wuts, P. G. M. and Greene, T.W., Greene's Protective Groups in Organic Synthesis, (4 th Ed., Wiley, 2006). For example, R' is depicted as l- butyloxycarbonyl (Boc) in FIGURE IE; other specific examples of amine protecting groups that can be represented by R' include trifluoroacetyl, fluorenylmethyloxycarbonyl (Fmoc) and carboxybenzyl (Cbz). The R" in FIGURE IE is depicted as ethyl; other specific examples of alcohol protecting groups that can be represented by R" include other optionally substituted C-.-io alkyl groups such as methyl, n-propyl, i -propyl. In an embodiment, such alcohol protecting groups are formed in a manner similar to that described in Step 1 of Method 1 using an optionally substituted C 1-10 alkyl alcohol.

[0229] Method 4 (Figure I F): Compound 1 is synthesized as illustrated in FIGURE I F in a manner analogous to that described in WO2015190587. With respect to the structures illustrated in FIGURE. I F, R' and R" represent any suitable protecting group such as those described in Kocienski, P.J. Protecting Groups (3 ui Ed., Theme, 2004), and/or Wuts, P. G. M. and Greene, T.W., Greene's Protective Groups in Organic Synthesis, (4 th Ed., Wiley, 2006). For example, R is depicted as allyioxycarbonyl (Alloc) in FIGURE. IF; other specific examples of amine protecting groups that can be represented by R' include trifluoroacetyl, fiuorenylmethyloxycarbonyl (Fmoc) and carboxybenzyl (Cbz). The R" in FIGURE IF is depicted as methyl: other specific examples of alcohol protecting groups that can be represented by R" include other optionally substituted d.jo alkyl groups such as ethyl, n-propyl, i-propyl. In an embodiment, such alcohol protecting groups are formed in a manner similar to that described in Step 1 of Method 1 using an optionally substituted C M O alkyl alcohol.

EXAMPLE 2

[0230] Compound 2 (FIGURE 2A) was prepared as follows (Figure 2B): Step 1 : To a stirred solution of Amphotericin B (25.0 g, 27.05 mmol) in DMF:MeOH (2: 1, 750 ml) and pyridine (25 ml, 308.4 mmol) was added alloc-succinimide (15.08 g, 75.75 mmol) at room temperature. After 16h, the reaction mixture was poured into cold Et 2 0. The resulting solid was filtered and dried under reduced pressure to provide a yellow solid. The solid compound was washed with diethyl ether (5 x 100 niL) to afford compound 2-1 as a yellow solid. Compound 2-1 analysis: LC/MS (ESI) m/z 1006.4 [M-H]/

[0231] Step 2; To a solution of compound 2-1 (4,0 g, 3.97 mmol) in a mixture of THF:MeOH (1 : 1 160 raL) was added camphor sulfonic acid (553.3 mg, 2.38 mmol) at 0 °C. The reaction mixture was stirred for 45 min and then quenched with triethylamine (0.335 ml, 2,38 mmol) at 0 °C. The reaction was filtered and the filtrate was concentrated to roughly half the starting volume and resulting solution was poured into cold diethyl ether to afford a yellow precipitate. The solid was filtered to afford compound 2-2 as a yellow solid. LC/MS (ESI): m/z 1020.7 [M-H] " .

[0232] Step 3: To a solution of compound 2-2 (20.0 g, 19.56 mmol) in DMF (220 ml) was added DIPEA (6.9 ml, 39.1 mmol ) at room temperature. The reaction mixture was cooled to 0 °C and all loxycarbonyl chloride (2.36 g, 19.56 mmol) was added slowly drop- wise at 0 °C. The reaction mixture was maintained at an internal temperature below 4 °C and stirred for 3 h at 0 °C. The reaction mixture was then allowed to warm to room temperature and stirring was continued for 16 h. The reaction mixture was poured into cold Et 2 0 (5 L) and the precipitate was filtered to afford 14 g (64.5%) of crude compound 2-3 as a yellow solid. LC/MS (ESI): m/z 1104.7 [M-H] " . [0233] Step 4: To a solution of compound 2-3 (1.0 g, 0.90 mmol) in DMF (10 ml), was added DIPEA (0.95 ml, 1.37 mmol) followed by DPP A (0.29 ml, 1.37 mmol) at 0 °C. The reaction mixture was stirred at 50 °C for 2 h and then cooled to room temperature. Bicyclo[l. l. l]pentan-l-amine hydrochloride (216 mg, 1.81 mmol) and DIPEA (0.32 ml, 1.81 mmol) were added sequentially and the reaction was stirred at room temperature . After 2 h the reaction mixture was poured into cold diethyl ether (100 mi) to afford a solid compound which was filtered to afford compound 2-4 as a brown solid. LC/MS (ESI): m z 1230.6 [M+HC0 2 H-H]\

[0234] Step 5: To a stirred solution of compound 2-4 (600 mg, 0.505 mmol) in DMF (5.0 ml) was added morpholine (0.87 ml, 10.12 mmol) followed by Pd(PPh 3 ) 4 (1 16.9 mg, 0.1 mmol) at room temperature. After 2 h, the reaction mixture was diluted with Et 2 0, to give a yellow solid. The crude product was filtered and dried under reduced pressure to afford compound 2-5 as a brown solid. LC/MS (ESI): m/z 1062.6 [M+HC0 2 H-H] " .

[0235] Step 6: To a stirred solution of compound 2-5 (450 mg, 0.44 mmol) in ACN:¾0 (1 : 1, 10 ml) was added camphor sulphonic acid (20.53 mg, 0.09 mmol) at 0 °C. The reaction mixture was warmed to rt and stirred for 1 h and then was directly lyophilized to provide crude compound 2. The crude product was purified by HPLC (CI 8, 5μ, 40:60 to 10:90 lOmM NH 4 CO 3 H (aq): (CH3CN:MeOH(l : l))) to afford compound 2 as a yellow solid. LC/MS (ESI): m/z 1026,4 [M+Na] + .

EXAMPLE 3

[0236] Compound 3 (FIGURE 3) is prepared using Method 1 described in Example 1 using (3-aminobicyclo[l . l. l ]pentan-l-yl)methanol in place of ethylamine.

EXAMPLE 4

[0237] Compound 4 (FIGURE 4) is prepared using Method 1 described in Example 1 using bicyclo[l . l. l ]pentane-l,3-diamine in place of ethylamine.

EXAMPLE 5

[0238] Compound 5 (FIGURE 5) was prepared using Method 2 described in Example 1 as follows: Step 1 : A suspension of Amphotericin B (15.0g, 16.23 mmol)) in 2: 1 DMF:MeOH(707 nil) was treated with pyridine (8.0 inL, 93.33 mmol.) and Fmoc-Succ (8.2 g, 24.35 mmol) at room temperature. After 3 h the reaction mixture was poured into Et?Q at 0 °C and stirred for 30 min to precipitate out the product. The crude product was collected and washed with additional and dried in vacuo. The crude product was dissolved in THF:MeOH (1 : 1, 360 mL) at O °C. The solution was then treated with CSA (1.6 g, 6.81 mmol). After 1 h, the reaction was quenched at 0 °C with triethylamine (870 u.L, 6.81 mmol) and filtered. The filtrate was concentrated to half the starting volume poured into a solution of hexanes:Et 2 0 (1 : 1, 5L). The resulting crashed out solid was collected to provide compound 5-1 (8.0g, 43%) as a yellow solid. LC/ S (ESI) m/z 1058.5 [M-H] " .

[0239] Step 2: A solution of compound 5-1 (2.0 g, 1.72 mmol) in THF (80 mL) was treated with triethylamine (0.24 mL, 1.72 mmol) followed by diphenyl phosphoryl azide (1.2 mL, 5.17 mmol) and heated to 50 °C. After 16 h the reaction was treated ethanoianime (0.83 mL, 13.79 mmol). After an additional 8 h at 50 °C, the reaction was poured into Et 2 0 (2.0 L) and the resulting yellow solid was isolated through filtration. The crude product was purified by HPLC to afford compound 5 (200 mg, 12%) as a light yellow colored solid. LC/MS (ESI) m/z 982.5 ! M - H )

EXAMPLE 6

[0240] Compound 6 (FIGURE 6) is prepared using Method 1 described in Example 1 using tert-butyl ((3-aminobicyclo[l . l. l]pentan-l-yl)methyl)carbamate in place of ethylamine.

EXAMPLE 7

[0241] Compound 7 (FIGURE, 7) is prepared using Method 1 described in Example 1 using cis-l ,3-diaminocyclopentane in place of ethylamine.

EXAMPLE 8

[0242] Compound 8 (FIGURE 8) is prepared using Method 1 described in Example 1 using trans- 1 ,3-diaminocyclopentane in place of ethylamine.

EXAMPLE 9 [0243] Compound 9 (FIGURE 9) is prepared usmg Method 1 described in Example 1 using 3-aminocyclopentanol in place of ethyiamme.

EXAMPLE 10

[0244] Compound 10 (FIGURE 10) is prepared using Method 1 described in Example 1 using 4-(aminomethyl)-lH-imidazol-2-amine in place of ethylamine.

EXAMPLE 11

[0245] Compound 11 (FIGURE 11) was prepared in a manner similar to

Compound 5 (Example 5) using oxetan-3 -amine in place of ethanolamine. Compound 11 analysis: MS m/z 994.6 [M+H] +

EXAMPLE 12

[0246] Compound 12 (FIGURE 12) is prepared using Method 1 described in Example 1 using 3-aminotetrahydrofuran in place of ethylamine.

EXAMPLE 13

[0247] Compound 13 (FIGURE 13) was prepared in a manner similar to Compound 5 (Example 5) using 4-aminotetrahydropyran in place of ethanolamine. Compound 13 analysis; LC/MS m/z 1022.7 [M+H] +

EXAMPLE 14

[0248] Compound 14 (FIGURE 14) is prepared using Method 1 described in Example 1 using 1 -Boc-4-aminopipef dine in place of ethylamine.

EXAMPLE 15

[0249] Compound 15 (FIGURE 15) is prepared using Method 1 described in Example 1 using l-BOC-3-aminopyrrolidine in place of ethylamine.

EXAMPLE 16 [0250] Compound 16 (FIGURE 16) was prepared in a manner similar to Compound 5 (Example 5) using piperazine in place of ethanolamine. Compound 16 analysis: MS m/z 1007.6 | M ! ! j

EXAMPLE 17

[0251] Compound 17 (FIGURE 17) was prepared in a manner similar to Compound 5 (Example 5) using morpholine in place of ethanolamine. Compound 17 analysis: MS m/z 1008.7 ! M - ! I ]

EXAMPLE 18

[0252] Compound IS (FIGURE 18A) is prepared as follows (see FIGURE 18B):

[0253] Step 1 : A solution of Amphotericin B in DMF and N-(9- fluorenylmethoxycarbonyl)-3-aminopropanal (3 eq.) is treated with NaBEUCN (3 eq.) followed by a drop of concentrated HC1 and stirred until completion at which point amberlite IRA-743 resin is added and stirred for 1 hour. The resin is filtered, and the reaction mixture is concentrated under vacuum and then diluted with Et 2 0. The resulting crude product is filtered off and purified by column chromatography to provide Int-7.

[0254] Step 2: A solution of Int-7 and imidazole (25 eq.) in DCM at 0 °C is treated with a solution of chlorotriethylsilane in THF (1 M, 20 eq.) After 1 .5 h the reaction is quenched with saturated aqueous sodium bicarbonate solution, and diluted with Et 2 0. The organic layer is washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer is then dried over sodium sulfate, filtered and concentrated under vacuum to provide the crude product. Purification by column chromatography provides Int-8.

[0255] Step 3: A solution of Int-8 in THF is treated with triethylamine (1.1 eq.) followed by diphenyl phosphoryl azide (3 eq.). The reaction is heated to 50 °C overnight and then treated with ethylamine. After the reaction is complete, the mixture is cooled to room temperature, concentrated under vacuum and purified by column chromatography to provide Int-9.

[0256] Step 4: A solution of Iot-9 in THF:H 2 0 (9: 1 ) is treated with CSA (5 eq.) and stirred until completion, at which point the reaction is quenched with Et-jN, and concentrated under vacuum to provide the crude product. The crude product is purified by HPLC to provide Compound 18.

EXAMPLE 19

[0257] Compound 19 (FIGURE 19) is prepared using the procedure described in Example 18 using bicyclo[l. l. l]pentan-l-amine hydrochloride in place of ethylamine.

EXAMPLE 20

[0258] Compound 20 (FIGURE 20 A) is prepared as follows (see FIGURE 20B): A solution of Compound 1 in DMSO is treated with solid NaHCO ? followed by Mel The reaction is heated to 40 °C until complete and purified by RP-HPLC to provide Compound

EXAMPLE 21

[0259] Compound 21 (FIGURE 21) is prepared using the procedure described in Example 20 using Compound 2 in place of Compound 1.

EXAMPLE 22

[0260] Compound 22 (FIGURE 22A) is prepared as follows (see FIGURE 22B); A solution of Compound 1 in DMSO is treated with solid NaHC0 3 followed by Mel (1 eq.). The reaction is stirred at room temperature until complete and purified by RP-HPLC to provide Compound 22.

EXAMPLE 23

[0261] Compound 23 (FIGURE 23) is prepared using the procedure described in Example 22 using Compound 2 in place of Compound 1.

EXAMPLE 24

[0262] Compound 24 (FIGURE 24A) can be prepared using Method 1, Method 2 and/or Method 3 : [0263] Method 1 (FIGURE 24B): Step 1 : A solution of Int-2 in THE is treated with triethylamine (1.1 eq.) followed by diphenyl phosphoryl azide (3 eq.). The reaction is heated to 50 °C overnight and then treated with H 2 0 (3 eq.) and heated to 70 °C. After the reaction is complete, the reaction mixture is cooled to room temperature, concentrated under vacuum and purified by column chromatography to provide let- 10.

[0264] Step 2: A solution of Lit- 10 in CH 2 C1 2 is treated with triethylamine followed by ethyl iodide (1 eq.). After the reaction is complete, the reaction mixture is concentrated under vacuum and purified by column chromatography to provide Lit- 11.

[0265] Step 3: A solution of Int-8 in THF:H 2 0 (9: 1) is treated with CSA (5 eq.) and stirred until completion, at which point the reaction is quenched with EtiN, and concentrated under vacuum to provide the crude product. The crude product is purified by RP-HPLC to provide Int-12.

[0266] Step 4: A solution of Int-12 in DMSO is treated with piperidine (2 eq.) Upon completion, the reaction is purified by HPLC to provide Compound 24.

[0267] Method 2 (FIGURE 24C) Step 1 : To a solution of compound 2-3 (5.0 g, 0.90 mmol) in DMA (92 ml), was added 3A molecular sieves (500 mg), DIPEA (1.20 ml, 6.89 mmol) followed by DPPA (1.28 ml, 5.97 mmol) at room temperature. The reaction mixture for 2 h and then heated to 50 °C. After 2 h the reaction mixture was cooled to room temperature poured into a solution of Et 2 0:hexanes (7: 1, 1 .60 L). The reaction mixture was filtered over Celite® 545 and the collected solid was washed with Et 2 0:hexanes (7: 1 , 200 mL). The crude isocyanate was then dissolved in THF (200 ml.) and then concentrated to approximately 60 mL. The crude isocyanate solution was then added dropwise to a rapidly stirring solution of triethylamine (32.0 mL, 230.0 mmol) in THF:H 2 0 (1 : 1, 120mL) over 20 min. The reaction was stirred for an additional 30 minutes at rt at which point the reaction was concentrated in vacuo using C¾CN to aid in the removal of water from the reaction mixture. The crude product was purified by HPLC to afford compound 24-1 as a yellow solid. LC/MS (ESI) m/z 1099.3 [M+Na] + .

[0268] Step 2: A solution of acetaldehyde (1.2 eq) and 24-1 in DMF:MeOH (1 : 1) is stirred at room temperature for 3 hours and then treated with NaB¾CN (3 eq.). The reaction mixture is stirred overnight and then poured into Et 2 0 and filtered over Celite® 545. The collected solid is then dissolved in THF MeOH and concentrated in vacuo to provide crude compound 24-2.

[0269] Step 3: A solution of compound 24-2 in 2:2: 1 CH 3 CN:THF:H 2 0 is cooled to 0 °C and treated with CSA (1 eq.). The reaction is warmed to 35 °C and stirred for 50 min at which time triethylamme (2.1 eq.) is added. The reaction is concentrated in vacuo and the crude product is purified by HPLC to provide Compound 24-3.

[0270] Step 4: To a solution of compound 24-3 in DMF is treated with Pd(PPh 3 ) 4 (0.1 eq.) followed by morpholine (25 eq.). The reaction is stirred for 16 h and then poured into Et 2 0 and filtered over Ceiite® 545. The collected solid is washed with Et 2 0, dissolved in THF/MeOH, and concentrated in vacuo to provide crude compound 24. The crude product is purified by HPLC to afford Compound 24.

[0271] Method 3 (FIGURE 24D) Step 1 : A solution of compound 24-1 in DMF is treated with triethylamme followed by ethyl iodide (1 eq.). After the reaction is complete, the reaction mixture is concentrated under vacuum and purified by column chromatography to provide Compound 24-2.

[0272] Step 2: A solution of compound 24-2 in 2:2: 1 O i -.C V Π IF: ! ! O is cooled to 0 °C and treated with CSA (1 eq.). The reaction is warmed to 35 °C and stirred for 50 min at which time triethylamine (2.1 eq.) is added. The reaction is concentrated in vacuo and the crude product is purified by HPLC to provide Compound 24-3.

[0273] Step 3: To a solution of compound 24-3 in DMF is treated with Ρά(ΡΡη 3 ) 4 (0.1 eq.) followed by morpholine (25 eq.). The reaction is stirred for 16 h and then poured into Et 2 0 and filtered over Ceiite® 545. The collected solid is washed with Et 2 0, dissolved in THF/MeOH, and concentrated in vacuo to provide crude compound 24. The crude product is purified by HPLC to afford Compound 24.

EXAMPLE 25

[0274] Compound 25 (FIGURE 25) is prepared using the procedures described in Example 24 using bromoethanol in place of ethyl iodide.

EXAMPLE 26

[0275] Compound 26 (FIGURE 26 A) is prepared as follows (see FIGURE 26B): [0276] Step 1 : A solution of Iiit-10 and dihydrofuran-3(2H)-one in CH 2 C1 2 is treated with sodium acetate followed by a NaBH(OAc) 3 and stirred until completion and the reaction is quenched with sat. aqueous NaHC0 3 . The aqueous phase is extracted with CH 2 C1 2 and the combined organic phases are dried over Na 2 S0 4 , filtered and concentrated under vacuum to provide crude product. The crude product is subjected to column chromatography to provide Int-13.

[0277] Step 2: A solution of Int-13 in THF:H 2 0 (9: 1) is treated with CSA (5 eq.) and stirred until completion, at which point the reaction is quenched with Et 3 N, and concentrated under vacuum to provide the crude product. The crude product is purified by RP-HPLC to provide Int-14.

[0278] Step 3: A solution of Int-14 in DMSO is treated with pipendine (2 eq.) Upon completion, the reaction is purified by RP-HPLC to provide Compound 26.

EXAMPLE 27

[0279] Compound 27 (FIGURE 27 A) can be prepared using Method 1 and/or Method 2:

[0280] Method 1 (Figure 27B), Step 1 : A solution of Lit- 10 m CH 2 C1 2 is treated with triethylamine followed by acetyl chloride (1.2 eq.). After the reaction is complete, the reaction mixture is concentrated under vacuum and purified by column chromatography to provide Int-15.

[0281] Step 2; A solution of Int-15 in THF:H 2 0 (9: 1) is treated with CSA (5 eq.) and stirred until completion, at which point the reaction is quenched with Et 3 N, and concentrated under vacuum to provide the crude product. The crude product is purified by RP-HPLC to provide Int-16.

[0282] Step 3: A solution of Int-16 in DMSO is treated with pipendine (2 eq.) Upon completion, the reaction is purified by HPLC to provide Compound 27.

[0283] Compound 27 (FIGURE 27 A) was prepared as follows: Method 2 (Figure 27C) Step 1 : To a stirred solution of acetic acid (12.8 JJL, 0.22 mmol) in DMF (4 mL) was added N, N- diisopropylethylamine (117 uL, 0.67 mmol), HATU (85.0 mg, 0.22 mmol) at rt. After 90 min, the reaction mixture was cooled to 0 °C and treated with a solution of Compound 24-1 in DMF (1 mL). The reaction was warmed to rt and stirred overnight. The mixture was then poured into Et 2 0 (100 mL) and filtered over Celite® 545. The collected solid was washed with Et 2 0 and then dissolved in THF MeOH and concentrated in vacuo to provide crude compound 27-1. LC MS (ESI) m/z 1141.5 [M+Naf.

[0284] Step 2: To a solution of compound 27-1 (35 mg, 31 μτηοΐ) in 2:2: 1 CH 3 CN:THF:H 2 0 (1.56 mL) at 0 °C was added CSA (7.7 mg, 31 μτηοΐ). The reaction was warmed to 35 °C and stirred for 50 min at which time triethylamine (8.8 LIL, 63 μιηοΐ) was added. The reaction was concentrated in vacuo and the crude product was purified by RP- HPLC to provide Compound 27-2 as a yellow solid. LC MS (ESI) m/z 1127.5 i .M · Na | .

[0285] Step 3: To a solution of compound 27-2 (7.0 mg, 6.6 μηιοΐ) in DMF (2 mL) was added Pd(PPh 3 ) 4 (2.7 mg, 2.3 μηιοΐ) followed by morpholine (17.3 μΕ, 0.19 mmol). The reaction was stirred for 16 h and then poured into Et 2 0 (10 mL) and filtered over Celite® 545. The collected solid was washed with hbO. dissolved in THF/MeOH, and concentrated in vacuo to provide crude Compound 27. The crude product was purified by HPLC to afford Compound 27 as a yellow solid. LC/MS (ESI) m/z 959.5 [M+Naf.

EXAMPLE 28

[0286] Compound 28 (FIGURE 28) is prepared using the procedure described in Example 27 using 2-Oxetanone in place of acetyl chloride.

EXAMPLE 29

[0287] Compound 29 (FIGURE 29) is prepared using the procedure described in Example 27 using 9H-Fluoren-9-ylmethyl (3-chloro-3-oxopropyl)carbamate in place of acetyl chloride.

EXAMPLE 30

[0288] Compound 30 (FIGURE 30) was prepared using Method 2 described in Example 27 using bicyclo[ 1.1.1 jpentane- 1 -carboxyiic acid in place of acetic acid. Compound 30 analysis: LC MS (ESI) m/z 1011.5 [M+Naf.

EXAMPLE 31

Compound 31 (FIGURE 31 A) is prepared as follows (see FIGURE [0290] Step 1 : A solution of Int-10 in CH 2 C1 2 is treated with triethylamine followed by ethyl isothiocyanate (1.2 eq.). After the reaction is complete, the reaction mixture is concentrated under vacuum and purified by column chromatography to provide Int-17.

[0291] Step 2: A solution of Int-17 in THF:H 2 0 (9: 1) is treated with CSA (5 eq.) and stirred until completion, at which point the reaction is quenched with Et-jN, and concentrated under vacuum to provide the crude product. The crude product is purified by RP-HPLC to provide Int-18.

[0292] Step 3: A solution of Int-18 in DMSO is treated with piperidine (2 eq.) Upon completion, the reaction is purified by HPLC to provide Compound 31.

EXAMPLE 32

[0293] Compound 32 (FIGURE 32) is prepared using the procedure described in Example 31 using 2-isothiocyanatoethan-l-ol in place of ethyl isothiocyanate.

EXAMPLE 33

[0294] Compound 33 (FIGURE 33) is prepared using the procedure described in Example 31 using Fmoc-NH(CH 2 ) 2 -NCS in place of ethyl isothiocyanate.

EXAMPLE 34

[0295] Compound 34 (FIGURE 34) is prepared using the procedure described in Example 31 using isothiocyanatocyciobutane in place of ethyl isothiocyanate.

EXAMPLE 35

[0296] Compound 35 (FIGURE. 35A) is prepared as follows (see FIGURE 35B):

[0297] Step 1 : A solution of Int-10 in CH 2 C1 2 is treated with triethylamine followed by methane sulfonyl chloride (1.2 eq. ). After the reaction is complete, the reaction mixture is concentrated under vacuum and purified by column chromatography to provide int-19.

[0298] Step 2: A solution of Int-19 in THF:H 2 0 (9: 1) is treated with CSA (5 eq.) and stirred until completion, at which point the reaction is quenched with Et-jN, and concentrated under vacuum to provide the crude product. The crude product is purified by RP-HPLC to provide lnt-20.

[0299] Step 3: A solution of Isit~20 in DMSO is treated with piperidine (2 eq.) Upon completion, the reaction is purified by HPLC to provide Compound 35.

EXAMPLE 36

[0300] Compound 36 (FIGURE 36) is prepared using the procedure described in Example 35 using benzenesulfonyl chloride in place of methanesulfonyl chloride.

EXAMPLE 37

[0301] Compound 37 (FIGURE 37) was prepared in a method similar to Compound 2 (Example 2) using bicycio[ 1. 1.1 ]pentan- 1 -ylmethanamine in place of ethylamme. LC/MS (ESI) m/z 0 8.59 [M+Hf.

IN VITRO MIC ASSAY

[0302] The broth microdilution assay method essentially followed the procedure described by CLSI (1 -3) and employed automated liquid handlers to conduct serial dilutions and liquid transfers. Automated liquid handlers included the Multidrop 384 (Labsystems, Helsinki, Finland) and Biomek 2000 (Beekman Coulter, Fullerton CA). The wells in columns 2-12 in standard 96-well microdilution plates (Costar 3795) were filled with 150 μΐ of the correct diluent. These would become the 'mother plates' from which 'daughter' or test plates would be prepared. The drugs (300 μ,Ε at 4Qx the desired top concentration in the test plates) were dispensed into the appropriate well in Column 1 of the mother plates. The Biomek 2000 was used to make serial two-fold dilutions through Column 11 in the "mother plate". The wells of Column 12 contained no drug and were the organism growth control wells.

[0303] The daughter plates were loaded with 185 i per well of the appropriate test media using the Multidrop 384. The daughter plates were prepared using the Biomek FX which transferred 5 \iL of drug solution from each well of a mother plate to the corresponding well of the correct daughter plate in a single step.

[0304] A standardized inoculum of each organism was prepared per CLSI methods (1-3). For yeast isolates, colonies were picked from the primaiy plate and a suspension was prepared to equal a 0.5 McFarland turbidity standard. Suspensions were then diluted 1 : 100 in RPML 1640 medium, resulting in a final inoculum concentration of 0.5-2.5 x 103 CFU/mL per test well. For the fungal isolates, spore suspensions previously prepared in 0.85% saline and enumerated were diluted to achieve a final inoculum concentration of 0.2 - 2.5 x 104 CFU/mL per test well. Standardized inoculum suspensions were transferred to compartments of sterile reservoirs divided by length (Beckman Coulter), and the Biomek 2000 was used to inoculate all plates. Daughter plates were placed on the Biomek 2000 in reverse orientation so that plates were inoculated from low to high drug concentration. The Biomek 2000 delivered 10 uL of standardized inoculum into each well of the appropriate daughter plate for an additional 1 :20 dilution. Thus, the wells of the daughter plates ultimately contained 185 μΐ, of the appropriate media, 5 μΕ of drug solution, and 10 of inoculum. The final concentration of DMSO (if used as a solvent) in the test well was 2.5%.

[0305] Plates were stacked 3 high, covered with a lid on the top plate, placed into plastic bags, and incubated at 35°C for approximately 24-48 hr for all yeast isolates excluding C. neofor ans (72 hr), and 48 hr for all fungal isolates excluding R. oryzae (24 hr) and T. rubrum (120 hr). Plates were viewed from the bottom using a plate viewer. An un-inoculated solubilit' control plate was observed for evidence of drug precipitation. MICs were read where visible growth of the organism was inhibited. MECs were read where evident for Aspergillus spp. where the growth shifted to a small, rounded, compact hyphal form as compared to the hyphal growth seen in the growth control well.

[0306] Results for Compounds 2, 5, 11, 13, 16, 17 and 37 are provided in Tables

2 and 3.

TABLE 2. IN VITRO ACTIVITY AGAINST YEAST

MIC reported at 24 hr, 48 hr CLSI QC range shown in parenthesis ' MIC reported at 48 hr, 72 hr

1 MIC MEC observed at 24 hr, 48 hr CLSI QC range shown in parenthesis MIC read at 24 hr

MIC read at 120 hr

3 MIC read at 6 days

Not Tested RED BLOOD CELL LYSIS ASSAY

[0307] Red blood cell (RBC) preparation: Packed defibrinated human red blood cells (Lampire Biological Laboratories, Pipersville, PA; Cat. No. 7243710; Unit No. LS 23- 80223D) were washed three times with buffer (10 mM Tris-HCl [pH 7.4], 0.9% NaCi) and resuspended to a final concentration of 3% RBCs prior to conducting the assays.

[0308] DMSO Pilot assay: Testing the compounds at high concentrations (up to 100 μΜ) required a final DMSO concentration of 4% in the RBC lysis assay. A pilot study was conducted to measure hemolysis in the presence of different DMSO concentrations as follows:

[0309] In general, the method described in Stasiuk, M. et al. Biochim. Biophys. Acta. 2004, 1667:215-221 was followed for the RBC lysis assay, DMSO was diluted in water to 75%, 50%, and 25% concentrations. Microfuge tubes were set up in triplicate with the volumes indicated above. Buffer (10 mM Tris-HCl (pH 7.4), 0.9% NaCl) was added to the tubes followed by the DMSO. Tubes were gently inverted 5 times. Ninety microliters of the 3% RBC preparation was added and gently inverted 5 times. The tubes were incubated for 30 min at 37°C, and centrifuged at 1 ,300 x g for 5 min to pellet the RBCs. Three hundred microliters of the supernatant were removed to a 96- well plate (Corning; Corning, NY; Cat. 3595; Lot No. 041 1 5045) and the released hemoglobin was measured at A540 using a SpectraMax (Molecular Dynamics) plate reader.

[0310] 100% DMSO stock solutions (2,560 ug/mL) of Amphotericin B and Compounds 5, 11, and 17 were prepared and each stock solution was diluted to 2.5 mM solution in 100% DMSO. The 2.5 mM stock was used for all subsequent dilutions. For each compound, a total of 15 different final compound concentrations were tested in duplicate as follows: 100, 80, 60, 40, 30, 20, 5, 10, 8, 6, 4, 3, 2, 1 , and 0 μΜ. DMSO alone (4% final concentration) served as the negative control to subtract the background, while a reaction with water substituted for buffer serves as a positive control that completely lyses the RBCs. Compounds were added to buffer and inverted gently 5 times. Ninety microliters of 3% RBCs were added to the tubes containing 510 μΐ buffer with various concentrations of the investigational compounds or control reagents. Tubes were inverted gently 5 times to mix. Incubation of buffer, compound, and RBCs was for 30 min at 37°C, followed by centrifugation at 1,300 x g for 5 min to pellet the RBCs. Finally, 300 μΐ of the supernatant was removed to a 96-well plate and the released hemoglobin was measured at A540 using a SpectraMax (Molecular Dynamics) plate reader.

[0311] Incubation of RBCs in the absence of any drug or buffer, using only water as the diluent, provided data representing 100% hemolysis. For each test agent, the amount of hemoglobin released was determined graphically as a per cent of the 100% water hemolysis. Maximum percent hydrolysis values for each of the tested compounds were as follows:

[0312] Amphotericin B produced 83% hemolysis at 15 μΜ and a maximum of 94% hemolysis at the highest concentration of 100 μΜ. Compound 5 produced a maximum of 84% hemolysis at 100 μΜ, Compound 11 produced a maximum of 4% hemolysis at 100 μΜ, and Compound 17 produced a maximum of 34% hemolysis at 100 μΜ.