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MALT1 INHIBITORS AND USES THEREOF

20190389904 ยท 2019-12-26

Assignee

Inventors

Cpc classification

International classification

Abstract

Provided herein are compounds of Formula (I) and pharmaceutical compositions thereof, which may be useful as MALT1 inhibitors. Also provided are for the treatment of proliferative disorders (e.g., cancer (e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, MALT, lymphoma), benign neoplasm, a disease associated with angiogenesis, an autoimmune disease, an inflammatory disease, an autoinflammatory disease) by administering a compound of Formula (I).

##STR00001##

Claims

1. A compound of Formula (I): ##STR00461## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R.sup.3 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R.sup.4 is hydrogen, halogen, or optionally substituted alkyl; R.sup.N is hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group; or R.sup.N and either R.sup.3 or R.sup.4 are joined to form an optionally substituted heterocyclic ring, or R.sup.3 and R.sup.4 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; R.sup.5 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R.sup.6 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R.sup.5 and R.sup.6 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; R.sup.8 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, C(O)R.sup.8b, C(O)OR.sup.8a, C(O)N(R.sup.8a).sub.2, S(O).sub.2R.sup.8a, or a nitrogen protecting group; each occurrence of R.sup.8a and R.sup.8b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or two R.sup.8a are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; L.sup.1 is a bond, an amino acid, or a dipeptide; each of R.sup.c and R.sup.d is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group; and each of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted sulfonyl, or a nitrogen protecting group, or any two of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; provided the compound is not of formula: ##STR00462##

2. The compound of claim 1, wherein R.sup.5 is hydrogen, halogen, or optionally substituted alkyl.

3. The compound of claim 1, wherein the compound is of Formula (I): ##STR00463## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R.sup.3 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R.sup.4 is hydrogen, halogen, or optionally substituted alkyl; R.sup.N is hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group; or R.sup.N and either R.sup.3 or R.sup.4 are joined to form an optionally substituted heterocyclic ring, or R.sup.3 and R.sup.4 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; R.sup.5 is hydrogen, halogen, or optionally substituted alkyl; R.sup.6 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R.sup.5 and R.sup.6 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; R.sup.8 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, C(O)R.sup.8b, C(O)OR.sup.8a, C(O)N(R.sup.8a).sub.2, S(O).sub.2R.sup.8a, or a nitrogen protecting group; each occurrence of R.sup.8a and R.sup.8b is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or two R.sup.8a are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; L.sup.1 is a bond, an amino acid, or a dipeptide; each of R.sup.c and R.sup.d is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group; and each of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted sulfonyl, or a nitrogen protecting group, or any two of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; provided the compound is not of formula: ##STR00464##

4. The compound of claim 1, wherein the compound is of Formula (I-A), (I-B), (I-C), or (I-D): ##STR00465## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

5.-7. (canceled)

8. The compound of claim 1, wherein R.sup.3 and R.sup.N are joined to form an optionally substituted 4-6-membered heterocyclic ring.

9.-14. (canceled)

15. The compound of claim 1, wherein R.sup.3 is of formula: ##STR00466##

16. The compound of claim 1, wherein R.sup.4 and R.sup.N are joined to form an optionally substituted 5-membered heterocyclic ring.

17. The compound of claim 1, wherein R.sup.4 is hydrogen.

18. The compound of claim 1, wherein R.sup.5 and R.sup.6 are each unsubstituted C.sub.1-12 alkyl.

19. The compound of claim 1, wherein R.sup.5 and R.sup.6 are joined to form an optionally substituted 3-6-membered carbocyclic or optionally substituted 3-6-membered heterocyclic ring.

20. (canceled)

21. The compound of claim 1, wherein R.sup.6 is optionally substituted 5-6-membered carbocyclyl or optionally substituted 5-6-membered heterocyclyl.

22. The compound of claim 1, wherein R.sup.6 is unsubstituted C.sub.1-12 alkyl.

23. The compound of claim 1, wherein R.sup.6 is of formula: ##STR00467##

24.-25. (canceled)

26. The compound of claim 1, wherein R.sup.8 is C(O)R.sup.8b, C(O)OR.sup.8a, or C(O)N(R.sup.8a).sub.2.

27.-34. (canceled)

35. The compound of claim 1, wherein the compound is of formula: ##STR00468## ##STR00469## ##STR00470## ##STR00471## ##STR00472## ##STR00473## ##STR00474## ##STR00475## ##STR00476## ##STR00477## ##STR00478## ##STR00479## ##STR00480## ##STR00481## ##STR00482## ##STR00483## ##STR00484## ##STR00485## ##STR00486## ##STR00487## ##STR00488## ##STR00489## ##STR00490## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

36.-38. (canceled)

39. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient.

40. A method of treating a proliferative disease comprising administering an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, to a subject in need thereof.

41.-54. (canceled)

55. A method of inhibiting MALT1 or API2-MALT1 in a subject, the method comprising administering to the subject a compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

56. (canceled)

57. A method of inhibiting cleavage of A20, RelB, Bcl10, CYLD, regnase-1, roquin-1, roquin-2, NIK, LIMA1, or MALT1 in a subject, the method comprising administering to the subject a compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

58.-59. (canceled)

60. A method of preparing a compound of Formula (I): ##STR00491## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, the method comprising coupling a carboxylic acid of Formula (D): ##STR00492## or a salt thereof, and a compound of Formula (E): ##STR00493## or a salt thereof, wherein: R.sup.3 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R.sup.4 is hydrogen, halogen, or optionally substituted alkyl; R.sup.N is hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group; or R.sup.N and either R.sup.3 or R.sup.4 are joined to form an optionally substituted heterocyclic ring, or R.sup.3 and R.sup.4 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; R.sup.5 is hydrogen, halogen, or optionally substituted alkyl; R.sup.6 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R.sup.5 and R.sup.6 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; R.sup.8 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, C(O)R.sup.8b, C(O)OR.sup.8a, C(O)N(R.sup.8a).sub.2, S(O).sub.2R.sup.8a, or a nitrogen protecting group; each occurrence of R.sup.8a and R.sup.8b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or two R.sup.8a are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; L.sup.1 is a bond, an amino acid, or a dipeptide; each of R.sup.c and R.sup.d is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group; and each of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted sulfonyl, or a nitrogen protecting group, or any two of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.

61.-62. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0118] The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

[0119] FIG. 1A. Western blots for RelB and MALT1 after 30 minutes pretreatment with indicated doses of compounds or vehicle, followed by proteasome inhibitor MG-132 (5 M) treatment for 2 hours in OCI-LY3. clev=cleavage product of RelB.

[0120] FIG. 1B. Western blots for RelB with indicated doses of compounds or vehicle in OCI-LY3.

[0121] FIG. 2. Dose-response effect of compound 202 in luciferase activity of MALT1 GLOSENSOR reporter. Luciferase activity is increased by MALT1 cleavage of the reporter protein. RAJI (Burkitt's lymphoma) cells were treated with different concentrations of 202 for 1 hour, and subsequently stimulated with phorbol myristate acetate+ionomycin (PMA/IO) for 1 hour.

[0122] FIG. 3 shows a co-crystal structure of compound 101 and MALT1. Compound 101 is in the MALT1 paracaspase pocket.

[0123] FIG. 4 shows Scheme E3.

[0124] FIG. 5 shows Scheme E4.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0125] Provided herein are compounds and pharmaceutical compositions that may inhibit MALT1, or a MALT1 variant, such as a fusion protein comprising a MALT1 sequence (e.g., API2-MALT1). The compounds and pharmaceutical compositions may be useful in methods provided herein for the treatment or prevention of proliferative disease (e.g., cancer (e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, MALT lymphoma), benign neoplasm, a disease associated with angiogenesis, an autoimmune disease, an inflammatory disease, an autoinflammatory disease).

[0126] Compound provided herein may be useful in inhibiting cell proliferation, inducing apoptosis of a cell, or inhibiting cell adhesion in a subject or biological sample. In some embodiments, the cell is a lymphocyte. In some embodiments, the cell is a B-cell. In some embodiments, the cell is a T-cell. The compounds may also be useful inhibiting activation of NF-B, inhibiting cleavage of A20, Bcl10, RelB, CYLD, NIK, regnase-1, roquin-1, roquin-2, LIMA1, or MALT1, modulating cytokine production (e.g., inhibiting expression of IL-2, IL-6, IL-8, IL-10, or IL-17), inhibiting lymphocyte adhesion to fibronectin, or up-regulating expression of a gene (e.g. IBNS, IB, c-Rel, IRF4, IL-2, IL-6, c-Rel, or Ox40).

[0127] Without wishing to be bound to any particular theory, the compounds may irreversibly inhibit MALT1, or a variant thereof, by forming a covalent attachment between MALT1 and the inhibitor. In some embodiments, the fluoromethylketone group is able to covalently bind Cys464 of MALT1. The proximity of the fluoromethylketone moiety and Cys464 of MALT1 is shown in a co-crystal structure of the paracaspase binding pocket with compound 101 (See FIG. 3). In some embodiments, the inhibitor is not cleaved by MALT1. In some embodiments, the inhibitor is cleaved by MALT1 (e.g., after the arginine moiety). In some embodiments, the covalently bound inhibitor prevents binding of a MALT1 substrate.

[0128] Provided herein are compounds of Formula (I):

##STR00006##

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, wherein: [0129] R.sup.3 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0130] R.sup.4 is hydrogen, halogen, or optionally substituted alkyl; [0131] R.sup.N is hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group; [0132] or R.sup.N and either R.sup.3 or R.sup.4 are joined to form an optionally substituted heterocyclic ring, or R.sup.3 and R.sup.4 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; [0133] R.sup.5 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0134] R.sup.6 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0135] or R.sup.5 and R.sup.6 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; [0136] R.sup.8 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, C(O)R.sup.8b, C(O)OR.sup.8a, C(O)N(R.sup.8a).sub.2, S(O).sub.2R.sup.8a, or a nitrogen protecting group; [0137] each occurrence of R.sup.8a and R.sup.8b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or two R.sup.8a are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; [0138] L.sup.1 is a bond, an amino acid, or a dipeptide; [0139] each of R.sup.c and R.sup.d is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group; and [0140] each of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted sulfonyl, or a nitrogen protecting group, or any two of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.

[0141] In certain embodiments, provided herein are compounds of Formula (I):

##STR00007##

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, wherein: [0142] R.sup.3 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0143] R.sup.4 is hydrogen, halogen, or optionally substituted alkyl; [0144] R.sup.N is hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group; [0145] or R.sup.N and either R.sup.3 or R.sup.4 are joined to form an optionally substituted heterocyclic ring, or R.sup.3 and R.sup.4 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; [0146] R.sup.5 is hydrogen, halogen, or optionally substituted alkyl; [0147] R.sup.6 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0148] or R.sup.5 and R.sup.6 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; [0149] R.sup.8 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, C(O)R.sup.8b, C(O)OR.sup.8a, C(O)N(R.sup.8a).sub.2, S(O).sub.2R.sup.8a, or a nitrogen protecting group; [0150] each occurrence of R.sup.8a and R.sup.8b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or two R.sup.8a are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; [0151] L.sup.1 is a bond, an amino acid, or a dipeptide; [0152] each of R.sup.c and R.sup.d is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group; and [0153] each of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted sulfonyl, or a nitrogen protecting group, or any two of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.

[0154] In certain embodiments, the compound is of Formula (I):

##STR00008##

or a pharmaceutically acceptable salt, wherein: [0155] R.sup.3 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0156] R.sup.4 is hydrogen, halogen, or optionally substituted alkyl; [0157] R.sup.N is hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group; [0158] or R.sup.N and either R.sup.3 or R.sup.4 are joined to form an optionally substituted heterocyclic ring, or R.sup.3 and R.sup.4 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; [0159] R.sup.5 is hydrogen, halogen, or optionally substituted alkyl; [0160] R.sup.6 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; [0161] or R.sup.5 and R.sup.6 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; [0162] R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, C(O)R.sup.8b, C(O)OR.sup.8a, C(O)N(R.sup.8a).sub.2, S(O).sub.2R.sup.8a, or a nitrogen protecting group; [0163] each occurrence of R.sup.8a and R.sup.8b is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or two R.sup.8a are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; [0164] L.sup.1 is a bond, an amino acid, or a dipeptide; [0165] each of R.sup.c and R.sup.d is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group; and [0166] each of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted sulfonyl, or a nitrogen protecting group, or any two of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.

[0167] In certain embodiments, the compounds is not of formula:

##STR00009##

[0168] In certain embodiments, R.sup.8 is not -L.sup.1-R.sup.8a. In certain embodiments, R.sup.8 is not C(O)R.sup.8b. In certain embodiments, R.sup.8b is not optionally substituted alkyl. In certain embodiments, R.sup.8 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, C(O)R.sup.8b, C(O)OR.sup.8a, C(O)N(R.sup.8a).sub.2, S(O).sub.2R.sup.8a, or a nitrogen protecting group. In certain embodiments, R.sup.8 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, C(O)OR.sup.8a, C(O)N(R.sup.8a).sub.2, S(O).sub.2R.sup.8a, or a nitrogen protecting group. In certain embodiments, each of R.sup.5 and R.sup.6 is not 3-gunaidinopropyl. In certain embodiments, each of R.sup.5 and R.sup.6 is not alkyl substituted with a guanidine or a guanidine derivative. In certain embodiments, each of R.sup.3 and R.sup.4 is not benzyl.

[0169] In certain embodiments, the compound of Formula (I) is a stereoisomer of formula:

##STR00010##

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

[0170] In certain embodiments, the compound of Formula (I) is a stereoisomer of formula:

##STR00011##

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

[0171] In certain embodiments, the compound of Formula (I) is of Formula (I-A):

##STR00012##

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

[0172] In certain embodiments, the compound of Formula (I) is of Formula (I-A-1):

##STR00013##

[0173] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

[0174] In certain embodiments, the compound of Formula (I) is of Formula (I-A-2):

##STR00014##

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

[0175] In certain embodiments, the compound of Formula (I) is of Formula (I-A-3):

##STR00015##

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

[0176] In certain embodiments, the compound of Formula (I) is of Formula (I-B):

##STR00016##

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

[0177] In certain embodiments, the compound of Formula (I) is of Formula (I-B-1):

##STR00017##

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

[0178] In certain embodiments, the compound of Formula (I) is of Formula (I-B-2):

##STR00018##

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

[0179] In certain embodiments, the compound of Formula (I) is of Formula (I-B-3):

##STR00019##

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

[0180] In certain embodiments, the compound of Formula (I) is of Formula (I-C):

##STR00020##

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

[0181] In certain embodiments, the compound of Formula (I) is of Formula (I-C-1):

##STR00021##

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

[0182] In certain embodiments, the compound of Formula (I) is of Formula (I-D):

##STR00022##

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

[0183] In certain embodiments, the compound of Formula (I) is of Formula (I-D-1):

##STR00023##

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

[0184] In certain embodiments, the carbon to which R.sup.3 and R.sup.4 is chiral. In some embodiments, the carbon to which R.sup.3 and R.sup.4 is attached is in the (S)-configuration. In some embodiments, the carbon to which R.sup.3 and R.sup.4 is attached is in the (R)-configuration.

[0185] In certain embodiments, R.sup.3 and R.sup.N are joined to form an optionally substituted heterocyclic ring. In certain embodiments, R.sup.3 and R.sup.N are joined to form an optionally substituted azetidine ring. In certain embodiments, R.sup.3 and R.sup.N are joined to form an optionally substituted pyrrolidene ring. In certain embodiments, R.sup.3 and R.sup.N are joined to form an optionally substituted oxazole or thiozole ring. In certain embodiments, R.sup.3 and R.sup.N are joined to form an optionally substituted oxazolidine ring. In certain embodiments, R.sup.3 and R.sup.N are joined to form an optionally substituted thiazolidine ring. In certain embodiments, R.sup.3 and R.sup.N are joined to form an optionally substituted piperidine ring. In certain embodiments, R.sup.3 and R.sup.N are joined to form an optionally substituted morpholine ring. In certain embodiments, R.sup.4 and R.sup.N are joined to form an optionally substituted heterocyclic ring. In certain embodiments, R.sup.4 and R.sup.N are joined to form an optionally substituted pyrrolidene ring. In certain embodiments, R.sup.4 and R.sup.N are joined to form an optionally substituted piperidine ring. In certain embodiments, R.sup.3 and R.sup.4 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring. In certain embodiments, R.sup.3 and R.sup.4 are joined to form an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring. In certain embodiments, no combination of R.sup.3, R.sup.4 and R.sup.N is joined. In certain embodiments, the heterocyclic ring formed by joining R.sup.3 and R.sup.N is substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6), as valency permits, substituents (e.g., substituents independently selected form the group consisting of halogen, substituted and unsubstituted C.sub.1-6 alkyl, OR.sup.8a (e.g., OH), and CN).

[0186] In certain embodiments, R.sup.3 and R.sup.N are taken together as a moiety of formula:

##STR00024##

[0187] In certain embodiments, R.sup.3 and R.sup.N are taken together as a moiety of formula:

##STR00025##

[0188] In certain embodiments, R.sup.3 and R.sup.N are taken together as a moiety of formula:

##STR00026##

[0189] In certain embodiments, R.sup.4 and R.sup.N are taken together as a moiety of formula:

##STR00027##

[0190] As generally defined herein R is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0191] In some embodiments, R.sup.3 is hydrogen. In some embodiments, R.sup.3 is a non-hydrogen group. In certain embodiments, R.sup.3 is halogen. In certain embodiments, R.sup.3 is F. In certain embodiments, R.sup.3 is Cl, Br, or I.

[0192] In certain embodiments, R.sup.3 is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R.sup.3 is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.3 is methyl. In certain embodiments, R.sup.3 is ethyl, propyl, or butyl. In certain embodiments, R.sup.3 is substituted methyl (e.g., methyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and OR.sup.8a (e.g., OH). In certain embodiments, R.sup.3 is CH.sub.2OH. In certain embodiments, R.sup.3 is haloalkyl, e.g., CHF.sub.2, CHCl.sub.2, CH.sub.2CHF.sub.2, CH.sub.2CHCl.sub.2. In certain embodiments, R.sup.3 is perhaloalkyl, e.g., CF.sub.3, CF.sub.2CF.sub.3, CCl.sub.3.

[0193] In certain embodiments, R.sup.3 is optionally substituted carbocyclyl, e.g., optionally substituted C.sub.3-6 carbocyclyl, optionally substituted C.sub.3-4 carbocyclyl, optionally substituted C.sub.4-5 carbocyclyl, or optionally substituted C.sub.5-6 carbocyclyl. In certain embodiments, R.sup.3 is unsubstituted carbocyclyl, e.g., unsubstituted C.sub.3-6 carbocyclyl. In some embodiments, R.sup.3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R.sup.3 is optionally substituted heterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl, optionally substituted 3-4 membered heterocyclyl, optionally substituted 4-5 membered heterocyclyl, or optionally substituted 5-6 membered heterocyclyl. In certain embodiments, R.sup.3 is unsubstituted heterocyclyl, e.g., unsubstituted 3-6 membered heterocyclyl, unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 membered heterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

[0194] In certain embodiments, R.sup.3 is optionally substituted aryl, e.g., optionally substituted phenyl. In certain embodiments, R.sup.3 is unsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments, R.sup.3 is optionally substituted heteroaryl, e.g., optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.3 is unsubstituted heteroaryl, e.g., unsubstituted 5-6 membered heteroaryl, or unsubstituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.3 is optionally substituted aralkyl, e.g., optionally substituted benzyl. In certain embodiments, R.sup.3 is optionally substituted heteroaralkyl, e.g., methyl substituted with an optionally substituted 5-6 membered heteroaryl ring. In certain embodiments, R.sup.3 is unsubstituted aralkyl, e.g., unsubstituted benzyl. In certain embodiments, R.sup.3 is unsubstituted heteroaralkyl, e.g., methyl substituted with an unsubstituted 5-6 membered heteroaryl ring.

[0195] In certain embodiments, R.sup.3 is of formula:

##STR00028##

[0196] In certain embodiments, R.sup.3 is of formula:

##STR00029##

[0197] In certain embodiments, R.sup.3 is of formula:

##STR00030##

[0198] As generally defined herein, R.sup.4 is hydrogen, halogen, or optionally substituted alkyl. In some embodiments, R.sup.4 is hydrogen. In some embodiments, R.sup.4 is a non-hydrogen group. In certain embodiments, R.sup.4 is halogen. In certain embodiments, R.sup.4 is F. In certain embodiments, R.sup.4 is Cl, Br, or I.

[0199] In certain embodiments, R.sup.4 is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R.sup.4 is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.4 is methyl. In certain embodiments, R.sup.4 is substituted methyl (e.g., methyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and OR.sup.8a (e.g., OH). In certain embodiments, R.sup.4 is CH.sub.2OH. In certain embodiments, R.sup.4 is ethyl, propyl, or butyl. In certain embodiments, R.sup.4 is haloalkyl, e.g., CHF.sub.2, CHCl.sub.2, CH.sub.2CHF.sub.2, CH.sub.2CHCl.sub.2. In certain embodiments, R.sup.4 is perhaloalkyl, e.g., CF.sub.3, CF.sub.2CF.sub.3, CCl.sub.3.

[0200] In certain embodiments, R.sup.4 is of formula:

##STR00031##

[0201] In certain embodiments, R.sup.4 is of formula:

##STR00032##

[0202] In certain embodiments, R.sup.4 is of formula:

##STR00033##

[0203] As generally defined herein, R.sup.N is hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group. In some embodiments, R.sup.N is hydrogen. In some embodiments, R.sup.N is a non-hydrogen group.

[0204] In certain embodiments, R.sup.N is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R.sup.N is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.N is methyl. In certain embodiments, R.sup.N is ethyl, propyl, or butyl.

[0205] In certain embodiments, R.sup.N is optionally substituted acyl, e.g., CHO, CO.sub.2H, or C(O)NH.sub.2. In certain embodiments, R.sup.N is C(O)R.sup.f, C(O)OR.sup.f, C(O)NH(R), or C(O)N(R.sup.f).sub.2, wherein each occurrence of R.sup.f is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or two R.sup.f are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In certain embodiments, R.sup.N is C(O)R.sup.f, and R.sup.f is optionally substituted alkyl, e.g., C(O)Me. In certain embodiments, R.sup.N is C(O)R.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.N is C(O)R.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.N is C(O)OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.N is C(O)OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.N is C(O)OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.N is C(O)N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.N is C(O)NHR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.N is C(O)NHR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.N is C(O)NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

[0206] In certain embodiments, R.sup.N is a nitrogen protecting group. In some embodiments, R.sup.N is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, tosyl, nosyl, brosyl, mesyl, or triflyl.

[0207] In certain embodiments, the carbon to which R.sup.5 and R.sup.6 is chiral. In some embodiments, the carbon to which R.sup.5 and R.sup.6 is attached is in the (S)-configuration. In some embodiments, the carbon to which R.sup.5 and R.sup.6 is attached is in the (R)-configuration.

[0208] In certain embodiments, R.sup.5 and R.sup.6 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring. In certain embodiments, R.sup.5 and R.sup.6 are joined to form an optionally substituted, 3-6 membered, monocyclic carbocyclic ring. In certain embodiments, R.sup.5 and R.sup.6 are joined to form an optionally substituted, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring. In certain embodiments, R.sup.5 and R.sup.6 are joined to form an optionally substituted, 3-6 membered, monocyclic heterocyclic ring. In certain embodiments, R.sup.5 and R.sup.6 are joined to form an optionally substituted tetrahydropyran ring.

[0209] In certain embodiments, R.sup.5 and R.sup.6 are not joined. In certain embodiments, R.sup.5 is optionally substituted alkyl, e.g., optionally substituted C.sub.1-12 alkyl. In certain embodiments, R.sup.5 is unsubstituted alkyl, e.g., unsubstituted C.sub.1-12 alkyl.

[0210] As generally defined herein R.sup.6 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0211] In some embodiments, R.sup.6 is hydrogen. In some embodiments, R.sup.6 is a non-hydrogen group. In certain embodiments, R.sup.6 is halogen. In certain embodiments, R.sup.6 is F. In certain embodiments, R.sup.6 is Cl, Br, or I.

[0212] In certain embodiments, R.sup.6 is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R.sup.6 is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.6 is methyl. In certain embodiments, R.sup.6 is ethyl, propyl, or butyl. In certain embodiments, R.sup.6 is haloalkyl, e.g., CHF.sub.2, CHCl.sub.2, CH.sub.2CHF.sub.2, CH.sub.2CHCl.sub.2. In certain embodiments, R.sup.6 is perhaloalkyl, e.g., CF.sub.3, CF.sub.2CF.sub.3, CCl.sub.3.

[0213] In certain embodiments, R.sup.6 is optionally substituted carbocyclyl, e.g., optionally substituted C.sub.3-6 carbocyclyl, optionally substituted C.sub.3-4 carbocyclyl, optionally substituted C.sub.4-5 carbocyclyl, or optionally substituted C.sub.5-6 carbocyclyl. In certain embodiments, R.sup.6 is unsubstituted carbocyclyl, e.g., unsubstituted C.sub.3-6 carbocyclyl. In some embodiments, R.sup.6 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R.sup.6 is optionally substituted heterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl, optionally substituted 3-4 membered heterocyclyl, optionally substituted 4-5 membered heterocyclyl, or optionally substituted 5-6 membered heterocyclyl. In certain embodiments, R.sup.6 is unsubstituted heterocyclyl, e.g., unsubstituted 3-6 membered heterocyclyl, unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 membered heterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

[0214] In certain embodiments, R.sup.6 is optionally substituted aryl, e.g., optionally substituted phenyl. In certain embodiments, R.sup.6 is unsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments, R.sup.6 is optionally substituted heteroaryl, e.g., optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.6 is unsubstituted heteroaryl, e.g., unsubstituted 5-6 membered heteroaryl, or unsubstituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.6 is optionally substituted aralkyl, e.g., optionally substituted benzyl. In certain embodiments, R.sup.6 is optionally substituted heteroaralkyl, e.g., methyl substituted with an optionally substituted 5-6 membered heteroaryl ring. In certain embodiments, R.sup.6 is unsubstituted aralkyl, e.g., unsubstituted benzyl. In certain embodiments, R.sup.6 is unsubstituted heteroaralkyl, e.g., methyl substituted with an unsubstituted 5-6 membered heteroaryl ring.

[0215] In certain embodiments, R.sup.6 is of formula:

##STR00034##

[0216] In certain embodiments, R.sup.6 is of formula:

##STR00035##

[0217] As generally defined herein, R.sup.5 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, R.sup.5 is hydrogen, halogen, or optionally substituted alkyl. In some embodiments, R.sup.5 is hydrogen. In some embodiments, R.sup.5 is a non-hydrogen group. In certain embodiments, R.sup.5 is halogen. In certain embodiments, R.sup.5 is F. In certain embodiments, R.sup.5 is Cl, Br, or I.

[0218] In certain embodiments, R.sup.5 is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R.sup.5 is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.5 is methyl. In certain embodiments, R.sup.5 is ethyl, propyl, or butyl. In certain embodiments, R.sup.5 is haloalkyl, e.g., CHF.sub.2, CHCl.sub.2, CH.sub.2CHF.sub.2, CH.sub.2CHCl.sub.2. In certain embodiments, R.sup.5 is perhaloalkyl, e.g., CF.sub.3, CF.sub.2CF.sub.3, CCl.sub.3.

[0219] In certain embodiments, R.sup.5 is optionally substituted carbocyclyl, e.g., optionally substituted C.sub.3-6 carbocyclyl, optionally substituted C.sub.3-4 carbocyclyl, optionally substituted C.sub.4-5 carbocyclyl, or optionally substituted C.sub.5-6 carbocyclyl. In certain embodiments, R.sup.5 is unsubstituted carbocyclyl, e.g., unsubstituted C.sub.3-6 carbocyclyl. In some embodiments, R.sup.5 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0220] In certain embodiments, R.sup.5 is optionally substituted heterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl, optionally substituted 3-4 membered heterocyclyl, optionally substituted 4-5 membered heterocyclyl, or optionally substituted 5-6 membered heterocyclyl. In certain embodiments, R.sup.5 is unsubstituted heterocyclyl, e.g., unsubstituted 3-6 membered heterocyclyl, unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 membered heterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

[0221] In certain embodiments, R.sup.5 is optionally substituted aryl, e.g., optionally substituted phenyl. In certain embodiments, R.sup.5 is unsubstituted aryl, e.g., unsubstituted phenyl.

[0222] In certain embodiments, R.sup.5 is optionally substituted heteroaryl, e.g., optionally substituted 5-6 membered monocyclic heteroaryl, or optionally substituted 9-10 membered bicyclic heteroaryl. In certain embodiments, R.sup.5 is unsubstituted heteroaryl, e.g., unsubstituted 5-6 membered monocyclic heteroaryl, or unsubstituted 9-10 membered bicyclic heteroaryl.

[0223] In certain embodiments, R.sup.5 is optionally substituted aralkyl, e.g., optionally substituted benzyl. In certain embodiments, R.sup.5 is optionally substituted heteroaralkyl, e.g., methyl substituted with an optionally substituted 5-6 membered monocyclic heteroaryl ring. In certain embodiments, R.sup.5 is unsubstituted aralkyl, e.g., unsubstituted benzyl. In certain embodiments, R.sup.5 is unsubstituted heteroaralkyl, e.g., methyl substituted with an unsubstituted 5-6 membered monocyclic heteroaryl ring.

[0224] In certain embodiments, R.sup.5 is of formula:

##STR00036##

[0225] In certain embodiments, R.sup.5 is of formula:

##STR00037##

[0226] As generally defined herein, R.sup.8 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, C(O)R.sup.8b, C(O)OR.sup.8a, C(O)N(R.sup.8a).sub.2, S(O).sub.2R.sup.8a.

[0227] In certain embodiments, R.sup.8 is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.8 is methyl. In certain embodiments, R.sup.8 is ethyl, propyl, or butyl. In certain embodiments, R.sup.8 is haloalkyl, e.g., CHF.sub.2, CHCl.sub.2, CH.sub.2CHF.sub.2, CH.sub.2CHCl.sub.2. In certain embodiments, R.sup.8 is perhaloalkyl, e.g., CF.sub.3, CF.sub.2CF.sub.3, CCl.sub.3. In certain embodiments, R.sup.8 is optionally substituted carbocyclyl, e.g., optionally substituted C.sub.3-6 carbocyclyl, optionally substituted C.sub.3-4 carbocyclyl, optionally substituted C.sub.4-5 carbocyclyl, or optionally substituted C.sub.5-6 carbocyclyl. In certain embodiments, R is unsubstituted carbocyclyl, e.g., unsubstituted C.sub.3-6 carbocyclyl. In some embodiments, R.sup.8 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R.sup.8 is optionally substituted heterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl, optionally substituted 3-4 membered heterocyclyl, optionally substituted 4-5 membered heterocyclyl, or optionally substituted 5-6 membered heterocyclyl. In certain embodiments, R.sup.8 is unsubstituted heterocyclyl, e.g., unsubstituted 3-6 membered heterocyclyl, unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 membered heterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

[0228] In certain embodiments, R.sup.8 is C(O)R.sup.8b, wherein R.sup.8b is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl. In certain embodiments, R.sup.8 is C(O)R.sup.8b, wherein R.sup.8b is hydrogen, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl. In certain embodiments, R.sup.8 is C(O)R.sup.8b, and R.sup.8b is optionally substituted alkyl, e.g., C(O)Me. In certain embodiments, R.sup.8 is C(O)R.sup.8b, and R.sup.8b is optionally substituted alkenyl. In certain embodiments, R.sup.8 is C(O)R.sup.8b, and R.sup.8b is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

[0229] In certain embodiments, R.sup.8 is C(O)R.sup.8b, wherein R.sup.8b is optionally substituted alkenyl. In certain embodiments, R.sup.8 is C(O)OR.sup.8a, wherein R.sup.8a is optionally substituted alkenyl.

[0230] In certain embodiments, R.sup.8 is C(O)OR.sup.8a, wherein R.sup.8a is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R.sup.8 is C(O)OR.sup.8a, and R.sup.8a is optionally substituted alkyl. In certain embodiments, R.sup.8 is C(O)OR.sup.8a, and R.sup.8a is optionally substituted alkenyl. In certain embodiments, R.sup.8 is C(O)OR.sup.8a, and R.sup.8a is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

[0231] In certain embodiments, R.sup.8 is C(O)N(R.sup.8a).sub.2, wherein each R.sup.8a is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, a nitrogen protecting group, or two R.sup.8a are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In certain embodiments, R.sup.8 is C(O)N(R.sup.8a).sub.2, and at least one R.sup.8a is optionally substituted alkyl. In certain embodiments, R.sup.8 is C(O)NHR.sup.8a, and R.sup.8a is optionally substituted alkyl. In certain embodiments, R.sup.8 is C(O)NHR.sup.8a, and R.sup.8a is optionally substituted alkenyl. In certain embodiments, R.sup.8 is C(O)NHR.sup.8a, and R.sup.8a is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

[0232] In certain embodiments, R.sup.8 is optionally substituted sulfonyl, e.g., S(O).sub.2OH. In certain embodiments, R.sup.8 is S(O).sub.2R.sup.8a, wherein R.sup.8a is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, R.sup.8 is S(O).sub.2R.sup.8a, and R.sup.8a is optionally substituted alkyl, e.g., S(O).sub.2Me. In certain embodiments, R.sup.8 is S(O).sub.2R.sup.8a, and R.sup.8a is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

[0233] In certain embodiments, R.sup.8 is a nitrogen protecting group. In some embodiments, R is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, tosyl, nosyl, brosyl, mesyl, or triflyl.

[0234] In certain embodiments, R.sup.8 is of formula:

##STR00038##

wherein each instance of R.sup.A is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, cyano, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted acyl, or two R.sup.A attached to neighboring atoms are joined to form an optionally substituted aryl or optionally substituted heteroaryl ring.

[0235] In certain embodiments, at least one R.sup.A is hydrogen. In certain embodiments, each R.sup.A is hydrogen. In certain embodiments, at least one R.sup.A is halogen. In certain embodiments, each R.sup.A is halogen. In certain embodiments, at least one R.sup.A is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, each R.sup.A is independently hydrogen, halogen, or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, each R.sup.A is independently halogen or substituted or unsubstituted C.sub.1-6 alkyl.

[0236] In certain embodiments, R.sup.8 is of formula:

##STR00039##

wherein X is N or CR.sup.A; Y is O, S, NR.sup.A, or C(R.sup.A).sub.2; and each occurrence of R.sup.A is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group, or two R.sup.A attached to neighboring atoms are joined to form an optionally substituted aryl or optionally substituted heteroaryl ring.

[0237] In certain embodiments, R.sup.8 is of formula:

##STR00040##

wherein X is N or CR.sup.A; Y is O, S, NR.sup.A, or C(R.sup.A).sub.2; and each occurrence of R.sup.A is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group, or two R.sup.A attached to neighboring atoms are joined to form an optionally substituted aryl or optionally substituted heteroaryl ring.

[0238] In certain embodiments, R.sup.8 is of formula:

##STR00041## ##STR00042##

[0239] In certain embodiments, R.sup.8 is of formula:

##STR00043## ##STR00044##

[0240] In certain embodiments, R is of formula:

##STR00045##

[0241] As generally defined herein, L.sup.1 is a bond, an amino acid, or a dipeptide. In certain embodiments, L.sup.1 is an L natural amino acid. In certain embodiments, L.sup.1 is a D natural amino acid. In certain embodiments, L.sup.1 is an unnatural amino acid. In certain embodiments, L.sup.1 is a dipeptide of two natural amino acids that are independently L or D. In certain embodiments, R is -L.sup.1-R.sup.8a, and L.sup.1 is an amino acid (e.g., a peptidically bound amino acid). In certain embodiments, R.sup.8 is -L.sup.1-R.sup.8a, and L.sup.1 is a dipeptide (e.g., two peptidically bound amino acids joined by a peptide bond).

[0242] In certain embodiments, L.sup.1 is of formula:

##STR00046##

wherein a is attached to R.sup.8a and b is attached to the nitrogen attached to R.sup.d, and R.sup.L is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.L is a side chain of a naturally occurring amino acid selected from glycine, cysteine, selenocysteine, serine, threonine, asparagine, glutamine, alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, arginine, histidine, lysine, aspartate, or glutamate.

[0243] In certain embodiments, L.sup.1 is of formula:

##STR00047##

wherein a is attached to R.sup.8 and b is attached to the nitrogen attached to R.sup.d, and R.sup.L is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R.sup.L is a side chain of a naturally occurring amino acid (e.g., glycine, cysteine, selenocysteine, serine, threonine, asparagine, glutamine, alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, arginine, histidine, lysine, aspartate, or glutamate).

[0244] In certain embodiments, L.sup.1 is of formula:

##STR00048##

wherein a is attached to R.sup.8a and b is attached to the nitrogen attached to R.sup.d, and each R.sup.L is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, each R.sup.L is independently a side chain of a naturally occurring amino acid selected from glycine, cysteine, selenocysteine, serine, threonine, asparagine, glutamine, alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, arginine, histidine, lysine, aspartate, or glutamate.

[0245] In certain embodiments, L.sup.1 is of formula:

##STR00049##

wherein a is attached to R.sup.8 and b is attached to the nitrogen attached to R.sup.d, and each R.sup.L is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, each R.sup.L is independently a side chain of a naturally occurring amino acid (e.g., glycine, cysteine, selenocysteine, serine, threonine, asparagine, glutamine, alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, arginine, histidine, lysine, aspartate, or glutamate). In certain embodiments, two instances of R.sup.L are the same. In certain embodiments, two instances of R.sup.L are different from each other.

[0246] As generally defined herein R.sup.c and R.sup.d is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group. In certain embodiments, R.sup.c is hydrogen. In certain embodiments, R.sup.d is hydrogen. In certain embodiments, both R.sup.c and R.sup.d are hydrogen. In certain embodiments, R.sup.c is hydrogen and R.sup.d is a non-hydrogen group (e.g., methyl). In certain embodiments, R.sup.c is a non-hydrogen group (e.g., methyl) and R.sup.d is hydrogen. In certain embodiments, both R.sup.c and R.sup.d are non-hydrogen group (e.g., methyl).

[0247] In certain embodiments, R.sup.c is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R.sup.c is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.c is methyl. In certain embodiments, R.sup.c is ethyl, propyl, or butyl.

[0248] In certain embodiments, R.sup.d is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, R.sup.d is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, R.sup.d is methyl. In certain embodiments, R.sup.d is ethyl, propyl, or butyl.

[0249] In certain embodiments, R.sup.c is optionally substituted acyl, e.g., CHO, CO.sub.2H, or C(O)NH.sub.2. In certain embodiments, R.sup.c is C(O)R.sup.f, C(O)OR.sup.f, C(O)NH(R), or C(O)N(R.sup.f).sub.2, wherein each occurrence of R.sup.f is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or two R.sup.f are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In certain embodiments, R.sup.c is C(O)R.sup.f, and R.sup.f is optionally substituted alkyl, e.g., C(O)Me. In certain embodiments, R.sup.c is C(O)R.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.c is C(O)R.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.c is C(O)OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.c is C(O)OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.c is C(O)OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.c is C(O)N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.c is C(O)NHR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.c is C(O)NHR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.c is C(O)NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

[0250] In certain embodiments, R.sup.c is a nitrogen protecting group. In some embodiments, R.sup.c is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, tosyl, nosyl, brosyl, mesyl, or triflyl.

[0251] In certain embodiments, R.sup.d is optionally substituted acyl, e.g., CHO, CO.sub.2H, or C(O)NH.sub.2. In certain embodiments, R.sup.d is C(O)R.sup.f, C(O)OR.sup.f, C(O)NH(R.sup.f), or C(O)N(R.sup.f).sub.2, wherein each occurrence of R.sup.f is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or two R.sup.f are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In certain embodiments, R.sup.d is C(O)R.sup.f, and R.sup.f is optionally substituted alkyl, e.g., C(O)Me. In certain embodiments, R.sup.d is C(O)R.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.d is C(O)R.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.d is C(O)OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.d is C(O)OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.d is C(O)OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R.sup.d is C(O)N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.d is C(O)NHR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, R.sup.d is C(O)NHR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, R.sup.d is C(O)NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

[0252] In certain embodiments, R.sup.d is a nitrogen protecting group. In some embodiments, R.sup.d is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, tosyl, nosyl, brosyl, mesyl, or triflyl.

[0253] As generally defined herein independently hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted sulfonyl, or a nitrogen protecting group, or any two of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring.

[0254] In certain embodiments, R.sup.A1 and R.sup.A2 are joined to form an optionally substituted heterocyclic ring. In certain embodiments, R.sup.A1 and R.sup.A3 or R.sup.A4 are joined to form an optionally substituted heterocyclic ring. In certain embodiments, R.sup.A2 and R.sup.A3 or R.sup.A4 are joined to form an optionally substituted heterocyclic ring. In certain embodiments, R.sup.A3 and R.sup.A4 are joined to form an optionally substituted heterocyclic ring. In certain embodiments, none of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 are joined to form a ring.

[0255] In certain embodiments, each of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is hydrogen. In certain embodiments, each of R.sup.A1, R.sup.A2, and R.sup.A3 is hydrogen, and R.sup.A4 is a non-hydrogen group. In certain embodiments, each of R.sup.A1, R.sup.A3, and R.sup.A4 is hydrogen, and R.sup.A2 is a non-hydrogen group. In certain embodiments, R.sup.A1 and R.sup.A3 are hydrogen, and R.sup.A2 and R.sup.A4 are non-hydrogen groups.

[0256] In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is optionally substituted alkyl, e.g., optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-2 alkyl, optionally substituted C.sub.2-3 alkyl, optionally substituted C.sub.3-4 alkyl, optionally substituted C.sub.4-5 alkyl, or optionally substituted C.sub.5-6 alkyl. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is unsubstituted alkyl, e.g., unsubstituted C.sub.1-6 alkyl, unsubstituted C.sub.1-2 alkyl, unsubstituted C.sub.2-3 alkyl, unsubstituted C.sub.3-4 alkyl, unsubstituted C.sub.4-5 alkyl, or unsubstituted C.sub.5-6 alkyl. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is methyl. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is ethyl, propyl, or butyl.

[0257] In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is optionally substituted acyl, e.g., CHO, CO.sub.2H, or C(O)NH.sub.2. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is C(O)R.sup.f, C(O)OR.sup.f, C(O)NH(R.sup.f), or C(O)N(R.sup.f).sub.2, wherein each occurrence of R.sup.f is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or two R.sup.f are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is C(O)R.sup.f, and R.sup.f is optionally substituted alkyl, e.g., C(O)Me. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is C(O)R.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is C(O)R.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is C(O)OR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is C(O)OR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is C(O)OR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is C(O)N(R.sup.f).sub.2, and at least one R.sup.f is optionally substituted alkyl. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is C(O)NHR.sup.f, and R.sup.f is optionally substituted alkyl. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is C(O)NHR.sup.f, and R.sup.f is optionally substituted alkenyl. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is C(O)NHR.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

[0258] In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is optionally substituted sulfonyl, e.g., S(O).sub.2OH. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is S(O).sub.2R.sup.f, wherein R.sup.f is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is S(O).sub.2R.sup.f, and R.sup.f is optionally substituted alkyl, e.g., S(O).sub.2Me. In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is S(O).sub.2R.sup.f, and R.sup.f is optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

[0259] In certain embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4 is a nitrogen protecting group. In some embodiments, R.sup.A4 is a nitrogen protecting group. In some embodiments, R.sup.A2 is a nitrogen protecting group. In some embodiments, R.sup.A2 is a nitrogen protecting group, and R.sup.A4 is a nitrogen protecting group. In some embodiments, the nitrogen protecting group is selected from the group consisting of selected from the group consisting of tosyl, 2,2,5,7,8-pentamethylchroman-6-yl, 2,2,4,5,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl, mesityl-2-sulfonyl, 4-methoxy-2,3,6-trimethylphenylsulfonyl, 1,2-dimethylindole-3-sulfonyl, tert-butoxycarbonyl, 5-dibenzosuberenyl, 5-dibenzosuberyl, 2-methoxy-5-dibenzosuberyl, trifluoroacetyl, benzyloxycarbonyl, allyloxycarbonyl, and NO.sub.2.

##STR00050##

[0260] In certain embodiments, the guanidine moiety is of formula:

##STR00051##

[0261] In certain embodiments, the guanidine moiety is of formula:

##STR00052##

[0262] In certain embodiments, the guanidine moiety is of formula:

##STR00053##

[0263] In certain embodiments, the guanidine moiety is of formula:

##STR00054##

[0264] In certain embodiments, the guanidine moiety is of formula:

##STR00055##

[0265] In certain embodiments, the guanidine moiety is of formula:

##STR00056##

[0266] In certain embodiments, the compound is a compound listed in Table 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

TABLE-US-00002 TABLE 1 Exemplary compounds of Formula (I) [00057]embedded image 101 [00058]embedded image 102 [00059]embedded image 103 [00060]embedded image 104 [00061]embedded image 105 [00062]embedded image 106 [00063]embedded image 107 [00064]embedded image 108 [00065]embedded image 109 [00066]embedded image 110 [00067]embedded image 111 [00068]embedded image 112 [00069]embedded image 113 [00070]embedded image 114 [00071]embedded image 115 [00072]embedded image 116 [00073]embedded image 117 [00074]embedded image 118 [00075]embedded image 119 [00076]embedded image 120 [00077]embedded image 121 [00078]embedded image 122 [00079]embedded image 123 [00080]embedded image 124 [00081]embedded image 125 [00082]embedded image 126 [00083]embedded image 127 [00084]embedded image 128 [00085]embedded image 129 [00086]embedded image 130 [00087]embedded image 201 [00088]embedded image 202 [00089]embedded image 203 [00090]embedded image 204 [00091]embedded image 205

[0267] In certain embodiments, the compound is a compound listed in Table 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

TABLE-US-00003 TABLE 2 Exemplary compounds of Formula (I) [00092]embedded image 131 [00093]embedded image 132 [00094]embedded image 133 [00095]embedded image 134 [00096]embedded image 135 [00097]embedded image 136 [00098]embedded image 137 [00099]embedded image 138 [00100]embedded image 139 [00101]embedded image 140 [00102]embedded image 141 [00103]embedded image 142 [00104]embedded image 143 [00105]embedded image 144 [00106]embedded image 145 [00107]embedded image 146 [00108]embedded image 147 [00109]embedded image 148 [00110]embedded image 149 [00111]embedded image 150 [00112]embedded image 151 [00113]embedded image 152 [00114]embedded image 153 [00115]embedded image 154 [00116]embedded image 155 [00117]embedded image 156 [00118]embedded image 157 [00119]embedded image 158 [00120]embedded image 159 [00121]embedded image [00122]embedded image [00123]embedded image [00124]embedded image [00125]embedded image [00126]embedded image [00127]embedded image [00128]embedded image [00129]embedded image [00130]embedded image [00131]embedded image [00132]embedded image [00133]embedded image [00134]embedded image [00135]embedded image [00136]embedded image [00137]embedded image [00138]embedded image [00139]embedded image [00140]embedded image [00141]embedded image [00142]embedded image [00143]embedded image [00144]embedded image [00145]embedded image [00146]embedded image

[0268] In certain embodiments, the compound described herein is of the formula:

##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153##

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug thereof.

[0269] In certain embodiments, the compound described herein is compound 172, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In certain embodiments, the compound described herein is compound 171, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In certain embodiments, the compound described herein is compound 135, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In certain embodiments, the compound described herein is compound 174, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In certain embodiments, the compound described herein is compound 116, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In certain embodiments, the compound described herein is compound 143, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In certain embodiments, the compound described herein is compound 173, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In certain embodiments, the compound described herein is compound 149, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In certain embodiments, the compound described herein is compound 151, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In certain embodiments, the compound described herein is compound 177, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0270] In certain embodiments, a compound described herein is a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, polymorph, co-crystal, or prodrug of a formula described herein.

[0271] Methods of Preparing the Compounds

[0272] Compounds described herein may be synthesized according to the schemes described below and procedures presented in the Examples. The reagents and conditions described are intended to be exemplary and are not limiting. As appreciated by one of skill in the art, various analogs may be prepared by modifying the synthetic reactions such as using different starting materials, different reagents, and different reaction conditions (e.g., temperature, solvent, concentration, etc.).

[0273] In one aspect, provided herein are methods for the preparation of a compound of Formula (I) and intermediates thereto. Exemplary synthetic methods are shown in Schemes 1 and 2. Unless otherwise stated, variables depicted in the schemes below are as generally described herein for compounds of Formula (I).

##STR00154##

[0274] P.sup.1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted acyl, or an oxygen protecting group.

[0275] Step S-1 comprises coupling an amino acid of Formula (B) with an amino acid ester of Formula (B), to form a dipeptide ester of Formula (C). All methods of peptide coupling are contemplated. In certain embodiments, the step of coupling is performed in the presence of a carboxyl activating agent. In certain embodiments, the carboxyl activating agent is a carbodiimide. In some embodiments, the carbodiimide is dicyclohexylcarbodiimide (DCC), diisoproylcarbodiimide (DIC), or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC), or a derivative thereof. In certain embodiments, the carboxyl activating agent is a triazole. In some embodiments, the triazole is 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 2-cyano-2-(hydroxyimino)acetate), HBTU, HATU, HCTU, TBTU, or PyBOP, or a derivative thereof. In certain embodiments, the step of coupling is performed in the presence of a base. In some embodiments, the base is a non-nucleophilic base. In some embodiments, the base is an amine. In some embodiments, the base is trimethyl amine, triethyl amine, diisopropyl ethyl amine (DIPEA), tetramethylpiperidine, 1,8-diazabicycloundec-7-ene (DBU), lutidene, or 2,6-di-tert-butylpyridine. In some embodiments, the coupling is performed in a solvent comprising DMF. In certain embodiments, P.sup.1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, P.sup.1 is methyl, ethyl, propyl, or butyl. In some embodiments, P.sup.1 is methyl. In certain embodiments, P.sup.1 is an oxygen protecting group. In certain embodiments, the oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0276] Step S-2 comprises converting the ester of a dipeptide ester of Formula (C) to a carboxylic acid of Formula (D). In certain embodiments, the step of converting is an acid hydrolysis of the ester. In certain embodiments, the step of converting is a base hydrolysis of the ester. In certain embodiments, the step of converting is performed in the presence of a base. In some embodiments, the base is a hydroxide, carbonate, or phosphate salt. In some embodiments, the base is lithium hydroxide, sodium hydroxide, or potassium hydroxide.

##STR00155##

[0277] Step S-3 comprises coupling a dipeptide ester of Formula (C) with an arginine analog of Formula (E). All methods of peptide coupling are contemplated. In some embodiments, the carbodiimide is dicyclohexylcarbodiimide (DCC), dissoproylcarbodiimide (DIC), or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC), or a derivative thereof. In certain embodiments, the carboxyl activating agent is a triazole. In some embodiments, the triazole is 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 2-cyano-2-(hydroxyimino)acetate), HBTU, HATU, HCTU, TBTU, or PyBOP, or a derivative thereof. In certain embodiments, the step of coupling is performed in the presence of a base. In some embodiments, the base is a non-nucleophilic base. In some embodiments, the base is an amine. In some embodiments, the base is trimethyl amine, triethyl amine, diisopropyl ethyl amine (DIPEA), tetramethylpiperidine, 1,8-diazabicycloundec-7-ene (DBU), lutidene, or 2,6-di-tert-butylpyridine. In some embodiments, the coupling is performed in a solvent comprising DMF.

[0278] In certain embodiments, the arginine analog of Formula (E) is a protected arginine (e.g., R.sup.A4 is protecting group, R.sup.A4 and R.sup.A2 are protecting groups). In some embodiments, each of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is hydrogen. In some embodiments, at least one of R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 is a non-hydrogen group. In some embodiments, the step of coupling (D) and (E) further comprises deprotecting the guanidine group (i.e., removing a non-hydrogen group from R.sup.A1, R.sup.A2, R.sup.A3, or R.sup.A4, or a combination thereof). In some embodiments, the guanidine moiety (e.g., in a compound of Formula (E) is of formula:

##STR00156## ##STR00157##

[0279] The method of preparing a compound of Formula (I) or an intermediate thereto may optionally further comprise one or more steps of protecting a nitrogen, oxygen, or sulfur atom, or deprotecting a nitrogen, oxygen, or sulfur atom. In certain embodiments, the step of deprotecting or protecting comprises replacing group R.sup.8 or -L.sup.1-R.sup.8. In certain embodiments, the step of deprotecting or protecting comprises replacing group R.sup.N. In certain embodiments, the step of deprotecting or protecting comprises replacing group R.sup.c. In certain embodiments, the step of deprotecting or protecting comprises replacing group R.sup.d. In certain embodiments, the step of deprotecting or protecting comprises replacing group R.sup.A1. In certain embodiments, the step of deprotecting or protecting comprises replacing group R.sup.A2. In certain embodiments, the step of deprotecting or protecting comprises replacing group R.sup.A3. In certain embodiments, the step of deprotecting or protecting comprises replacing group R.sup.A4.

[0280] In one aspect, provided herein is a method of preparing a compound of Formula (I):

##STR00158##

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, the method comprising coupling a carboxylic acid of Formula (D):

##STR00159##

or a salt thereof, and a compound of Formula (E):

##STR00160##

or a salt thereof, wherein R.sup.3, R.sup.4, R.sup.N, R.sup.5, R.sup.6, R, L.sup.1, R.sup.c, R.sup.d, R.sup.A1, R.sup.A2, R.sup.A3, and R.sup.A4 are as defined herein.

[0281] In certain embodiments, the method of preparing a compound of Formula (I) further comprises converting an ester of Formula (C):

##STR00161##

or a salt thereof, to a carboxylic acid of Formula (D), wherein P.sup.1 is optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group.

[0282] In certain embodiments, the method of preparing a compound of Formula (I) further comprises coupling a compound of Formula (A):

##STR00162##

or a salt thereof, and a compound of Formula (B):

##STR00163##

or a salt thereof, to yield an ester of Formula (C).

Pharmaceutical Compositions and Administration

[0283] The present invention also provides pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is useful for treating a patient with a proliferative disease. In certain embodiments, the pharmaceutical composition is useful for treating a patient with cancer. In certain embodiments, the pharmaceutical composition is useful for treating a patient with a lymphoma. In certain embodiments, the pharmaceutical composition is useful for treating a patient with a leukemia. In certain embodiments, the pharmaceutical composition is useful for treating a patient with Hodgkin's lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, or MALT lymphoma. In certain embodiments, the pharmaceutical composition is useful for treating a patient with diffuse large B-cell lymphoma.

[0284] In certain embodiments, the compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a proliferative disease (e.g., cancer (e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, MALT lymphoma), benign neoplasm, a disease associated with angiogenesis, an autoimmune disease, an inflammatory disease, an autoinflammatory disease) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a proliferative disease (e.g., cancer (e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, MALT lymphoma), benign neoplasm, a disease associated with angiogenesis, an autoimmune disease, an inflammatory disease, an autoinflammatory disease) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a proliferative disease (e.g., cancer (e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, MALT lymphoma), benign neoplasm, a disease associated with angiogenesis, an autoimmune disease, an inflammatory disease, an autoinflammatory disease) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for inhibiting MALT1 in a subject. In certain embodiments, the effective amount is an amount effective for inhibiting a MALT1 fusion protein (e.g. API2-MALT1) in a subject. In certain embodiments, the effective amount is an amount effective for inhibiting the cleavage of A20, Bcl10, RelB, CYLD, NIK, regnase-1, roquin-1, roquin-2, LIMA1, or MALT1 in a subject. In certain embodiments, the effective amount is an amount effective for inhibiting secretion of IL-6 in a subject.

[0285] In certain embodiments, the effective amount is an amount effective for inhibiting MALT1 by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, the effective amount is an amount effective for inhibiting MALT1 by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%. In certain embodiments, the effective amount is an amount effective for a range of inhibition between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0286] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the active ingredient) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.

[0287] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A unit dose is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0288] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.

[0289] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0290] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0291] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0292] Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.

[0293] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

[0294] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0295] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0296] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0297] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0298] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0299] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0300] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0301] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0302] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0303] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0304] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0305] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0306] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0307] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0308] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0309] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(S) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0310] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(S) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0311] Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.

[0312] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0313] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0314] Low boiling propellants generally include liquid propellants having a boiling point of below 65 F. at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0315] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0316] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0317] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0318] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.

[0319] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.

[0320] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0321] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[0322] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.

[0323] In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 ag and 1 ag, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0324] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. In certain embodiments, a dose described herein is a dose to an adult human whose body weight is 70 kg.

[0325] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and/or in inhibiting MALT1), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.

[0326] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which are different from the compound described herein and may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0327] DLBCLs display a large mutational burden that affects multiple protein coding genes. Because of that, single-agent therapy would not be expected to eradicate disease. ABC-DLBCLs are more resistant to current chemotherapy regimens. For instance, ABC-DLBCL is less responsive to the standard of care, R-CHOP, with 40% 3-year progression free survival versus 74% for GCB-DLBCL. Combination therapy, e.g. R-CHOP, may be useful for treating and/or preventing DLBCLs. It is possible that MALT1 inhibition could sensitize ABC-DLBCLs to R-CHOP by disrupting cell survival signaling through NF-B. It is also possible that MALT1-targeted therapy could synergistically kill lymphoma cells when a MALT1 inhibitor is combined with other more upstream BCR pathway inhibitors that might complement MALT1 inhibition. For example, inhibiting phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), spleen tyrosine kinase (SYK), or Bruton's tyrosine kinase (BTK) could allow the inhibition of pathways parallel to NF-B like mitogen-activated protein kinase (MAPK), JNK, or NFAT (nuclear factor of activated T cells) to further inhibit survival and proliferation signals. Inhibitors of these proteins include: PI3K inhibitors BEZ235, BKM120, GDC-0941, BYL719 or CAL-101; SYK inhibitors R-406 or Fostamatinib; BTK inhibitors Ibrutinib or CC-292. Other potential targets for MALT1 combination therapy in ABC-DLBCL include other oncogenes frequently deregulated in this subtype of lymphoma: BCL2, BCL6, and MYC. BCL2 is frequently amplified and overexpressed in ABC-DLBCL. Several agents have been developed to inhibit BCL2 and its antiapoptotic family members, including small-molecule BH3-mimetic compounds such as ABT-737 and obatoclax. Simultaneous inhibition of MALT1 and BCL2 would be expected to reduce NF-B activation and induce apoptosis, with potential to synergistically kill lymphoma cells. The BCL6 gene is also frequently translocated or mutated, resulting in its deregulated expression in ABC-DLBCL, where it suppresses cell-cycle checkpoint genes as well as terminal differentiation through repression of PRDM1 and other genes. Peptidomimetic and small-molecule inhibitors of BCL6 that disrupt its ability to form repression complexes have potent antilymphoma activity against DLBCLs, including ABC-DLBCLs. BCL6 inhibitors do not seem to induce toxic effects in animals, supporting the suitability of their use in combinatorial regimens. Concurrent inhibition of MALT1 paracaspase activity and BCL6 would be expected to simultaneously attenuate NF-B activation and promote checkpoint growth suppression and apoptosis. MYC is frequently overexpressed in DLBCL. Deregulated expression of MYC affects many cellular processes, including proliferation, differentiation, and metabolism. An inhibitor of the bromodomain-containing protein 4 (BRD4), JQ1 downregulates MYC transcription, resulting in downregulation of MYC-induced target genes. JQ1 caused cell-cycle arrest and cellular senescence in multiple myeloma, Burkitt lymphoma, and acute myeloid leukemia. Combination of MALT1 inhibition with JQ1 is expected to synergistically collaborate to kill lymphoma by concomitantly affecting fundamental pathways for cell proliferation. Around 30% of ABC-DLBCLs display activating mutations of MYD88 that in a large proportion of the cases coexist with B-cell receptor activating mutations, therefore combination of MALT1 inhibition with TLR 7/8/9 antagonist or inhibition of MYD88 or its downstream targets IRAK1 and IRAK4 is expected to synergistically kill lymphoma by parallel inhibition of the two pathways. Hsp90 is a heat shock protein required for survival of cancer cells and in particular DLBCL. There are several inhibitors of Hsp90 in clinical trials including 17-N-Allylamino-17-demethoxygeldanamycin (17AAG) and PUH71. Hsp90 inhibition has been shown to inhibit NF-B signaling at various levels and concomitant treatment with MALT1 inhibition is expected to have additive or synergistic effect in killing DLBCL.

[0328] In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a proliferative disease (e.g., cancer (e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, MALT lymphoma), benign neoplasm, a disease associated with angiogenesis, an autoimmune disease, an inflammatory disease, an autoinflammatory disease). Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0329] The additional pharmaceutical agents include, but are not limited to, anti-diabetic agents, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, anti-bacterial agents, anti-viral agents, cardiovascular agents, and pain-relieving agents. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-angiogenesis agent. In certain embodiments, the additional pharmaceutical agent is an anti-inflammatory agent. In certain embodiments, the additional pharmaceutical agent inhibits MALT1.

[0330] In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, transplantation (e.g., bone marrow transplantation, stem cell transplantation), surgery, radiation therapy, immunotherapy, and chemotherapy.

[0331] In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent (e.g., anti-cancer agent). In certain embodiments, the additional pharmaceutical agent is an anti-leukemia agent. In certain embodiments, the additional pharmaceutical agent is an anti-lymphoma agent. In certain embodiments, the additional pharmaceutical agent is an anti-myelodysplasia agent. In certain embodiments, the additional pharmaceutical agent is an agent listed elsewhere herein.

[0332] In certain embodiments, the additional pharmaceutical agent is rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, prednisolone, lenalidomide, etoposide, or bortezomib, or a combination thereof. In certain embodiments, the additional pharmaceutical agent is a proteasome inhibitor (e.g., bortezomib). In certain embodiments, the compound or pharmaceutical composition described herein is administered in combination with a chemotherapy regimen, such as CHOP or R-CHOP. CHOP comprises administration of cyclophosphamide, hydroxydaunorubicin, vincristine (ONCOVIN), and prednisone or prednisolone. R-CHOP adds rituximab to the CHOP regimen.

[0333] In certain embodiments, the additional pharmaceutical agent is an upstream-BCR-pathway inhibitor. In certain embodiments, the additional pharmaceutical agent is a PI3K inhibitor (e.g., BEZ235, BKM120, GDC-0941, BYL719, CAL-101, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof). In certain embodiments, the PI3K inhibitor is tozasertib, GSK1059615, PX866, LY294002, SF1126, XL147, XL765, BGT226, BAY80946, BAY841236, GDC-0941, GDC-0032, GDC-0980, GDC-0941, PX-866, GSK2126458, INK1117, ZSTK474, PWT33597, AEZS-136, PKI-587, PF-4691502, PF-05212384, wortmannin, demethoxyviridin, pictilisib, idelalisib, IPI-145, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, the additional pharmaceutical agent is a SYK inhibitor (e.g., Staurosporine (antibiotic AM-2282), BAY 61-3606 (SYK Inhibitor IV), Piceatannol (astringinin), R406, PKC-412, R788 (Fostamatinib), 2-(2-aminoethylamino)-4-(3-trifluoromethylanilino)-pyrimidine-5-carboxamide (SYK Inhibitor II), MNS (SYK Inhibitor III), (2-oxo-morpholin-4-yl)-acetic acid, PRT062607 (P505-15, BIIB057), Entospletinib (GS-9973), PRT318, P505-15, ER-27139, R112, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof). In certain embodiments, the additional pharmaceutical agent is a BTK inhibitor (e.g., GDC-0834, CGI-560, CGI-1746, HM-71224, CC-292 (AVL-292), ONO-4059, CNX-774, LFM-A13, PCI-32765 (Imbruvica), QL47, BGB-3111, ACP-196, Ibrutinib, LMA-13 (-cyano--hydroxy--methyl-N-(2,5dibromophenyl)propenamide), DDE11, CI32765, AVL-292, AVL-101, PRN1008, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof). In certain embodiments, the additional pharmaceutical agent is a MAPK inhibitor (e.g., AMG548, AS1940477, CBS3830, Dilmapimod (SB-6813123), Doramapimod (BIRB-796), FR-167653, JLU1124, LASSBio-998, Losmapimod (GW856553), LY2228820, LY3007113, ML3403, Pamapimod, PD-98059 (PD098059), PD-169316, PH-797804, R-130823, RO3201195, RPR-200765A, RPR-203494, RWJ-67657, SB-202190, SB-203580, SB-239063, SB-242235, SCIO-323, SD-282, Semapimod (CNI-1493), Soblidotin (TZT-1027), TAK-715, Talmapimod (SCIO-469), UO126, UR-13756, VX-702, VX-745, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof). In certain embodiments, the additional pharmaceutical agent is a JNK inhibitor (e.g., AS007149, AS601245, Berberine, CDDO-Me (Triterpenoid), Curcumin, DA-125, DIM, echinocystic acid, Eupalmerin acetate, Isoobtusilactone A, Mangostin, Norcantharidin, Plumbagin, Rocaglamide, SAMC, SP-600125 (anthrapyrazolone), SP600129, Tanzisertib (CC-930), Tetrahydroxyquinone, Vitamin E succinate, XG-102 (D-JNKI-1), RWJ 67657, CC-401, Bentamapimod, Aloisine A, AEG 3482, BI 78D3, SU 3327, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof). In certain embodiments, the additional pharmaceutical agent is a NFAT inhibitor (e.g., VIVIT peptide, MAGPHPVIVITGPHEE (SEQ ID NO: 3), cyclosporin-A (CsA), FK506, Tacrolimus, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof). In certain embodiments, the additional pharmaceutical agent is a BCL2 inhibitor (e.g., ABT-737, ABT 263 (Navitoclax), Gossypol, ()-Epigallocatechin gallate, Obatoclax, Licochalcone A, HA14-1, TW-37, EM20-25, 4-methoxy-2-[2-(5-methoxy-2-nitrosophenyl)ethyl]-1-nitrosobenzene, Nilotinib-d3, YC137, ABT 737-d8, ABT 263-d8, 2-Methoxy-antimycin A3, ABT-199 (Venetoclax, GDC-0199), Gambogic acid, Nilotinib, Obatoclax (GX15-070), UMI-77, Sabutoclax, AT101, BAM7, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof). In certain embodiments, the additional pharmaceutical agent is a BCL6 inhibitor (e.g., 2-((5Z)-5-(5-bromo-2-oxo-1H-indol-3-ylidene)-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl)butanedioic acid (CID5721353), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof). In certain embodiments, the additional pharmaceutical agent is a MYC inhibitor (e.g., F3680 (10058-F4), Omomyc, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof). In certain embodiments, the additional pharmaceutical agent is a bromodomain-containing protein inhibitor (e.g., bromodomain-containing protein 2 (BRD2) inhibitor, bromodomain-containing protein 3 (BRD3) inhibitor, bromodomain-containing protein 4 (BRD4) inhibitor, TBP (TATA box binding protein)-associated factor protein (TAF) inhibitor, CREB-binding protein (CBP) inhibitor, or E1A binding protein p300 (EP300) inhibitor). In certain embodiments, the bromodomain-containing protein inhibitor is JQ1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, the bromodomain-containing protein inhibitor is I-BET 151, I-BET 762, OTX-015, TEN-010, CPI-203, CPI-0610, RVX-208, LY294002, BMS-986158, GSK525762, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, the additional pharmaceutical agent is a TLR 7/8/9 antagonist (e.g., IRS 661, IRS 954, Chloroquine (NBP2-29386), Quinacrine (NBP2-29385), IMO-8400, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof). In certain embodiments, the additional pharmaceutical agent is a MYD88 inhibitor (e.g., Pepinh-MYD, ST 2825, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof). In certain embodiments, the additional pharmaceutical agent is an IRAK1 inhibitor (e.g., 1-(2-(4-Morpholinyl)ethyl)-2-(3-nitrobenzoylamino)benzimidazole, Pacritinib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof). In certain embodiments, the additional pharmaceutical agent is an IRAK4 inhibitor (e.g., 1-(2-(4-Morpholinyl)ethyl)-2-(3-nitrobenzoylamino)benzimidazole, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof). In certain embodiments, the additional pharmaceutical agent is a Hsp90 inhibitor (e.g., Tanespimycin (17-N-allylamino-17-demethoxygeldanamycin (17-AAG)), Luminespib (AUY-922, NVP-AUY922), 17-DMAG (Alvespimycin), Ganetespib (STA-9090), VER155008, PUH71, HSP990 (NVP-HSP990), BIIBO21, AICAR, Geldanamycin, IPI-504, Radicicol, Herbimycin A, Gedunin, Celastrol, Celastrus scandens, NVP-AUY922, Novobiocin, Macbecin I, MPC-3100, CAY10607, 17-GMB-APA-GA, 17-AEP-GA, 17-DMAP-GA, KW-2478, NVP-BEP800, AT13387, Nelfinavir, Novobiocin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof). In certain embodiments, the additional pharmaceutical agent is BEZ235, BKM120, GDC-0941, BYL719, CAL-101, R-406, Fostamatinib, Ibrutinib, CC-292, ABT-737, obatoclax, JQ1, 17AAG, PUH71, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0334] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and optionally a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.

[0335] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a proliferative disease (e.g., cancer (e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, MALT lymphoma), benign neoplasm, a disease associated with angiogenesis, an autoimmune disease, an inflammatory disease, an autoinflammatory disease) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a proliferative disease (e.g., cancer (e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, MALT lymphoma), benign neoplasm, a disease associated with angiogenesis, an autoimmune disease, an inflammatory disease, an autoinflammatory disease) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing proliferative disease (e.g., cancer (e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, MALT lymphoma), benign neoplasm, a disease associated with angiogenesis, an autoimmune disease, an inflammatory disease, an autoinflammatory disease) in a subject in need thereof. In certain embodiments, the kits are useful for inhibiting MALT1, or a MALT1 fusion protein (e.g., API2-MALT1) in a subject.

[0336] In certain embodiments, a kit described herein further includes instructions for using the kit (e.g., instructions for using the compound or pharmaceutical composition included in the kit, such as instructions for administering the compound or pharmaceutical composition to a subject in need thereof). A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a proliferative disease (e.g., cancer (e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, MALT lymphoma), benign neoplasm, a disease associated with angiogenesis, an autoimmune disease, an inflammatory disease, an autoinflammatory disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a proliferative disease (e.g., cancer (e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, MALT lymphoma), benign neoplasm, a disease associated with angiogenesis, an autoimmune disease, an inflammatory disease, an autoinflammatory disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing proliferative disease (e.g., cancer (e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, MALT lymphoma), benign neoplasm, a disease associated with angiogenesis, an autoimmune disease, an inflammatory disease, an autoinflammatory disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for inhibiting MALT1 in a subject or in an infectious microorganism. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

Methods of Treatment and Uses

[0337] The present invention also provides methods for the treatment or prevention of a proliferative disease. In certain embodiments, the proliferative disease is cancer. In certain embodiments, the disease in an autoimmune disease. In certain embodiments, the proliferative disease is benign neoplasm, a disease associated with angiogenesis, an inflammatory disease, an autoinflammatory disease, or an autoimmune disease. In certain embodiments, the cancer is a lymphoma. In certain embodiments, the cancer is a leukemia. In certain embodiments, the cancer is Hodgkin's lymphoma. In certain embodiments, the cancer is non-Hodgkin's lymphoma. In certain embodiments, the cancer is Burkitt's lymphoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In certain embodiments, the cancer is MALT lymphoma. In some embodiments, the cancer is germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) or primary mediastinal B-cell lymphoma (PMBL). In some embodiments, the cancer is activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL).

[0338] The compounds described herein (e.g., compounds of Formula (I)) may exhibit a therapeutic and/or preventative effect in the treatment of proliferative diseases (e.g., cancer (e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, MALT lymphoma), benign neoplasm, a disease associated with angiogenesis, an autoimmune disease, an inflammatory disease, an autoinflammatory disease) and/or may exhibit a therapeutic or preventative effect superior to existing agents for treatment of a proliferative disease. Additionally, the compounds described herein (e.g., compounds of Formula (I)) may exhibit inhibitory activity towards mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) or a MALT1 fusion protein (e.g., API2-MALT1); may exhibit the ability to inhibit cleavage of a peptide selected from A20, Bcl10, RelB, CYLD, NIK, regnase-1, roquin-1, roquin-2, LIMA1, and MALT1; may exhibit the ability to inhibit activation of nuclear factor-B (NF-B); may exhibit the ability to down-regulate expression of a gene selected from FLIP, A1, A20, IL-2, IL-6, IL-10 or STAT3; may exhibit the ability to inhibit phosphorylation of STAT3; may inhibit T-cell or B-cell activation and/or may inhibit T-cell or B-cell proliferation.

[0339] The compounds described herein (e.g., compounds of Formula (I)) may exhibit selective inhibition of MALT1 or a MALT1 fusion protein (e.g., API2-MALT1) versus inhibition of other proteins. In certain embodiments, the compound of Formula (I) selectively inhibits MALT1 or API2-MALT1 over another protease. In certain embodiments, the compound of Formula (I) selectively inhibits MALT1 or API2-MALT1 over another paracaspase. In certain embodiments, the selectivity versus inhibition of another protein is between about 2 fold and about 10 fold. In certain embodiments, the selectivity is between about 10 fold and about 50 fold. In certain embodiments, the selectivity is between about 50 fold and about 100 fold. In certain embodiments, the selectivity is between about 100 fold and about 500 fold. In certain embodiments, the selectivity is between about 500 fold and about 1000 fold. In certain embodiments, the selectivity is between about 1000 fold and about 5000 fold. In certain embodiments. In certain embodiments, the selectivity is between about 5000 fold and about 10000 fold. In certain embodiments, or at least about 10000 fold.

[0340] The present invention provides methods that may be useful for the treatment of an proliferative disease by administering a compound described herein, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or prodrug thereof, or pharmaceutical composition thereof, to a subject in need thereof. In certain embodiments, the compound is administered as a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In certain embodiments, the compound is administered as a pharmaceutically acceptable salt of the compound. In certain embodiments, the compound is administered as a specific stereoisomer or mixture of stereoisomers of the compound. In certain embodiments, the compound is administered as a specific tautomer or mixture of tautomers of the compound. In certain embodiments, the compound is administered as a pharmaceutical composition as described herein comprising the compound.

[0341] The present invention also provides uses of the inventive compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, prodrugs, and pharmaceutical compositions thereof, in the manufacture of medicaments for the treatment and prevention of a proliferative disease. In certain embodiments, the proliferative disease is cancer. In certain embodiments, the proliferative disease is benign neoplasm, a disease associated with angiogenesis, an inflammatory disease, an autoinflammatory disease, or an autoimmune disease. In certain embodiments, the cancer is a lymphoma. In certain embodiments, the cancer is a leukemia. In certain embodiments, the cancer is Hodgkin's lymphoma. In certain embodiments, the cancer is non-Hodgkin's lymphoma. In certain embodiments, the cancer is Burkitt's lymphoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In certain embodiments, the cancer is MALT lymphoma. In some embodiments, the cancer is germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) or primary mediastinal B-cell lymphoma (PMBL). In some embodiments, the cancer is activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL).

[0342] In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0343] In certain embodiments, the proliferative disease to be treated or prevented using the compounds described herein is cancer. All types of cancers disclosed herein or known in the art are contemplated as being within the scope of the invention. In certain embodiments, the proliferative disease is a cancer associated with or dependent on MALT1. In certain embodiments, the proliferative disease is a cancer associated with or dependent on a MALT1 fusion protein (e.g., API2-MALT1). In certain embodiments, the proliferative disease is a cancer associated with dependence on B-cell lymphoma 10 (Bcl10). In certain embodiments, the proliferative disease is a cancer associated with dependence on caspase recruitment domain-containing protein (CARD1). In certain embodiments, the proliferative disease is a cancer associated with dependence on NF-B. Exemplary cancers include, but are not limited to, hematological malignancies. Additional exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast, triple negative breast cancer (TNBC)); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarcinoma); Ewing's sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease; hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

[0344] In certain embodiments, the cancer is a hematological malignancy. Exemplary hematological malignancies include, but are not limited to, leukemia, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma, such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL, e.g., activated B-cell (ABC) DLBCL (ABC-DLBCL))), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, Waldenstrim's macroglobulinemia (WM, lymphoplasmacytic lymphoma), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, central nervous system (CNS) lymphoma (e.g., primary CNS lymphoma and secondary CNS lymphoma); and T-cell NHL, such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); lymphoma of an immune privileged site (e.g., cerebral lymphoma, ocular lymphoma, lymphoma of the placenta, lymphoma of the fetus, testicular lymphoma); a mixture of one or more leukemia/lymphoma as described above; myelodysplasia; and multiple myeloma (MM).

[0345] In certain embodiments, the disease is an autoimmune disease. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis/polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barr syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

[0346] In certain embodiments, the disease is a cancer associated with a viral infection. In some embodiments, the disease is a cancer resulting from infection with an oncovirus. In some embodiments, the oncovirus is hepatitis A, hepatitis B, hepatitis C, human T-lymphotropic virus (HTLV), human papillomavirus (HPV), Kaposi's sarcoma-associated herpesvirus (HHV-8), Merkel cell polyomavirus, or Epstein-Barr virus (EBV). In some embodiments, the disease is human T-lymphotropic virus. In some embodiments, the disease is Kaposi's sarcoma-associated herpesvirus. In some embodiments, the disease is Epstein-Barr virus. Leukemias and lymphomas which may be associated with an oncoviral include: for HTLV, adult T-cell leukemia; for HHV-8, Castleman's disease and primary effusion lymphoma; and for EBV, Burkitt's lymphoma, Hogdkin's lymphoma, and post-transplant lymphoproliferative disease.

[0347] In another aspect, provided herein are methods of down-regulating expression of a gene in a subject by administering to the subject a compound described herein (e.g., a compound of Formula (I)), or down-regulating expression of a gene in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula (I)). In some embodiments, the gene which is down-regulated is a NF-B dependent gene. Genes which may be down-regulated include, but are not limited to, FLIP, A1, A20, IL-2, IL-6, IL-8, IL-10 and STAT3.

[0348] In another aspect, provided herein are methods of inhibiting cell proliferation in a subject by administering to the subject a compound described herein (e.g., a compound of Formula (I)), or inhibiting cell proliferation in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula (I)). In some embodiments, cell proliferation is inhibited for T-cells. In some embodiments, cell proliferation is inhibited for B-cells. In some embodiments, cell proliferation is inhibited for T-cells and B-cells.

[0349] In another aspect, provided herein are methods of inducing apoptosis of a cell in a subject by administering to the subject a compound described herein (e.g., a compound of Formula (I)), or inducing apoptosis of a cell in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula (I)). In some embodiments, cell is a tumor cell. In some embodiments, the cell is a lymphocyte. In some embodiments, the cell is a T-cell. In some embodiments, the cell is a B-cell.

[0350] In another aspect, provided herein are methods of inhibiting adhesion of a cell in a subject by administering to the subject a compound described herein (e.g., a compound of Formula (I)), or inhibiting adhesion of a cell in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula (I)). In some embodiments, cell is a tumor cell. In some embodiments, the cell is a lymphocyte. In some embodiments, the cell is a T-cell. In some embodiments, the cell is a B-cell.

[0351] In another aspect, provided herein are methods of inhibiting activation of T-cells or B-cells in a subject by administering to the subject a compound described herein (e.g., a compound of Formula (I)), or inhibiting activation of T-cells or B-cells in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula (I)).

[0352] In another aspect, provided herein are methods of inhibiting activation of nuclear factor B (NF-B) in a subject by administering to the subject a compound described herein (e.g., a compound of Formula (I)), or inhibiting activation of nuclear factor B (NF-B) in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula (I)).

[0353] In another aspect, provided herein are methods of inhibiting the activity of mucosa-associated lymphoid tissue lymphoma translation protein 1 (MALT1) or a MALT1 fusion protein in a subject by administering to the subject a compound described herein (e.g., a compound of Formula (I)), or inhibiting the activity of mucosa-associated lymphoid tissue lymphoma translation protein 1 (MALT1) or a MALT1 fusion protein in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula (I)). In certain embodiments, the method inhibits the protease activity of MALT1. In certain embodiments, the method inhibits the protease activity of a MALT1 fusion protein (e.g., API2-MALT1). In certain embodiments, the method inhibits the protease activity of MALT1 or a MALT1 fusion protein for cleavage of a peptide substrate. In certain embodiments, the peptide substrate is A20, Bcl10, RelB, CYLD, NIK, regnase-1, roquin-1, roquin-2, LIMA1, or MALT1. The inhibitor may selectively inhibit the protease activity of MALT1 or a MALT1 fusion protein for cleavage of a first peptide substrate over protease activity for cleavage of a second peptide substrate. In some embodiments, the first and/or second substrate is A20, Bcl10, RelB, CYLD, NIK, regnase-1, roquin-1, roquin-2, LIMA1, or MALT1. In certain embodiments, the selectivity is between about 1.25 fold and about 5 fold. In certain embodiments, the selectivity is between about 5 fold and about 10 fold. In certain embodiments, the selectivity is between about 10 fold and about 25 fold. In certain embodiments, the selectivity is between about 25 fold and about 50 fold. In certain embodiments, the selectivity is between about 50 fold and about 100 fold. In certain embodiments, the selectivity is between about 100 fold and about 250 fold. In certain embodiments. In certain embodiments, the selectivity is between about 250 fold and about 500 fold. In certain embodiments, the selectivity is between about 500 fold and about 1000 fold. In certain embodiments, or at least about 1000 fold.

[0354] In another aspect, provided herein are methods of modulating cytokine production in a subject by administering to the subject a compound described herein (e.g., a compound of Formula (I)), or modulating cytokine production in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula (I)). In some embodiments, the method inhibits production of a cytokine selected from IL-2, IL-6, IL-8, IL-10, or IL-17. In some embodiments, the method promotes production of a cytokine selected from IL-2, IL-6, IL-8, IL-10, or IL-17. In some embodiments, the method inhibits production of cytokines in T-cells. In some embodiments, the method inhibits production of cytokines in B-cells.

[0355] In another aspect, provided herein are methods of inhibiting phosphorylation of a c-Jun N-terminal kinase (JNK) in a subject by administering to the subject a compound described herein (e.g., a compound of Formula (I)), or inhibiting phosphorylation of a c-Jun N-terminal kinase (JNK) in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula (I)).

[0356] In another aspect, provided herein are methods of inhibiting lymphocyte adhesion to fibronectin in a subject by administering to the subject a compound described herein (e.g., a compound of Formula (I)), or inhibiting lymphocyte adhesion to fibronectin in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula (I)).

[0357] In another aspect, provided herein are methods of up-regulating expression of a gene by administering to the subject a compound described herein (e.g., a compound of Formula (I)), or up-regulating expression of a gene in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula (I)). In some embodiments, the gene encodes a transcription factor or transcriptional regulator. In some embodiments, the transcription factor is c-Rel or IRF4. In some embodiments, the transcription factor is IBNS or IB. In some embodiments, the gene encodes a cytokine (e.g., IL-17). In some embodiments, the gene is up-regulating by inhibiting degradation of a mRNA. In some embodiments, the mRNA is encoding a T-cell effector gene. In some embodiments, the mRNA is encoding a gene selected from IL-2, IL-6, c-Rel, or Ox40.

[0358] In another aspect, provided herein are methods of inhibiting phosphorylation of STAT3 in a subject by administering to the subject a compound described herein (e.g., a compound of Formula (I)), or inhibiting phosphorylation of STAT3 in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula (I)).

[0359] Certain methods described herein, may further comprise administering one or more additional pharmaceutical agents in combination with the compounds described herein, or administration of the compounds described herein may be combined with other treatment methods, e.g., an anti-cancer therapy. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, transplantation (e.g., bone marrow transplantation, stem cell transplantation), surgery, radiation therapy, immunotherapy, and chemotherapy. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a proliferative disease (e.g., cancer (e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, MALT lymphoma), benign neoplasm, a disease associated with angiogenesis, an autoimmune disease, an inflammatory disease, an autoinflammatory disease). Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0360] The additional pharmaceutical agents include, but are not limited to, anti-diabetic agents, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, anti-bacterial agents, anti-viral agents, cardiovascular agents, and pain-relieving agents. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-angiogenesis agent. In certain embodiments, the additional pharmaceutical agent is an anti-inflammatory agent. In certain embodiments, the additional pharmaceutical agent inhibits MALT1. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-leukemia agent. In certain embodiments, the additional pharmaceutical agent is an anti-leukemia agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ADE, Adriamycin RDF (doxorubicin hydrochloride), Ambochlorin (chlorambucil), ARRANON (nelarabine), ARZERRA (ofatumumab), BOSULIF (bosutinib), BUSULFEX (busulfan), CAMPATH (alemtuzumab), CERUBIDINE (daunorubicin hydrochloride), CLAFEN (cyclophosphamide), CLOFAREX (clofarabine), CLOLAR (clofarabine), CVP, CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), ERWINAZE (Asparaginase Erwinia Chrysanthemi), FLUDARA (fludarabine phosphate), FOLEX (methotrexate), FOLEX PFS (methotrexate), GAZYVA (obinutuzumab), GLEEVEC (imatinib mesylate), Hyper-CVAD, ICLUSIG (ponatinib hydrochloride), IMBRUVICA (ibrutinib), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), MARQIBO (vincristine sulfate liposome), METHOTREXATE LPF (methorexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), mitoxantrone hydrochloride, MUSTARGEN (mechlorethamine hydrochloride), MYLERAN (busulfan), NEOSAR (cyclophosphamide), ONCASPAR (Pegaspargase), PURINETHOL (mercaptopurine), PURIXAN (mercaptopurine), Rubidomycin (daunorubicin hydrochloride), SPRYCEL (dasatinib), SYNRIBO (omacetaxine mepesuccinate), TARABINE PFS (cytarabine), TASIGNA (nilotinib), TREANDA (bendamustine hydrochloride), TRISENOX (arsenic trioxide), VINCASAR PFS (vincristine sulfate), ZYDELIG (idelalisib), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is an anti-lymphoma agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABVD, ABVE, ABVE-PC, ADCETRIS (brentuximab vedotin), ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride), AMBOCHLORIN (chlorambucil), AMBOCLORIN (chlorambucil), ARRANON (nelarabine), BEACOPP, BECENUM (carmustine), BELEODAQ (belinostat), BEXXAR (tositumomab and iodine I 131 tositumomab), BICNU (carmustine), BLENOXANE (bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN (cyclophosphamide), COPP, COPP-ABV, CVP, CYTOXAN (cyclophosphamide), DEPOCYT (liposomal cytarabine), DTIC-DOME (dacarbazine), EPOCH, FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLOTYN (pralatrexate), HYPER-CVAD, ICE, IMBRUVICA (ibrutinib), INTRON A (recombinant interferon alfa-2b), ISTODAX (romidepsin), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), Lomustine, MATULANE (procarbazine hydrochloride), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MOPP, MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), NEOSAR (cyclophosphamide), OEPA, ONTAK (denileukin diftitox), OPPA, R-CHOP, REVLIMID (lenalidomide), RITUXAN (rituximab), STANFORD V, TREANDA (bendamustine hydrochloride), VAMP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VINCASAR PFS (vincristine sulfate), ZEVALIN (ibritumomab tiuxetan), ZOLINZA (vorinostat), ZYDELIG (idelalisib), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is an anti-myelodysplasia agent. In certain embodiments, the additional pharmaceutical agent is REVLIMID (lenalidomide), DACOGEN (decitabine), VIDAZA (azacitidine), CYTOSAR-U (cytarabine), IDAMYCIN (idarubicin), CERUBIDINE (daunorubicin), or a combination thereof.

[0361] In certain embodiments, the additional pharmaceutical agent is an anti-macroglobulinemia agent. In certain embodiments, the additional pharmaceutical agent is LEUKERAN (chlorambucil), NEOSAR (cyclophosphamide), FLUDARA (fludarabine), LEUSTATIN (cladribine), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABRAXANE (paclitaxel albumin-stabilized nanoparticle formulation), AC, AC-T, ADE, ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRUCIL (fluorouracil), AFINITOR (everolimus), AFINITOR DISPERZ (everolimus), ALDARA (imiquimod), ALIMTA (pemetrexed disodium), AREDIA (pamidronate disodium), ARIMIDEX (anastrozole), AROMASIN (exemestane), AVASTIN (bevacizumab), BECENUM (carmustine), BEP, BICNU (carmustine), BLENOXANE (bleomycin), CAF, CAMPTOSAR (irinotecan hydrochloride), CAPOX, CAPRELSA (vandetanib), CARBOPLATIN-TAXOL, CARMUBRIS (carmustine), CASODEX (bicalutamide), CEENU (lomustine), CERUBIDINE (daunorubicin hydrochloride), CERVARIX (recombinant HPV bivalent vaccine), CLAFEN (cyclophosphamide), CMF, COMETRIQ (cabozantinib-s-malate), COSMEGEN (dactinomycin), CYFOS (ifosfamide), CYRAMZA (ramucirumab), CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), DACOGEN (decitabine), DEGARELIX, DOXIL (doxorubicin hydrochloride liposome), DOXORUBICIN HYDROCHLORIDE, DOX-SL (doxorubicin hydrochloride liposome), DTIC-DOME (dacarbazine), EFUDEX (fluorouracil), ELLENCE (epirubicin hydrochloride), ELOXATIN (oxaliplatin), ERBITUX (cetuximab), ERIVEDGE (vismodegib), ETOPOPHOS (etoposide phosphate), EVACET (doxorubicin hydrochloride liposome), FARESTON (toremifene), FASLODEX (fulvestrant), FEC, FEMARA (letrozole), FLUOROPLEX (fluorouracil), FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, GARDASIL (recombinant human papillomavirus (HPV) quadrivalent vaccine), GEMCITABINE-CISPLATIN, GEMCITABINE-OXALIPLATIN, GEMZAR (gemcitabine hydrochloride), GILOTRIF (afatinib dimaleate), GLEEVEC (imatinib mesylate), GLIADEL (carmustine implant), GLIADEL WAFER (carmustine implant), HERCEPTIN (trastuzumab), HYCAMTIN (topotecan hydrochloride), IFEX (ifosfamide), IFOSFAMIDUM (ifosfamide), INLYTA (axitinib), INTRON A (recombinant interferon alfa-2b), IRESSA (gefitinib), IXEMPRA (ixabepilone), JAKAFI (ruxolitinib phosphate), JEVTANA (cabazitaxel), KADCYLA (ado-trastuzumab emtansine), KEYTRUDA (pembrolizumab), KYPROLIS (carfilzomib), LIPODOX (doxorubicin hydrochloride liposome), LUPRON (leuprolide acetate), LUPRON DEPOT (leuprolide acetate), LUPRON DEPOT-3 MONTH (leuprolide acetate), LUPRON DEPOT-4 MONTH (leuprolide acetate), LUPRON DEPOT-PED (leuprolide acetate), MEGACE (megestrol acetate), MEKINIST (trametinib), METHAZOLASTONE (temozolomide), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MITOXANTRONE HYDROCHLORIDE, MITOZYTREX (mitomycin c), MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), MUTAMYCIN (mitomycin c), MYLOSAR (azacitidine), NAVELBINE (vinorelbine tartrate), NEOSAR (cyclophosphamide), NEXAVAR (sorafenib tosylate), NOLVADEX (tamoxifen citrate), NOVALDEX (tamoxifen citrate), OFF, PAD, PARAPLAT (carboplatin), PARAPLATIN (carboplatin), PEG-INTRON (peginterferon alfa-2b), PEMETREXED DISODIUM, PERJETA (pertuzumab), PLATINOL (cisplatin), PLATINOL-AQ (cisplatin), POMALYST (pomalidomide), prednisone, PROLEUKIN (aldesleukin), PROLIA (denosumab), PROVENGE (sipuleucel-t), REVLIMID (lenalidomide), RUBIDOMYCIN (daunorubicin hydrochloride), SPRYCEL (dasatinib), STIVARGA (regorafenib), SUTENT (sunitinib malate), SYLATRON (peginterferon alfa-2b), SYLVANT (siltuximab), SYNOVIR (thalidomide), TAC, TAFINLAR (dabrafenib), TARABINE PFS (cytarabine), TARCEVA (erlotinib hydrochloride), TASIGNA (nilotinib), TAXOL (paclitaxel), TAXOTERE (docetaxel), TEMODAR (temozolomide), THALOMID (thalidomide), TOPOSAR (etoposide), TORISEL (temsirolimus), TPF, TRISENOX (arsenic trioxide), TYKERB (lapatinib ditosylate), VECTIBIX (panitumumab), VEIP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VEPESID (etoposide), VIADUR (leuprolide acetate), VIDAZA (azacitidine), VINCASAR PFS (vincristine sulfate), VOTRIENT (pazopanib hydrochloride), WELLCOVORIN (leucovorin calcium), XALKORI (crizotinib), XELODA (capecitabine), XELOX, XGEVA (denosumab), XOFIGO (radium 223 dichloride), XTANDI (enzalutamide), YERVOY (ipilimumab), ZALTRAP (ziv-aflibercept), ZELBORAF (vemurafenib), ZOLADEX (goserelin acetate), ZOMETA (zoledronic acid), ZYKADIA (ceritinib), ZYTIGA (abiraterone acetate), or a combination thereof.

[0362] In certain embodiments, the additional pharmaceutical agent is rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, prednisolone, lenalidomide, etoposide, or bortezomib, or a combination thereof. In certain embodiments, the additional pharmaceutical agent is a proteasome inhibitor (e.g., bortezomib). In certain embodiments, the compound or pharmaceutical composition described herein is administered in combination with a chemotherapy regimen, such as CHOP or R-CHOP. CHOP comprises administration of cyclophosphamide, hydroxydaunorubicin, vincristine (ONCOVIN), prednisone, prednisolone, or rituximab.

EXAMPLES

[0363] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

Synthesis of the Compounds

[0364] Exemplary compounds of Formula (I) were prepared according to the Schemes E1 to E4. Generally, the sequence begins with preparation of a dipeptide ester (e.g., DE-101) by coupling of two protected amino acids. Hydrolysis of the ester affords a dipeptide acid (e.g., DA-101), which is coupled with an arginine analog followed by deprotection to give the Compound of Formula (I) (e.g., 101).

[0365] Compounds 101-111 were prepared according to Scheme E1. For Compound 101, N-((benzyloxy)carbonyl) protected valine and proline methyl ester were combined, and the methyl ester deprotected with base to give the dipeptide acid Z-VP. The second peptide bond was formed by coupling Pmc-arginine-fmk with the dipeptide acid. Deprotection of the guanidine with TFA afforded compound 101 (Z-VPR-fmk). Compounds 102-111 were made by an analogous route with different amino acids in place of valine or proline, or both.

##STR00164##

Benzyl ((S)-1-((S)-2-(((S)-1-fluoro-6-guanidino-2-oxohexan-3-yl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate 2,2,2-trifluoroacetate (Compound 101)

[0366] ##STR00165##

[0367] (S)N(N-(4-amino-6-fluoro-5-oxohexyl)carbamimidoyl)-2,2,5,7,8-pentamethylchromane-6-sulfonamide 2,2,2-trifluoroacetate (PmcR-fmk, 0.10 g, 0.175 mmol), HATU (0.166 g, 0.438 mmol) and DIPEA (0.38 mL, 2.19 mmol) were added to a solution of ((benzyloxy)carbonyl)-L-valyl-L-proline (0.084 g, 0.241 mmol) in DMF (3 mL) and the mixture was stirred for 10 minutes. The reaction mixture was purified by reverse-phase HPLC (10-100% CH.sub.3CN in H.sub.2O) and the resulting brown oil was dissolved in a mixture of 90% TFA in DCM (30 mL) and stirred for 1 hour. The solvent was removed under reduced pressure and the residue purified by reverse-phase HPLC (1-50% CH.sub.3CN in H.sub.2O) to give a brown oil (0.018 g, 16% yield over 2 steps). 1H NMR (500 MHz, d.sub.6-DMSO) 8.51 (d, 1H), 7.48 (t, 1H), 7.42 (d, 1H), 7.36 (m, 5H), 5.21 (dd, 1H), 5.12 (dd, 1H), 5.05 (d, 1H), 4.99 (d, 1H), 4.31 (m, 1H), 4.20 (m, 1H), 4.05 (m, 1H), 3.75 (m, 1H), 3.58 (m, 1H), 3.09 (m, 2H), 2.09 (m, 1H), 1.90 (m, 3H), 1.78 (m, 2H), 1.48 (m, 3H), 0.91 (d, 3H), 0.88 (s, 3H); .sup.19F NMR (500 MHz) 232.48 (t, 1F); MS (m/z): 521.4 [M+1].sup.+.

((Benzyloxy)carbonyl)-L-valyl-L-proline (DA-101)

[0368] ##STR00166##

[0369] LiOH monohydrate (0.116 g, 2.76 mmol) in H.sub.2O (20 mL) was added to a solution of methyl ((benzyloxy)carbonyl)-L-valyl-L-prolinate (0.50 g, 1.38 mmol) in THF (50 mL). The reaction mixture was stirred for 4 hours, then diluted with H.sub.2O (50 mL), acidified to pH 4 with 3N HCl solution and extracted with EtOAc (350 mL). The combined organic layer was washed with brine, dried (MgSO.sub.4) and concentrated to give a white solid (0.45 g, 94% yield). MS (m/z): 348.3 [M+1].sup.+.

Methyl ((benzyloxy)carbonyl)-L-valyl-L-prolinate (DE-101)

[0370] ##STR00167##

[0371] HATU (3.03 g, 7.95 mmol) and DIPEA (3.46 mL, 19.9 mmol) were added to a solution of ((benzyloxy)carbonyl)-L-valine (1.0 g, 3.98 mmol) and methyl L-prolinate (0.51 g, 3.98 mmol) in DCM (75 mL). The reaction mixture was stirred for 30 minutes, then quenched with water (50 mL) and extracted with DCM (350 mL). The combined organic layer was washed with brine, dried (MgSO.sub.4) and concentrated. The residue was purified by column chromatography (10-40% EtOAc in Hexanes) to give a colorless oil (1.31 g, 91% yield). MS (m/z): 363.8 [M+1].sup.+.

##STR00168##

[0372] Compound 112 was made according to Scheme E2. N-methyl-N-tert-butyloxycarbonyl was coupled with proline methyl ester. The Boc groups was removed and replaced with N-((benzyloxy)carbonyl). Base hydrolysis of the ester gave dipeptide acid DA-112, which was coupled with PmcR-fmk and deprotected to give compound 112 (Cbz-N-Me-VPR-fmk).

[0373] Compounds 113 to 130 with various R.sup.8 groups were made according to Scheme E3 (FIG. 4). N-tert-butyloxycarbonyl-valine and methyl L-prolinate were coupled and the Boc group removed to give methyl L-valyl-L-prolinate. Amides were formed by reaction with acids (RCO.sub.2H) or acyl chloride (RCOCl), ureas by reaction with isocyanates (RNCO), and sulfonamides by reaction with sulfonyl chloride (RSO.sub.2Cl). Analogously to Compound 101, the proline methyl ester was hydrolyzed and the dipeptide acids coupled with Pmc-R-fmk.

[0374] Compounds 131 to 159 were prepared by similar methods to those described in Schemes E2 and E3. Compounds 141 and 150 were prepared from the corresponding dipeptide acids and the Pmc-R-fmk intermediate prepared from the D-arginine.

##STR00169## ##STR00170##

##STR00171##

[0375] Compounds 160 to 186 were prepared by similar methods to those described in Schemes E2, E3, and E13 from the corresponding dipeptide acids and (S)N(N-(4-amino-6-fluoro-5-oxohexyl)carbamimidoyl)-2,2,5,7,8-pentamethylchromane-6-sulfonamide or the Pbf-protected arginine fluoromethyl ketone: (S)N(N-(4-amino-6-fluoro-5-oxohexyl)carbamimidoyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonamide. Compounds 161 and 166 were prepared from the corresponding dipeptide acids and the Pbf-R-fmk intermediate derived from D-arginine. Compound 187 was prepared as described in Scheme E6.

[0376] Compounds 101 to 187 are listed in Table E1 with mass spectrometry data and the corresponding dipeptide acid or amine used in their preparation.

TABLE-US-00004 TABLE E1 Characterization data for compounds 101 to 187. m/z Com- [M + Dipeptide pound Formula/Name 1].sup.+ acid 101 [00172]embedded image 521.4 DA-101 102 [00173]embedded image 561.5 DA-102 103 [00174]embedded image 535.5 DA-103 104 [00175]embedded image 555.3 DA-104 105 [00176]embedded image 556.6 DA-105 106 [00177]embedded image DA-105 107 [00178]embedded image 535.9 DA-107 108 [00179]embedded image 575.8 DA-108 109 [00180]embedded image 537.7 DA-109 110 [00181]embedded image 537.4 DA-110 111 [00182]embedded image 535.7 DA-111 112 [00183]embedded image 535.7 DA-112 113 [00184]embedded image 491.3 DA-113 114 [00185]embedded image 571.4 DA-114 115 [00186]embedded image 569.3 DA-115 116 [00187]embedded image 569.4 DA-116 117 [00188]embedded image 505.4 DA-117 118 [00189]embedded image 585.4 DA-118 119 [00190]embedded image 519.6 DA-119 120 [00191]embedded image 497.4 DA-120 121 [00192]embedded image 521.5 DA-121 122 [00193]embedded image 521.7 DA-122 123 [00194]embedded image 521.6 DA-123 124 [00195]embedded image 495.6 DA-124 125 [00196]embedded image 521.5 DA-125 126 [00197]embedded image 516.1 DA-126 127 [00198]embedded image 576.8 DA-127 128 [00199]embedded image 583.4 DA-128 129 [00200]embedded image 506.3 DA-129 130 [00201]embedded image 606.1 DA-130 131 [00202]embedded image 576.8 DA-131 132 [00203]embedded image 589.8 DA-132 133 [00204]embedded image 548.5 DA-133 134 [00205]embedded image 516.5 DA-134 135 [00206]embedded image 559.6 DA-135 136 [00207]embedded image 525.6 DA-136 137 [00208]embedded image 567.7 DA-137 138 [00209]embedded image 575.6 DA-138 139 [00210]embedded image 574.7 DA-139 140 [00211]embedded image 511.6 DA-140 141 [00212]embedded image 521.6 DA-101 142 [00213]embedded image 620.7 DA-142 143 [00214]embedded image 609.7 DA-143 144 [00215]embedded image 583.7 DA-144 145 [00216]embedded image 575.6 DA-145 146 [00217]embedded image 596.7 DA-146 147 [00218]embedded image 550.7 DA-147 148 [00219]embedded image 575.6 DA-148 149 [00220]embedded image 559.5 DA-149 150 [00221]embedded image 571.4 DA-116 151 [00222]embedded image 589.6 DA-151 152 [00223]embedded image 541.5 DA-152 153 [00224]embedded image 541.4 DA-153 154 [00225]embedded image 517.6 DA-154 155 [00226]embedded image 542.7 DA-155 156 [00227]embedded image 542.8 DA-156 157 [00228]embedded image 542.7 DA-157 158 [00229]embedded image 542.6 DA-158 159 [00230]embedded image 542.5 DA-159 160 [00231]embedded image 509.35 DA-160 161 [00232]embedded image DA-160 162 [00233]embedded image 546.97 DA-162 163 [00234]embedded image 532.73 DA-163 164 [00235]embedded image 540.4 DA-164 165 [00236]embedded image 540.55 DA-165 166 [00237]embedded image DA-165 167 [00238]embedded image 539.69 DA-167 168 [00239]embedded image 554.77 DA-168 169 [00240]embedded image 555.50 DA-169 170 [00241]embedded image 555.4 DA-170 171 [00242]embedded image 587.5 DA-171 172 [00243]embedded image 624.51 DA-172 173 [00244]embedded image 601.5 DA-173 174 [00245]embedded image 571.24 DA-174 175 [00246]embedded image 587.34 DA-175 176 [00247]embedded image 555.29 DA-176 177 [00248]embedded image 594.34 DA-177 178 [00249]embedded image 543.32 DA-178 179 [00250]embedded image 587.3 DA-179 180 [00251]embedded image 535.2 DA-180 181 [00252]embedded image 533 DA-181 182 [00253]embedded image 569.1 DA-182 183 [00254]embedded image 583.4 DA-183 184 [00255]embedded image 535.2 DA-184 185 [00256]embedded image 583.4 DA-185 186 [00257]embedded image 685.4 DA-186 187 [00258]embedded image 623.4 [00259]embedded image

[0377] The dipeptide acid intermediates were prepared in a similar manner to ((benzyloxy)carbonyl)-L-valyl-L-proline (DA-101), and are listed in Table E2, along with characterization data and the corresponding dipeptide ester from which they were prepared.

TABLE-US-00005 TABLE E2 Characterization data for dipeptide acids intermediates. .sup.1H NMR (ppm; 500 MHz, d.sub.6- Dipeptide DMSO; or 400 MHz, m/z Dipeptide Acid Formula/Name CDCl.sub.3*) [M + 1].sup.+ ester DA-101 [00260]embedded image 389.4 DE-101 DA-102 [00261]embedded image 389.4 DE-102 DA-103 [00262]embedded image 363.5 DE-103 DA-104 [00263]embedded image 383.4 DE-104 DA-105 [00264]embedded image 398.2 DE-105 DA-107 [00265]embedded image 363.3 DE-107 DA-108 [00266]embedded image 403.8 DE-108 DA-109 [00267]embedded image 12.29 (br s, 1H), 7.47 (d, 1H), 7.35 (m, 5H), 5.04 (d, 1H), 4.98 (d, 1H), 4.29 (m, 2H), 4.01 (m, 2H), 3.30 (m, 1H), 2.31 (m, 1H), 1.94 (m, 1H), 1.80 (m, 1H), 0.95 (d, 3H), 0.89 (d, 3H) 365.8 DE-109 DA-110 [00268]embedded image 12.37 (br s, 1H), 7.39 (d, 1H), 7.35 (m, 5H), 5.17 (d, 1H), 5.05 (d, 1H), 4.99 (d, 1H), 4.34 (m, 1H), 4.26 (m, 1H), 4.07 (m, 1H), 3.65 (m, 2H), 2.10 (m, 1H), 1.95 (m, 2H), 0.92 (d, 3H), 0.87 (d, 3H) 365.3 DE-110 DA-111 [00269]embedded image 12.20 (br s, 1H), 7.42 (d, 1H), 7.32 (m, 5H), 5.02 (s, 2H), 3.99 (m, 1H), 3.86 (m, 1H), 3.60 (m, 1H), 2.02 (m, 1H), 1.94 (m, 3H), 1.81 (m, 1H), 1.37 (s, 3H), 0.90 (d, 3H), 0.87 (d, 3H) 363.1 DE-111 DA-112 [00270]embedded image 363.5 DE-112 DA-113 [00271]embedded image 319.3 DE-113 DA-114 [00272]embedded image 397.3 DE-114 DA-115 [00273]embedded image 399.3 DE-115 DA-116 [00274]embedded image 397.3 DE-116 DA-117 [00275]embedded image 333.3 DE-117 DA-118 [00276]embedded image 411.3 DE-118 DA-119 [00277]embedded image 347.4 DE-119 DA-120 [00278]embedded image 325.4 DE-120 DA-121 [00279]embedded image 349.3 DE-121 DA-122 [00280]embedded image 349.5 DE-122 DA-123 [00281]embedded image 349.3 DE-123 DA-124 [00282]embedded image 8.21 (s, 1H), 8.14 (d, 1H), 7.91 (s, 1H), 4.42 (m, 1H), 4.24 (m, 1H), 3.92 (m, 1H), 3.84 (s, 3H), 3.63 (m, 1H), 2.15 (m, 1H), 2.10 (m, 1H), 1.91 (m, 2H), 1.86 (m, 1H), 0.97 (d, 3H), 0.92 (d, 3H) 323.7 DE-124 DA-125 [00283]embedded image 12.50 (br s, 1H), 8.14 (s, 1H), 7.89 (d, 1H), 4.62 (m, 1H), 4.27 (m, 1H), 3.78 (m, 1H), 3.64 (m, 1H), 2.71 (s, 3H), 2.21 (m, 1H), 2.11 (m, 1H), 1.93 (m, 2H), 1.84 (m, 1H), 0.99 (d, 3H), 0.89 (d, 3H) 340.3 DE-125 DA-126 [00284]embedded image 12.44 (br s, 1H), 8.86 (d, 1H), 8.04 (d, 2H), 7.95 (d, 2H), 4.47 (m, 1H), 4.25 (m, 1H), 3.95 (m, 1H), 3.67 (m, 1H), 2.17 (m, 2H), 1.95 (m, 2H), 1.86 (m, 1H), 1.02 (d, 3H), 0.97 (d, 3H) 344.4 DE-126 DA-127 [00285]embedded image 12.25 (br s, 1H), 8.20 (d, 1H), 7.82 (d, 2H), 6.95 (d, 2H), 4.45 (m, 1H), 4.25 (m, 1H), 3.96 (m, 1H), 3.73 (m, 4H), 3.64 (m, 1H), 3.21 (m, 4H), 2.14 (m, 2H), 1.92 (m, 2H), 1.84 (m, 1H), 0.99 (d, 3H), 0.94 (d, 3H) 404.2 DE-127 DA-128 [00286]embedded image 12.26 (br s, 1H), 7.77 (d, 1H), 7.49 (s, 1H), 4.57 (m, 1H), 4.26 (m, 1H), 3.80 (m, 1H), 3.72 (m, 4H), 3.63 (m, 1H), 3.43 (m, 4H), 2.18 (m, 1H), 2.09 (m, 1H), 1.93 (s, 2H), 1.84 (m, 1H), 0.97 (d, 3H), 0.87 (d, 3H) 411.5 DE-128 DA-129 [00287]embedded image 12.13 (br s, 1H), 8.63 (s, 1H), 7.36 (d, 2H), 7.21 (m, 2H), 6.89 (m, 1H), 6.40 (d, 1H), 4.33 (m, 1H), 4.27 (m, 1H), 3.76 (m, 1H), 3.60 (m, 1H), 2.18 (m, 1H), 1.91 (m, 3H), 1.84 (m, 1H), 0.96 (d, 3H), 0.90 (d, 3H) 334.6 DE-129 DA-130 [00288]embedded image 434.5 DE-130 DA-131 [00289]embedded image 404.6 DE-131 DA-132 [00290]embedded image 417.5 DE-132 DA-133 [00291]embedded image 376.6 DE-133 DA-134 [00292]embedded image DE-134 DA-135 [00293]embedded image 387.5 DE-135 DA-136 [00294]embedded image 353.5 DE-136 DA-137 [00295]embedded image 395.6 DE-137 DA-138 [00296]embedded image 405.3 DE-138 DA-139 [00297]embedded image 402.5 DE-139 DA-140 [00298]embedded image 339.5 DE-140 DA-142 [00299]embedded image 447.6 DE-142 DA-143 [00300]embedded image 439.8 DE-143 DA-144 [00301]embedded image 413.5 DE-144 DA-145 [00302]embedded image 403.6 DE-145 DA-146 [00303]embedded image 424.2 DE-146 DA-147 [00304]embedded image 378.8 DE-147 DA-148 [00305]embedded image 403.6 DE-148 DA-149 [00306]embedded image 389.4 DE-149 DA-151 [00307]embedded image 417.4 DE-151 DA-152 [00308]embedded image 369.6 DE-152 DA-153 [00309]embedded image 369.8 DE-153 DA-154 [00310]embedded image 345.7 DE-154 DA-155 [00311]embedded image 370.4 DE-155 DA-156 [00312]embedded image 370.8 DE-156 DA-157 [00313]embedded image 370.6 DE-157 DA-158 [00314]embedded image 370.9 DE-158 DA-159 [00315]embedded image 370.6 DE-159 DA-160 [00316]embedded image (400 MHz, CDCl.sub.3): 7.84 (m, 2H), 7.22 (d, 1H), 7.10 (m, 2H), 4.82 (m, 1H), 4.57 (m, 1H), 3.99 (m, 1H), 3.75 (m, 1H), 2.19 (m, 3H), 2.07 (m, 2H), 1.07 (d, 3H), 1.02 (d, 3H)* 337.41 DE-160 DA-162 [00317]embedded image (400 MHz, CDCl.sub.3): 7.77 (d, 2H), 7.44 (d, 2H), 7.25 (d, 1H), 4.83 (m, 1H), 4.57 (m, 1H), 4.01 (m, 1H), 3.75 (m, 1H), 2.17 (m, 3H), 2.05 (m, 2H), 1.34 (s, 9H), 1.07 (d, 3H), 1.00 (d, 3H)* 373.32 DE-162 DA-163 [00318]embedded image (400 MHz, CDCl.sub.3): 7.75 (d, 2H), 7.28 (d, 2H), 6.99 (d, 1H), 4.84 (m, 1H), 4.58 (m, 1H), 3.97 (m, 1H), 3.74 (m, 1H), 2.94 (m, 1H), 2.22 (m, 3H), 2.07 (m, 2H), 1.26 (d, 6H), 1.06 (d, 3H), 1.02 (d, 3H)* 361.46 DE-163 DA-164 [00319]embedded image (400 MHz, CDCl.sub.3): 9.37 (br, 1H), 7.69 (s, 1H), 7.22 (d, 2H), 7.14 (d, 2H), 6.70 (d, 1H), 4.52 (m, 1H), 4.45 (m, 1H), 3.95 (m, 1H), 3.68 (m, 1H), 2.20 (m, 1H), 2.01 (m, 4H), 1.01 (d, 3H), 0.93 (d, 3H)* DE-164 DA-165 [00320]embedded image (400 MHz, CDCl.sub.3): 7.65 (br, 1H), 7.43 (br, 1H), 7.10 (m, 2H), 6.91 (m, 1H), 6.67 (m, 1H), 4.54 (m, 1H), 4.48 (m, 1H), 3.95 (m, 1H), 3.70 (m, 1H), 2.22 (m, 1H), 2.04 (m, 4H), 1.02 (d, 3H), 0.94 (d, 3H)* DE-165 DA-167 [00321]embedded image (400 MHz, CDCl.sub.3): 8.06 (d, 1H), 7.41 (s, 1H), 7.24 (d, 2H), 7.15 (m, 1H), 6.89 (m, 1H), 4.59 (m, 1H), 4.53 (m, 1H), 3.92 (m, 1H), 3.71 (m, 1H), 2.17 (m, 1H), 2.03 (m, 4H), 1.02 (d, 3H), 0.95 (d, 3H)* DE167 DA-168 [00322]embedded image (400 MHz, CDCl.sub.3): 7.30 (m, 4H), 5.66 (d, 1H), 5.05 (s, 2H), 4.59 (m, 1H), 4.33 (m, 1H), 3.82 (m, 1H), 3.68 (m, 1H), 2.22 (m, 1H), 2.06 (m, 4H), 1.01 (d, 3H), 0.95 (d, 3H)* 383.52 DE-168 DA-169 [00323]embedded image (400 MHz, CDCl.sub.3): 7.26 (m, 4H), 5.77 (d, 1H), 5.07 (s, 2H), 4.59 (m, 1H), 4.33 (m, 1H), 3.84 (m, 1H), 3.67 (m, 1H), 2.20 (m, 2H), 2.04 (m, 3H), 0.96 (d, 3H), 0.91 (d, 3H)* 383.52 DE-169 DA-170 [00324]embedded image (400 MHz, CDCl.sub.3): 7.41 (m, 2H), 7.28 (m, 2H), 5.71 (d, 1H), 5.25 (d, 1H), 5.18 (d, 1H), 4.59 (m, 1H), 4.34 (m, 1H), 3.81 (m, 1H), 3.67 (m, 1H), 2.19 (m, 2H), 2.07 (m, 3H), 1.02 (d, 3H), 0.96 (d, 3H)* 383.53 DE-170 DA-171 [00325]embedded image 12.47 (br, 1H), 8.64 (d, 1H), 7.85 (d, 2H), 7.67 (d, 2H), 5.19 (br, 1H), 4.49 (m, 1H), 4.36 (m, 1H), 4.26 (m, 1H), 3.81 (m, 1H), 3.73 (m, 1H), 2.14 (m, 2H), 1.89 (m, 1H), 0.98 (d, 3H), 0.93 (d, 3H)* 413.31 DE-171 DA-172 [00326]embedded image 12.44 (br, 1H), 8.60 (d, 1H), 7.84 (d, 2H), 7.67 (d, 2H), 5.17 (br, 1H), 4.53 (m, 1H), 4.35 (m, 1H), 4.25 (m, 1H), 3.80 (m, 1H), 3.72 (m, 1H), 2.08 (m, 1H), 1.83 (m, 4H), 1.64 (m, 3H), 1.15 (m, 3H), 0.99 (m, 2H)* 453.32 DE-172 DA-173 [00327]embedded image 12.52 (br, 1H), 8.40 (d, 1H), 8.20 (d, 1H), 7.82 (d, 2H), 7.67 (d, 2H), 4.95 (br, 1H), 4.43 (m, 1H), 4.26 (m, 1H), 3.69 (m, 2H), 1.54-1.83 (m, 6H), 0.96- 1.23 (m, 5H)* 429.32 DE-173 DA-174 [00328]embedded image 12.86 (br, 1H), 8.22 (d, 1H), 7.86 (d, 2H), 7.68 (d, 2H), 5.49 (d, 1H), 5.11 (d, 1H), 4.45 (dd, 1H), 4.26 (dd, 1H), 4.11 (dd, 1H), 3.98 (dd, 1H), 2.21-2.12 (m, 1H), 1.02 (d, 3H), 0.98 (d, 3H)* 400.29 DE-174 DA-175 [00329]embedded image 414.65 DE-175 DA-176 [00330]embedded image 12.52 (br, 1H), 8.69 (d, 1H), 7.86 (d, 2H), 7.67 (d, 2H), 4.56 (dd, 1H), 4.39 (m, 1H), 4.26 (m, 1H), 4.13 (m, 1H), 2.58 (m, 1H), 2.13 (m, 2H), 1.01 (d, 3H), 0.96 (d, 3H)* 383.59 DE-176 DA-177 [00331]embedded image 422.61 DE-177 DA-178 [00332]embedded image 12.45 (br, 1H), 8.33 (dd, 2H), 7.83 (d, 2H), 7.67 (d, 2H), 4.33 (m, 1H), 4.18 (m, 1H), 2.11 (m, 1H), 1.28 (d, 3H), 0.96 (d, 3H), 0.91 (d, 3H)* 371.52 DE-178 DA-179 [00333]embedded image 12.44 (br s, 1H), 8.47 (d, 1H), 7.64 (d, 1H), 7.51 (m, 2H), 4.52 (m, 1H), 4.26 (dd, 1H), 3.84 (m, 1H), 3.63 (m, 1H), 2.18 (m, 1H), 2.08 (m, 1H), 1.93 (m, 2H), 1.84 (m, 1H), 0.99 (d, 3H), 0.94 (d, 3H)* 415.5 DE-179 DA-180 [00334]embedded image 12.42 (br s, 1H), 7.51 (d, 1H), 7.34 (m, 5H), 5.03 (d, 1H), 4.98 (d, 1H), 4.24 (m, 1H), 4.09 (t, 1H), 3.79 (m, 1H), 3.60 (m, 1H), 2.14 (m, 1H), 1.87 (m, 3H), 1.74 (m, 1H), 1.51 (m, 1H), 1.11 (m, 1H), 0.89 (d, 3H), 0.81 (t, 3H)* 363 DE-180 DA-181 [00335]embedded image 361.3 DE-181 DA-182 [00336]embedded image 12.50 (br s, 1H), 7.65 (d, 1H), 7.26 (m, 10H), 4.93 (s, 2H), 4.41 (m, 1H), 4.27 (dd, 1H), 3.68 (m, 1H), 3.56 (m, 1H), 2.93 (m, 1H), 2.77 (m, 1H), 2.15 (m, 1H), 1.93 (m, 2H), 1.85 (m, 1H)* 396.9 DE182 DA-183 [00337]embedded image 12.43 (br s, 1H), 8.48 (d, 1H), 7.51 (m, 2H), 7.20 (d, 1H), 4.45 (t, 1H), 4.26 (dd, 1H), 3.89 (m, 1H), 3.63 (m, 1H), 2.29 (s, 3H), 2.17 (m, 1H), 2.07 (m, 1H), 1.94 (m, 2H), 1.85 (m, 1H), 0.99 (d, 3H), 0.95 (d, 3H)* 411.4 DE-183 DA-184 [00338]embedded image 12.42 (br s, 1H), 7.50 (d, 1H), 7.34 (m, 5H), 5.00 (s, 2H), 4.28 (m, 2H), 3.68 (m, 1H), 3.50 (m, 1H), 2.13 (m, 1H), 1.93 (m, 2H), 1.83 (m, 1H), 1.67 (m, 1H), 1.47 (m, 1H), 1.37 (m, 1H), 0.89 (d, 6H)* 363 DE-184 DA-185 [00339]embedded image 12.42 (br s, 1H), 8.68 (d, 1H), 7.84 (d, 2H), 7.67 (d, 2H), 4.74 (m, 1H), 4.26 (m, 1H), 3.78 (m, 1H), 3.56 (m, 1H), 2.16 (m, 1H), 1.93 (m, 2H), 1.83 (m, 1H), 1.71 (m, 2H), 1.47 (m, 1H), 0.91 (m, 6H)* 411.4 DE-185 DA-186 [00340]embedded image 513.5 DE-186

[0378] Dipeptide esters DE-102-DE-105, DE-A1, and DE-A2 were prepared in a similar manner to methyl ((benzyloxy)carbonyl)-L-valyl-L-prolinate (DE-101) from the corresponding acid and methyl L-prolinate. Dipeptide esters DE-107 and DE-108 were prepared from the corresponding acid and methyl (S)-piperidine-2-carboxylate. Dipeptide esters DE-109-DE-111 and DE-140 were prepared from ((benzyloxy)carbonyl)-L-valine and the corresponding proline and serine esters. Dipeptide esters DE-113, DE-115 to DE-139, DE-145 to DE-148, and DE-151 to DE-159 were prepared in a similar manner to methyl (2-bromobenzoyl)-L-valyl-L-prolinate (DE-114) from methyl L-valyl-L-prolinate and the corresponding acid, acid chloride, isocyanate, or sulfonyl chloride. Dipeptide esters DE-142 to DE-144 and DE-149 were prepared from 4-bromobenzoyl chloride and the corresponding esters. Dipeptide esters DE-160, DE-162, DE-163 and DE-171 to DE-186 were prepared in a similar manner to DE-101 or DE-114 from the corresponding amine ester and acid or acid chloride in Table E3.

[0379] Dipeptide esters used as intermediates are summarized in Table E3 with characterization data and corresponding starting materials.

TABLE-US-00006 TABLE E3 Characterization data for dipeptide ester intermediates. Dipep- .sup.1H NMR m/z tide (ppm; 400 MHz, [M + Ester Formula/Name d.sub.6-DMSO) 1].sup.+ Starting materials DE- 102 [00341]embedded image 7.45 (d, 1H), 7.34 (m, 5H), 5.04 (d, 1H), 4.98 (d, 1H), 4.32 (dd, 1H), 4.10 (t, 1H), 3.80 (m, 1H), 3.60 (s, 3H), 3.58 (m, 1H), 2.17 (m, 1H), 1.90 (m, 2H), 1.82 (m, 1H), 1.75 (m, 2H), 1.63 (m, 4H), 1.13 (m, 2H), 0.99 (m, 2H) 403.5 [00342]embedded image DE- 103 [00343]embedded image 7.36 (m, 6H), 5.05 (d, 1H), 4.99 (d, 1H), 4.33 (m, 1H), 4.23 (m, 1H), 3.76 (m, 1H), 3.63 (m, 1H), 3.61 (s, 3H), 2.18 (m, 1H), 1.91 (m, 2H), 1.81 (m, 1H), 0.97 (s, 9H) 377.4 [00344]embedded image DE- 104 [00345]embedded image 397.4 [00346]embedded image DE- 105 [00347]embedded image 384.5 [00348]embedded image DE- 107 [00349]embedded image 377.3 [00350]embedded image DE- 108 [00351]embedded image 417.4 [00352]embedded image DE- 109 [00353]embedded image 379.3 [00354]embedded image DE- 110 [00355]embedded image 379.6 [00356]embedded image DE- 111 [00357]embedded image 377.3 [00358]embedded image DE- 112 [00359]embedded image 377.3 DE- 113 [00360]embedded image 333.4 Benzoic acid DE- 114 [00361]embedded image 8.65 (d, 1H), 7.63 (dd, 1H), 7.41 (m, 1H), 7.34 (dd, 1H), 7.30 (m, 1H), 4.48 (t, 1H), 4.34 (m, 1H), 3.94 (m, 1H), 3.67 (m, 1H), 3.61 (s, 3H), 2.20 (m, 1H), 2.07 (m, 1H), 1.95 (m, 1H), 1.84 (m, 1H), 0.99 (d, 3H), 0.97 (d, 3H) 413.3 2-Bromobenzoyl chloride DE- 115 [00362]embedded image 8.72 (d, 1H), 8.11 (s, 1H), 7.89 (m, 1H), 7.75 (m, 1H), 7.44 (t, 1H), 4.47 (m, 1H), 4.34 (m, 1H), 3.96 (m, 1H), 3.67 (m, 1H), 3.63 (s, 3H), 2.19 (m, 2H), 1.95 (m, 1H), 1.85 (m, 1H), 1.00 (d, 3H), 0.97 (d, 3H) 413.3 3-Bromobenzoic acid DE- 116 [00363]embedded image 4-Bromobenzoyl chloride DE- 117 [00364]embedded image 8.28 (d, 1H), 7.25 (m, 5H), 4.30 (m, 2H), 3.77 (m, 1H), 3.61 (s, 3H), 3.59 (m, 1H), 3.52 (d, 1H), 3.42 (d, 1H), 2.16 (m, 1H), 1.97 (m, 1H), 1.85 (m, 3H), 0.90 (d, 3H), 0.86 (d, 3H) 347.4 2-Phenylacetic acid DE- 118 [00365]embedded image 8.36 (d, 1H), 7.47 (s, 1H), 7.41 (m, 1H), 7.25 (m, 2H), 4.31 (m, 2H), 3.75 (m, 1H), 3.61 (s, 3H), 3.59 (m, 1 H), 3.54 (d, 1H), 3.44 (d, 1H), 2.16 (m, 1H), 1.98 (m, 1H), 1.86 (m, 3H), 0.90 (d, 3H), 0.86 (d, 3H) 427.3 2-(3-Bromophenyl)acetic acid DE- 119 [00366]embedded image 8.07 (d, 1H), 7.20 (m, 5H), 4.31 (m, 2H), 3.80 (m, 1H), 3.61 (s, 3H), 3.59 (m, 1H), 2.80 (t, 2H), 2.50 (m, 1H), 2.44 (m, 1H), 2.15 (m, 1H), 1.88 (m, 4H), 0.88 (d, 3H), 0.81 (d, 3H) 361.4 3-Phenylpropanoic acid DE- 120 [00367]embedded image 7.82 (d, 1H), 4.30 (m, 2H), 3.79 (m, 1H), 3.61 (s, 3H), 3.58 (m, 1H), 2.20 (m, 2H), 1.91 (m, 3H), 1.80 (m, 1H), 1.68 (m, 3H), 1.59 (m, 2H), 1.28 (m, 2H), 1.16 (m, 3H), 0.90 (d, 3H), 0.86 (d, 3H) 339.3 Cyclohexanecarboxylic acid DE- 121 [00368]embedded image 363.5 2-Methoxybenzoyl chloride DE- 122 [00369]embedded image 363.6 3-Methoxybenzoyl chloride DE- 123 [00370]embedded image 363.4 4-Methoxybenzoyl chloride DE- 124 [00371]embedded image 337.4 1-Methyl-1H-pyrazole-4- carboxylic acid DE- 125 [00372]embedded image 354.5 2-Methylthiazole-4- carboxylic acid DE- 126 [00373]embedded image 358.6 4-Cyanobenzoic acid DE- 127 [00374]embedded image 418.4 4-Morpholinobenzoic acid DE- 128 [00375]embedded image 425.5 2-Morpholinothiazole-4- carboxylic acid DE- 129 [00376]embedded image 348.4 Phenyl isocyanate DE- 130 [00377]embedded image 448.8 4-Bromobenzenesulfonyl chloride DE- A1 [00378]embedded image 377.3 [00379]embedded image DE- A2 [00380]embedded image 329.2 [00381]embedded image DE- A3 [00382]embedded image 229.7 DE- 131 [00383]embedded image 418.6 3-Morpholinobenzoic acid DE- 132 [00384]embedded image 431.7 3-(4-Methylpiperazin-1- yl)benzoic acid DE- 133 [00385]embedded image 390.6 3-Acetamidobenzoic acid DE- 134 [00386]embedded image 358.4 3-Cyanobenzoic acid DE- 135 [00387]embedded image 401.4 4- (Trifluoromethyl)benzoyl chloride DE- 136 [00388]embedded image 367.5 4-Chlorobenzoyl chloride DE- 137 [00389]embedded image 409.5 [1,1-Biphenyl]-4-carbonyl chloride DE- 138 [00390]embedded image 419.4 5-Bromothiophene-2- carboxylic acid DE- 139 [00391]embedded image 416.6 5-Phenylthiazole-2- carboxylic acid DE- 140 [00392]embedded image 353.7 [00393]embedded image DE- 142 [00394]embedded image 462.4 Methyl ((S)-2-amino-3- (pyridin-3-yl)propanoyl)- L-prolinate AE-1 DE- 143 [00395]embedded image 452.6 Methyl ((S)-2-amino-2- cyclohexylacetyl)-L- prolinate AE-2 DE- 144 [00396]embedded image 426.6 Methyl (S)-1-(L- valyl)piperidine-2- carboxylate AE-3 DE- 145 [00397]embedded image 417.5 4- (Trifluoromethoxy)benzoyl chloride DE- 146 [00398]embedded image 437.9 4-Bromo-3-cyanobenzoic acid DE- 147 [00399]embedded image 392.6 4-Chloro-3-cyanobenzoic acid DE- 148 [00400]embedded image 417.3 3- (Trifluoromethoxy)benzoyl chloride DE- 149 [00401]embedded image 402.6 Methyl L-valyl-L-serinate AE-4 DE- 151 [00402]embedded image 431.7 4-Bromo-3-fluorobenzoic acid DE- 152 [00403]embedded image 382.4 2-Naphthoyl chloride DE- 153 [00404]embedded image 382.4 1-Naphthoyl chloride DE- 154 [00405]embedded image 359.7 Cinnamoyl chloride DE- 155 [00406]embedded image 384.9 Quinoline-2-carboxylic acid DE- 156 [00407]embedded image 384.6 Quinoline-3-carboxylic acid DE- 157 [00408]embedded image 384.4 Isoquinoline-6-carboxylic acid DE- 158 [00409]embedded image 384.3 Isoquinoline-7-carboxylic acid DE- 159 [00410]embedded image 384.8 Quinoline-4-carboxylic acid DE- 160 [00411]embedded image 7.81 (m, 2H), 7.10 (m, 2H), 6.96 (d, 1H), 4.84 (m, 1H), 4.51 (m, 1H), 3.90 (m, 1H), 3.74 (s, 3H), 3.72 (m, 1H), 2.22 (m, 2H), 2.09 (m, 1H), 2.01 (m, 2H), 1.11 (d, 3H), 1.01 (d, 3H) 351.39 Methyl L-valyl-L-prolinate (dipeptide ester 32) and 4- fluorobenzoic acid DE- 162 [00412]embedded image 7.74 (d, 2H), 7.43 (d, 2H), 6.89 (d, 1H), 4.86 (m, 1H), 4.51 (m, 1H), 3.90 (m, 1H), 3.75 (s, 3H), 3.73 (m, 1H), 2.22 (m, 2H), 2.06 (m, 3H), 1.99 (s, 9H), 1.10 (d, 3H), 1.01 (d, 3H) 389.58 Methyl L-valyl-L-prolinate (dipeptide ester 32) and 4- (tert-butyl)benzoic acid DE- 163 [00413]embedded image 7.74 (d, 2H), 7.27 (d, 2H), 6.87 (d, 1H), 4.86 (m, 1H), 4.51 (m, 1H), 3.90 (m, 1H), 3.75 (s, 3H), 3.72 (m, 1H), 2.94 (m, 1H), 2.23 (m, 2H), 2.04 (m, 3H), 1.25 (d, 6H), 1.10 (d, 3H), 1.01 (d, 3H) 375.46 Methyl L-valyl-L-prolinate (dipeptide ester 32) and 4- isopropylbenzoic acid DE- 171 [00414]embedded image 7.61 (d, 2H), 7.54 (dd, 2H), 7.04 (br, 1H), 4.69 (m, 2H), 4.58 (m, 1H), 4.13 (m, 1H), 3.79 (m, 1H), 3.75 (s, 3H), 2.36 (m, 1H), 2.20 (m, 1H), 2.04 (m, 1H), 1.09 (d, 3H), 1.02 (d, 3H) 426.71 AE-5 Methyl (2S,4R)-1-(L- valyl)-4- hydroxypyrrolidine-2- carboxylate and 4- bromobenzoic acid DE- 172 [00415]embedded image 7.57 (dd, 2H), 7.50 (d, 2H), 7.16 (br, 1H), 4.68 (m, 2H), 4.58 (m, 1H), 4.18 (m, 1H), 3.77 (m, 1H), 3.75 (s, 3H), 2.38 (m, 2H), 2.04 (m, 1H), 1.73-1.96 (m, 5H), 1.04-1.28 (m, 5H) 468.55 AE-6 Methyl (2S,4R)-1-((S)-2- amino-2- cyclohexylacetyl)-4- hydroxypyrrolidine-2- carboxylate and 4- bromobenzoic acid DE- 173 [00416]embedded image 8.39 (m, 2H), 7.82 (d, 2H), 7.67 (d, 2H), 5.05 (br, 1H), 4.43 (m, 1H), 4.34 (m, 1H), 3.72 (m, 1H), 3.65 (s, 1H), 3.61 (s, 3H), 1.57- 1.86 (m, 6H), 0.95- 1.22 (m, 5H) 443.32 AE-7 Methyl ((S)-2-amino-2- cyclohexylacetyl)-L- serinate and 4- bromobenzoic acid DE- 174 [00417]embedded image 413.73 AE-8 Methyl (S)-3-(L- valyl)oxazolidine-4- carboxylate and 4- bromobenzoyl chloride DE- 175 [00418]embedded image 427.35 AE-9 Methyl (S)-4-(L- valyl)morpholine-3- carboxylate and 4- bromobenzoyl chloride DE- 176 [00419]embedded image 397.86 AE-10 Methyl (S)-1-(L- valyl)azetidine-2- carboxylate and 4- bromobenzoyl chloride DE- 177 [00420]embedded image 436.48 AE-11 Methyl (2S,4R)-1-(L- valyl)-4-cyanopyrrolidine- 2-carboxylate and 4- bromobenzoyl chloride DE- 178 [00421]embedded image 385.74 Acid 1 (4-Bromobenzoyl)-L- valine and methyl L- alaninate DE- 179 [00422]embedded image 429.4 Methyl L-valyl-L-prolinate (dipeptide ester 32) and 4- bromo-2-fluorobenzoic acid DE- 180 [00423]embedded image 377.2 ((Benzyloxy)carbonyl)-L- isoleucine and methyl L- prolinate DE- 181 [00424]embedded image 375.2 1- (((Benzyloxy)carbonyl) amino)cyclopentane-1- carboxylic acid and methyl L-prolinate DE- 182 [00425]embedded image 412.4 ((Benzyloxy)carbonyl)-L- phenylalanine and methyl L-prolinate DE- 183 [00426]embedded image 425.5 Methyl L-valyl-L-prolinate (dipeptide ester 32) and 4- bromo-2-fluorobenzoic acid DE- 184 [00427]embedded image 377.3 ((Benzyloxy)carbonyl)-L- leucine and methyl L- prolinate DE- 185 [00428]embedded image 425.4 Acid 2 (4-Bromobenzoyl)-L- leucine and methyl L- prolinate DE- 186 [00429]embedded image 527.4 Acid 3 (S)-2-(4- Bromobenzamido)-3-(4- (trifluoromethyl)phenyl) propanoic acid and methyl L-prolinate

Methyl N-((benzyloxy)carbonyl)-N-methyl-L-valyl-L-prolinate (DE-112)

[0380] ##STR00430##

[0381] Methyl (tert-butoxycarbonyl)-L-valyl-L-prolinate (856 mg) was dissolved in 1,4-dioxane (10 mL). HCl in 1,4-dioxane (4 M, 5 mL) was added and the reaction stirred for 1 hour. The solvent was removed under reduced pressure to give a white solid (700 mg), used directly without purification. This compound was dissolved in DCM (50 mL) and cooled to 0 C. Benzyl chloroformate (0.48 mL) and triethylamine (2.14 mL) were added, and the mixture stirred for 1 hour. The reaction mixture was quenched with sat. aq. NaHCO.sub.3 and extracted with DCM (350 mL). The combined organic layer was washed with brine, dried (MgSO.sub.4) and concentrated, and the residue purified by column chromatography (50 to 70% EtOAc in hexanes) to give a colorless oil. MS (m/z): 377.3 [M+1].sup.+.

Methyl (2-bromobenzoyl)-L-valyl-L-prolinate (DE-114)

[0382] ##STR00431##

[0383] Triethylamine (1.21 mL, 8.76 mmol) was added to a solution of methyl L-valyl-L-prolinate (1.00 g, 4.38 mmol) and 2-bromobenzoyl chloride (961 mg, 4.38 mmol) in DCM (20 mL) at 0 C. After 30 minutes, the reaction mixture was diluted with DCM and washed with 1M HCl. The organic layer was dried (MgSO4), concentrated, and the residue purified by column chromatography (EtOAc in Hexanes, gradient) to give 1.20 g product. 1H NMR (400 MHz, d.sub.6-DMSO) 8.65 (d, 1H), 7.63 (dd, 1H), 7.41 (m, 1H), 7.34 (dd, 1H), 7.30 (m, 1H), 4.48 (t, 1H), 4.34 (m, 1H), 3.94 (m, 1H), 3.67 (m, 1H), 3.61 (s, 3H), 2.20 (m, 1H), 2.07 (m, 1H), 1.95 (m, 1H), 1.84 (m, 1H), 0.99 (d, 3H), 0.97 (d, 3H); MS (m/z): 413.3 [M+1].sup.+.

Methyl (phenylcarbamoyl)-L-valyl-L-prolinate (DE-129)

[0384] ##STR00432##

[0385] Phenyl isocyanate (0.23 mL, 1.89 mmol) and triethylamine (0.79 mL, 5.67 mmol) were added to a solution of methyl L-valyl-L-prolinate (0.50 g, 1.89 mmol) in DCM (25 mL) at 0 C. The mixture was warmed to RT and stirred for 1 hour. The reaction was quenched with H.sub.2O (10 mL) and extracted with DCM (350 mL). The combined organic layer was washed with brine, dried (MgSO.sub.4) and concentrated, and the residue purified by column chromatography (10-50% EtOAc in Hexanes) to give a colorless oil (0.57 g, 88% yield). MS (m/z): 348.4 [M+1].sup.+.

Methyl ((4-bromophenyl)sulfonyl)-L-valyl-L-prolinate (DE-130)

[0386] ##STR00433##

[0387] 4-Bromobenzenesulfonyl chloride (0.48 g, 1.89 mmol) and triethylamine (0.79 mL, 5.67 mmol) were added to a solution of methyl L-valyl-L-prolinate (0.50 g, 1.89 mmol) in DCM (25 mL) at 0 C. The mixture was warmed to RT and stirred for 1 hour. The reaction was quenched with H.sub.2O (10 mL) and extracted with DCM (350 mL). The combined organic layer was washed with brine, dried (MgSO.sub.4) and concentrated, and the residue purified by column chromatography (10-50% EtOAc in Hexanes) to give a colorless oil (0.80 g, 95% yield). MS (m/z): 448.8 [M+1].sup.+.

Methyl L-valyl-L-prolinate HCl (DE-A3)

[0388] ##STR00434##

[0389] Methyl (tert-butoxycarbonyl)-L-valyl-L-prolinate (1.0 g, 3.04 mmol) was dissolved in anhydrous 1,4-dioxane (10 mL) under an inert atmosphere. HCl in 1,4-dioxane (4 M, 7.5 mL, 30.4 mmol) was added and the mixture heated to 60 C. After 5 hours the solvent was removed under reduced pressure to give a white solid (0.8 g, 99% yield). MS (m/z): 229.7 [M+1].sup.+.

Methyl ((4-chlorophenyl)carbamoyl)-L-valyl-L-prolinate (DE-164)

[0390] ##STR00435##

[0391] Triphosgene (0.28 g, 0.94 mmol) was added to a solution of 3-chloroaniline (0.27 g, 2.1 mmol) and triethylamine (0.96 g, 9.5 mmol) in dichloromethane (10 mL) at 5 C. The reaction was stirred for 30 min at 5 C. and methyl L-valyl-L-prolinate (0.5 g, 1.9 mmol) was added. The reaction was stirred for another 30 min at 5 C., quenched with water (20 mL) and extracted with dichloromethane (320 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica chromatography (Hexanes:EA=3:1) to give the title compound (440 mg, 61% yield). MS (m/z): 382.39 [M+1].sup.+.

[0392] Dipeptide Esters DE-165 and DE-167 were prepared in a similar manner to DE-164 from the corresponding aniline and methyl L-valyl-L-prolinate.

TABLE-US-00007 TABLE E4 Characterization of Dipeptide Esters DE-165 and DE-167. Aniline Dipeptide .sup.1H NMR m/z Starting Ester Formula/Name (ppm; 400 MHz, CDCl.sub.3) [M + 1].sup.+ Material DE-165 [00436]embedded image : 7.81 (br, 1H), 7.50 (s, 1H), 7.15 (m, 2H), 6.92 (m, 2H), 4.55 (m, 2H), 4.09 (m, 1H), 3.78 (m, 1H), 3.64 (s, 3H), 2.28 (m, 1H), 2.06 (m, 4H), 1.11 (d, 3H), 1.03 (d, 3H) 382.4 3-Chloro aniline DE-167 [00437]embedded image : 7.88 (d, 1H), 7.40 (s, 1H), 7.25 (m, 1H), 7.21 (d, 1H), 7.06 (m, 1H), 6.86 (m, 1H), 4.62 (m, 1H), 4.57 (m, 1H), 3.96 (m, 1H), 3.71 (m, 1H), 3.64 (s, 3H), 2.23 (m, 1H), 2.04 (m, 4H), 1.11 (d, 3H), 1.02 (d, 3H) 382.4 2-Chloro aniline

Methyl (((4-chlorobenzyl)oxy)carbonyl)-L-valyl-L-prolinate (DE-168)

[0393] ##STR00438##

[0394] A solution of methyl ((S)-2-isocyanato-3-methylbutanoyl)-L-prolinate (0.93 g, 3.6 mmol), 4-chlorobenzyl alcohol (0.54 g, 3.9 mmol), and triethylamine (0.75 g, 7.4 mmol) in acetonitrile (20 mL) was refluxed for 2 hours. The solvent was removed under reduced pressure, and the residue dissolved in ethyl acetate (20 mL) and washed with 5% KHSO.sub.4 solution. The organic layer was dried over anhydrous sodium sulfate, concentrated and the residue purified by silica chromatography (PE:EA=4:1) to give the title compound (0.78 g, 52%). 1H NMR (CDCl.sub.3, 400 MHz) : 7.32 (d, 2H), 7.28 (d, 2H), 5.47 (d, 1H), 5.04 (m, 2H), 4.52 (m, 1H), 4.33 (m, 1H), 3.73 (m, 1H), 3.71 (s, 3H), 3.66 (m, 1H), 2.24 (m, 1H), 2.03 (m, 4H), 1.05 (d, 3H), 0.94 (d, 3H). MS (m/z): 397.08 [M+1].sup.+.

[0395] Dipeptide Esters DE-169 and DE-170 were prepared in a similar manner to DE-168 from the corresponding alcohol and methyl ((S)-2-isocyanato-3-methylbutanoyl)-L-prolinate.

TABLE-US-00008 TABLE E5 Characterization of Dipeptide Esters DE-169 and DE-170. .sup.1H NMR Alcohol Dipeptide (ppm; 400 MHz, m/z Starting Ester Formula/Name CDCl.sub.3) [M + 1].sup.+ Material DE-169 [00439]embedded image : 7.34 (s, 1H), 7.28 (m, 2H), 7.22 (m, 1H), 5.53 (d, 1H), 5.05 (m, 2H), 4.53 (m, 1H), 4.33 (m, 1H), 3.78 (m, 1H), 3.73 (s, 3H), 3.70 (m, 1H), 2.23 (m, 1H), 2.01 (m, 4H), 1.05 (d, 3H), 0.95 (d, 3H) 397.09 3- Chlorobenzyl alcohol DE-170 [00440]embedded image : 7.39 (m, 2H), 7.25 (m, 2H), 5.53 (d, 1H), 5.24 (d, 1H), 5.18 (d, 1H), 4.53 (m, 1H), 4.35 (m, 1H), 3.76 (m, 1H), 3.73 (s, 3H), 3.70 (m, 1H), 2.23 (m, 1H), 2.02 (m, 4H), 1.06 (d, 3H), 0.97 (d, 3H) 397.08 2- Chlorobenzyl alcohol

Methyl ((S)-2-isocyanato-3-methylbutanoyl)-L-prolinate

[0396] ##STR00441##

[0397] Triphosgene (1.11 g, 3.7 mmol) was added in portions to a mixture of methyl L-valyl-L-prolinate (3 g, 11.4 mmol) and sodium bicarbonate (4.8 g, 56.8 mmol) in DCM/water (60 mL/45 mL) at 5 C. The reaction was stirred for 5 min at 5 C. The organic layer was separated and the water phase was re-extracted with dichloromethane (50 mL2). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound (2.8 g, 97%), which was used without further purification.

[0398] Amino Esters AE-1 to AE-11 were prepared in a similar manner to methyl L-valyl-L-prolinate (DE-A3), by deprotection of the coupling products of the corresponding acid starting materials and amine starting materials are shown in Table E6.

TABLE-US-00009 TABLE E6 Characterization of Amino Esters AE-1 to AE-4. m/z Amino Ester Formula/Name [M + 1].sup.+ Starting materials AE-1 [00442]embedded image 277.08 (S)-2-((tert- Butoxycarbonyl)amino)-3- (pyridin-3-yl)propanoic acid and methyl-L-prolinate AE-2 [00443]embedded image (S)-2-((tert- Butoxycarbonyl)amino)-2- cyclohexylacetic acid and methyl L-prolinate AE-3 [00444]embedded image 243.46 (tert-Butoxycarbonyl)-L-valine and methyl (S)-piperidine-2- carboxylate AE-4 [00445]embedded image 219.28 (tert-Butoxycarbonyl)-L-valine and methyl L-serinate AE-5 [00446]embedded image (tert-Butoxycarbonyl)-L-valine and methyl (2S,4R)-4- hydroxypyrrolidine-2- carboxylate AE-6 [00447]embedded image (S)-2-((tert- Butoxycarbonyl)amino)-2- cyclohexylacetic acid and methyl (2S,4R)-4- hydroxypyrrolidine-2- carboxylate AE-7 [00448]embedded image (S)-2-((tert- Butoxycarbonyl)amino)-2- cyclohexylacetic acid and methyl L-serinate AE-8 [00449]embedded image 231.05 (tert-Butoxycarbonyl)-L-valine and methyl (S)-oxazolidine-4- carboxylate AE-9 [00450]embedded image 245.14 (tert-Butoxycarbonyl)-L-valine and methyl (S)-morpholine-3- carboxylate AE-10 [00451]embedded image 215.01 (tert-Butoxycarbonyl)-L-valine and methyl (S)-azetidine-2- carboxylate AE-11 [00452]embedded image 254.18 (tert-Butoxycarbonyl)-L-valine and methyl (2S,4R)-4- cyanopyrrolidine-2-carboxylate

[0399] Acids 1 to 3 were prepared by coupling of 4-bromobenzoyl chloride and the corresponding amines, followed by hydrolysis of the methyl ester in the case of acid 1.

TABLE-US-00010 TABLE E7 Characterization of Acids 1 to 3. m/z Starting Acid Formula/Name [M + 1].sup.+ material Acid 1 [00453]embedded image 300.16 Methyl L- valinate Acid 2 [00454]embedded image 314.1 L-Leucine Acid 3 [00455]embedded image 415.9 (S)-2- Amino-3-(4- (trifluoro- methyl) phenyl) propanoic acid

(S)-1-((S)-2-Amino-3-cyclohexylpropanoyl)-N((S)-1-fluoro-2-oxo-6-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)hexan-3-yl)pyrrolidine-2-carboxamide

[0400] ##STR00456##

[0401] The title compound was prepared by coupling of ((S)-2-(((benzyloxy)carbonyl)amino)-3-cyclohexylpropanoyl)-L-proline (Acid 4) and (S)N(N-(4-amino-6-fluoro-5-oxohexyl)carbamimidoyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonamide. MS (m/z): 693.5 [M+1].sup.+.

((S)-2-(((Benzyloxy)carbonyl)amino)-3-cyclohexylpropanoyl)-L-proline (Acid 4)

[0402] ##STR00457##

[0403] Acid 4 was prepared by coupling of (S)-2-(((benzyloxy)carbonyl)amino)-3-cyclohexylpropanoic acid (Acid 5) and methyl L-prolinate, followed by ester hydrolysis. MS (m/z): 403.2 [M+1].sup.+.

(S)-2-(((Benzyloxy)carbonyl)amino)-3-cyclohexylpropanoic acid (Acid 5)

[0404] ##STR00458##

[0405] Acid 5 was prepared by Cbz protection of (S)-2-amino-3-cyclohexylpropanoic acid. MS (m/z): 306.4 [M+1].sup.+.

[0406] The synthesis of (Pmc)arginine-fmk is shown in Scheme E4 (FIG. 5), and described below. The reagent magnesium benzyl fluoromalonate is further described in U.S. Pat. No. 5,210,272 which is incorporated herein by reference.

(S)N(N-(4-Amino-6-fluoro-5-oxohexyl)carbamimidoyl)-2,2,5,7,8-pentamethylchromane-6-sulfonamide 2,2,2-trifluoroacetate

[0407] ##STR00459##

[0408] tert-Butyl (S)-(1-fluoro-2-oxo-6-(3-((2,2,5,7,8-pentamethylchroman-6-yl)sulfonyl)guanidino) hexan-3-yl)carbamate (0.125 g, 0.225 mmol) was dissolved in DCM (10 mL). TFA (1 mL) was added and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure to give a brown oil (0.1 g, 98% yield). MS (m/z): 457.4 [M+1].sup.+.

tert-Butyl (S)-(1-fluoro-2-oxo-6-(3-((2,2,5,7,8-pentamethylchroman-6-yl)sulfonyl)guanidino)hexan-3-yl)carbamate

[0409] ##STR00460##

[0410] N-(tert-Butoxycarbonyl)-N-((2,2,5,7,8-pentamethylchroman-6-yl)sulfonyl)-L-arginine (1.0 g, 1.85 mmol) was dissolved in THF (75 mL) and cooled to 0 C. CDI (0.75 g, 4.63 mmol) was added and the reaction was stirred under N.sub.2 for 2 hours. Magnesium benzyl fluoromalonate (2.39 g, 5.55 mmol) was added and the mixture stirred at RT overnight. The reaction was quenched with sat. aq. NaHCO.sub.3 and extracted with EtOAc (3100 mL). The combined organic layer was washed with brine, dried (MgSO4) and concentrated. The crude product was dissolved in EtOH (100 mL), Pd/C (0.25 g) was added and the reaction vessel was evacuated to hydrogen using a balloon. The mixture was stirred under hydrogen for 24 hours, then filtered through Celite, washing with EtOH (150 mL) and concentrated. The residue was purified by column chromatography (10-70% EtOAc in Hexanes) to give a colorless oil (0.63 g, 61% yield). 1H NMR (400 MHz, d.sub.6-DMSO) 7.28 (d, 1H), 6.68 (br s, 1H), 6.41 (br s, 2H), 5.18 (dd, 1H), 5.12 (dd, 1H), 4.00 (m, 1H), 3.02 (m, 2H), 2.59 (t, 2H), 2.47 (s, 6H), 2.03 (s, 3H), 1.78 (t, 2H), 1.64 (m, 1H), 1.41 (m, 3H), 1.39 (s, 9H), 1.26 (s, 6H); MS (m/z): 557.4 [M+1].sup.+.

X-Ray Co-crystal Structure of Compound 101 and MALT1

[0411] Compound 101 was incubated with MALT1 to form a complex, and the complex was purified and crystallized for structure determination. X-ray diffraction data was collected, and the compound 101-MALT1 structure was solved in 2.0 angstrom resolution. Exemplary results are shown in FIG. 3. FIG. 3 indicates the formation of a covalent bond between: (1) the carbon atom to which the fluorine atom is directly attached in compound 101; and (2) the sulfur atom of the Cys464 residue of MALT1. Exemplary evidence for the formation of the covalent bond is the existence of continuous electron density from compound 101 to the Cys464 residue of MALT1. The electron density is 2Fo-Fc map contoured at 1.0 sigma.

Biological Assays of the Compounds

Inhibition Constants (Ki's)

[0412] For exemplary compounds of the disclosure, Ki for inhibition of MALT1 was measured (Table E11). A concentration of 100 nM MALT1 was used for the assay.

Cell Growth Inhibition Assays

[0413] DLBCL cell lines were grown in exponential growth conditions during the 96 hours of treatment. Cells were treated twice: at t=0 and t=48 hours, and cell viability was determined by ATP quantification using a luminescent method (CELLTITER-GLO, Promega, Madison, Wis.). Cell viability in drug-treated cells was normalized to vehicle controls (fractional viability) and results are given as 1-fractional viability. PRISM GRAPHPAD software (Biosoft, Cambridge, UK) was used to determine the drug concentration that inhibits the growth of cell lines by 50% compared to control (GI.sub.50). Experiments were performed in triplicate.

[0414] Western blot: OCI-Ly3 cells (a line of human diffuse large B-cell lymphoma (ABC type)) were pre-treated for 30 minutes with indicated doses of MALT1 inhibitors followed by a 2-hour treatment with proteasome inhibitor MG-132 at 5 M. Protein was then extracted in a PBS-based lysis buffer containing 1% NP-40. Equal amounts of total protein (50 to 75 g) were separated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and electrotransferred onto nitrocellulose membranes. Membranes were incubated with primary antibodies (MALT1, from Santa Cruz Biotechnologies, Santa Cruz, Calif.; RELB from Cell Signaling, Danvers, Mass., and -Tubulin from Sigma), followed by secondary antibodies conjugated to horseradish peroxidase, which were detected by chemiluminescence (Pierce, Thermo Scientific, Rockford, Ill.).

[0415] Exemplary results of the cell growth inhibition assays are shown in Table E11.

TABLE-US-00011 TABLE E11 Enzyme K.sub.i and OCI-LY3 GI.sub.50 of exemplary compounds Compound MALT1 K.sub.i (nM) OCI-LY3 GI.sub.50 (M) 101 40 8.52 102 44 1.45 103 43 1.44 104 154 8.05 105 55 4.26 106 146 8.43 107 40 0.73 108 37 1.33 109 53 0.29 110 49 1.07 111 158 10.5 112 808 >20 113 40 0.66 114 105 4.24 115 41 0.53 116 10 0.13 117 42 3.37 118 46 2.91 119 43 1.88 120 56 0.94 121 109 7.29 122 75 2 123 50 1.67 124 100 16.8 125 52 9.65 126 60 6.66 127 75 >20 128 111 >20 129 52 1.52 130 66 3.72 201 >5 202 90 1.05 203 0.819 204 120 205 >200 131 58 14.5 132 175 >20 133 54 >20 134 39 3.69 135 132 0.12 136 67 1.24 137 30 0.55 138 1.24 139 121 1.75 140 64 0.29 141 142 >1000 14.1 143 45 0.13 144 79 0.46 145 27 0.7 146 13 0.5 147 24 0.55 148 15 0.53 149 64 150 151 78 152 47 153 102 0.16 154 36 0.11 155 55 0.57 156 40 3.88 157 59 0.63 158 110 1.7 159 139 4.22 160 13 2.34 161 346 0.91 162 45 0.98 163 22 0.27 164 62 0.78 165 27 0.52 166 557 167 24 168 32 169 22 170 27 171 50 0.07 172 34 0.06 173 46 0.24 174 20 0.12 175 70 0.46 176 118 0.77 177 28 178 38 179 71 0.81 180 30 2.44 181 1185 4.31 182 76 2.30 183 40 0.85 184 93 5.49 185 182 1.10 186 448 1.37 187 122

Maximum Killing Effects on Select Cell-Lines

[0416] The maximum killing effects on cell-lines OCI-LY3, TMD8, and OCI-LY1 were also measured for select compounds at inhibitor concentration of 20 M and 5 M. TMD8 is another line of ABC type diffuse large-B cell lymphoma, while OCI-LY1 is a DLBCL line of the germinal center B-cell subtype. Table E12 lists the measured killing effect for Z-VRPR-fmk, mepazine, and exemplary compounds of the disclosure at concentration of 20 M or 5 M.

TABLE-US-00012 TABLE E12 Maximum killing effect for exemplary compounds with DLBCL cell lines. OCI-LY3 TMD8 OCI-LY1 Compound 20 M 5 M 20 M 5 M 20 M 5 M Z-VRPR-fmk 62% 42% 67% 27% <0% <0% mepazine 97% 35% 99% 32% 82% 6% 101 79% 70% 63% 50% 7% <0% 102 85% 54% 19% 107 85% 38% 58% 29% 11% 3% 112 51% 28% 66% 2% 5% 114 80% 40% 9% 115 84% 64% 15% 116 90% 76% 19% 120 81% 52% <0% 202 87% 71% 59% <0% 6% 203 79% 59% 3%

[0417] Western blots for RelB and MALT1 show inhibition of RelB cleavage by inhibitors 202, 109, 116, 203, 112, and 107. OCI-LY3 cells were pretreated with the an inhibitor at the desired concentration and subsequently treated with 5 M MG-132, a proteasome inhibitor, for 2 hours. Results are shown in FIGS. 1A and 1B.

REFERENCES

[0418] 1. Swerdlow, S. H., Campo, E., Harris, N. L., Jaffe, E. S., Pileri, S. A., Stein, H., Thiele, J., Vardiman, J. W (2008). World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, (Lyon: IARC Press). [0419] 2. Alizadeh, A. A., Eisen, M. B., Davis, R. E., Ma, C, Lossos, I. S., Rosenwald, A., Boldrick, J. C., Sabet, H., Tran, T., Yu, X., et al. (2000). Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 403, 503-511. [0420] 3. Rosenwald, A., Wright, G., Chan, W. C, Connors, J. M., Campo, E., Fisher, R. I., Gascoyne, R. D., Muller-Hermelink, H. K., Smeland, E. B., Giltnane, J. M., et al. (2002). The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. New Eng. J. Med. 346, 1937-1947. [0421] 4. Davis, R. E., Ngo, V. N., Lenz, G., Tolar, P., Young, R. M., Romesser, P. B., Kohlhammer, H., Lamy, L., Zhao, H., Yang, Y., et al. (2010). Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 463, 88-92. [0422] 5. Afonina, I. S., Elton, L. Carpentier, I., Beyaert, R. (2015). FEBS Journal. DOI: 10.1111/febs.13325. [0423] 6. Ruefli-Brasse, A. A., French, D. M., and Dixit, V. M. (2003). Regulation of NF-wB-dependent lymphocyte activation and development by paracaspase. Science. 302, 1581-1584. [0424] 7. Ruland, J., Duncan, G. S., Wakeham, A., and Mak, T. W. (2003). Differential requirement for MALT1 in T and B cell antigen receptor signaling. Immunity. 19, 749-758. [0425] 8. Rebeaud, F., Hailfinger, S., Posevitz-Fejfar, A., Tapernoux, M., Moser, R., Rueda, D., Gaide, O., Guzzardi, M., Iancu, E. M., Rufer, N., et al. (2008). The proteolytic activity of the paracaspase MALT1 is key in T cell activation. Nat Immunol 9, 272-281. [0426] 9. Coornaert, B., Baens, M., Heyninck, K., Bekaert, T., Haegman, M., Staal, J., Sun, L., Chen, Z. J., Marynen, P., Beyaert, R. (2008) T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20. Nat Immunol. 9, 263-271. [0427] 10. Staal, J., Driege, Y., Bekaert, T., Demeyer, A., Muyllaert, D., Van Damme, P., Gevaert, K., Beyaert, R. (2011) T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1. EMBO J. 30, 1742-1752. [0428] 11. Hailfinger, S., Nogai, H., Pelzer, C., Jaworski, M., Cabalzar, K., Charton, J. E., Guzzardi, M., Decaillet, C., Grau, M., Dorken, B., et al. (2011) Maltl-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines. PNAS. 108, 14596-14601. [0429] 12. Jeltsch, K. M., Hu, D., Brenner, S., Zoller, J., Heinz, G. A., Nagel, D., Vogel, K. U., Rehage, N., Warth, S. C., Edelmann, S. L. et al., (2014) Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation. Nat. Immunol. 15, 1079-1089. 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EQUIVALENTS AND SCOPE

[0438] In the claims articles such as a, an, and the may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include or between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0439] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(S) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms comprising and containing are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0440] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0441] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.