Methods to treat lymphoplasmacytic lymphoma

Abstract

The present invention provides compounds of any one of Formulae (A), (I-11), (II), and (V) (e.g., compounds of Formula (A-1)-(A-18)), and methods for treating Waldenstrm's macroglobulinemia (WM) and other B cell neoplasm in a subject using the compounds. The methods comprise administering to a subject in need thereof an effective amount of the compounds. Also provided are methods to treat B cell neoplasms using the compounds in combination with inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase. ##STR00001##

Claims

1. A compound of Formula (A): ##STR00709## or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative, thereof; wherein: each instance of R.sup.A is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, OR.sup.A1, N(R.sup.A1).sub.2, CN, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, NO.sub.2, NR.sup.A1C(O)R.sup.A1, NR.sup.A1C(O)OR.sup.A1, NR.sup.A1S(O).sub.2R.sup.A1, S(O).sub.2R.sup.A1, or S(O).sub.2N(R.sup.A1).sub.2; each instance of R.sup.B is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, OR.sup.A1, N(R.sup.A1).sub.2, CN, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, NO.sub.2, NR.sup.A1C(O)R.sup.A1, NR.sup.A1C(O)OR.sup.A1, NR.sup.A1S(O).sub.2R.sup.A1, S(O).sub.2R.sup.A1, or S(O).sub.2N(R.sup.A1).sub.2, provided that at least one instance of R.sup.B is optionally substituted heterocyclyl, optionally substituted (CH.sub.2)(heterocyclyl), optionally substituted (CH.sub.2).sub.2(heterocyclyl), or optionally substituted (CH.sub.2).sub.3(heterocyclyl); each instance of R.sup.A1 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R.sup.A1 groups are joined to form an optionally substituted heterocyclic ring; Ring B is of the formula: ##STR00710## R.sup.Y is hydrogen, halogen, or substituted or unsubstituted C.sub.1-6 alkyl; R.sup.X is R.sup.D, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or N(R.sup.A1)(R.sup.Xa); each instance of R.sup.Xa is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, S(O)R.sup.A1, S(O)N(R.sup.A1).sub.2, S(O).sub.2R.sup.A1, S(O).sub.2OR.sup.A1, S(O).sub.2N(R.sup.A1).sub.2, N(R.sup.A1).sub.2, or a nitrogen protecting group; k is 0, 1, 2, 3, or 4; l is 1, 2, 3, 4, or 5; -U-Q- is NR.sup.A(CO) or (CO)NR.sup.A; and R.sup.D is an electrophilic moiety of any one of Formulae (i-1) to (i-18): ##STR00711## ##STR00712## R.sup.D1 is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, NO.sub.2, OR.sup.D1a, N(R.sup.D1a).sub.2, SR.sup.D1a, CH.sub.2OR.sup.D1a, CH.sub.2N(R.sup.D1a).sub.2, CH.sub.2SR.sup.D1a, C(O)R.sup.D1a, C(O)OR.sup.D1a, C(O)SR.sup.D1a, C(O)N(R.sup.D1a).sub.2, C(S)R.sup.D1a, C(S)OR.sup.D1a, C(S)SR.sup.D1a, C(S)N(R.sup.D1a).sub.2, C(NR.sup.D1a)R.sup.D1a, C(NR.sup.D1a)OR.sup.D1a, C(NR.sup.D1a)SR.sup.D1a, or C(NR.sup.D1a)N(R.sup.D1a).sub.2, wherein each occurrence of R.sup.D1a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R.sup.D1a groups are joined to form an optionally substituted heterocyclic ring; R.sup.D2 is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, NO.sub.2, OR.sup.D2a, N(R.sup.D2a).sub.2, SR.sup.D2a, CH.sub.2OR.sup.D2a, CH.sub.2N(R.sup.D2a).sub.2, CH.sub.2SR.sup.D2a, C(O)R.sup.D2a, C(O)OR.sup.D2a, C(O)SR.sup.D2a, C(O)N(R.sup.D2a).sub.2, C(S)R.sup.D2a, C(S)OR.sup.D2a, C(S)SR.sup.D2a, C(S)N(R.sup.D2a).sub.2, C(NR.sup.D2a)R.sup.D2a, C(NR.sup.D2a)OR.sup.D2a, C(NR.sup.D2a)SR.sup.D2a, or C(NR.sup.D2a)N(R.sup.D2a).sub.2, wherein each occurrence of R.sup.D2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R.sup.D2a groups are joined to form an optionally substituted heterocyclic ring; R.sup.D3 is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, NO.sub.2, OR.sup.D3a, N(R.sup.D3a).sub.2, SR.sup.D3a, CH.sub.2OR.sup.D3a, CH.sub.2N(R.sup.D3a).sub.2, CH.sub.2SR.sup.D3a, C(O)R.sup.D3a, C(O)OR.sup.D3a, C(O)SR.sup.D3a, C(O)N(R.sup.D3a).sub.2, C(S)R.sup.D3a, C(S)OR.sup.D3a, C(S)SR.sup.D3a, C(S)N(R.sup.D3a).sub.2, C(NR.sup.D3a)R.sup.D3a, C(NR.sup.D3a)OR.sup.D3a, C(NR.sup.D3a)SR.sup.D3a, ands C(=NR.sup.D3a)N(R.sup.D3a).sub.2, wherein each occurrence of R.sup.D3a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R.sup.D3a groups are joined to form an optionally substituted heterocyclic ring; optionally R.sup.D1 and R.sup.D3, or R.sup.D2 and R.sup.D3, or R.sup.D1 and R.sup.D2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; R.sup.D4 is a leaving group; R.sup.D5 is hydrogen, C.sub.1-6 alkyl, or a nitrogen protecting group; Y.sup.Z is O, S, or NR.sup.D6, wherein R.sup.D6 is hydrogen, C.sub.1-6 alkyl, or a nitrogen protecting group; a is 1 or 2; and z is 0, 1, 2, 3, 4, 5, or 6; wherein, unless otherwise provided: each instance of the alkyl is independently C.sub.1-6 alkyl; each instance of the alkenyl is independently C.sub.2-6 alkenyl; each instance of the alkynyl is independently C.sub.2-6 alkynyl; each instance of the carbocyclyl and carbocyclic ring is independently 3- to 10-membered, monocyclic or bicyclic carbocyclyl; each instance of the heterocyclyl and heterocyclic ring is independently 5- to 10-membered, monocyclic or bicyclic heterocyclyl; each instance of the aryl is independently 6- or 10-membered, monocyclic or bicyclic aryl; and each instance of the heteroaryl is independently 5- to 10-membered, monocyclic or bicyclic heteroaryl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein -U-Q- is ##STR00713##

3. The compound of claim 1, wherein the compound is of Formula (A1): ##STR00714## or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof.

4. The compound of claim 3, wherein the compound is of Formula (A1-a), (A1-b), (A1-c), or (A1-d): ##STR00715## or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein: each instance of R.sup.Xc is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, OR.sup.A1, N(R.sup.A1).sub.2, SR.sup.A1, CN, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, NO.sub.2, N.sub.3, NR.sup.A1C(O)R.sup.A1, NR.sup.A1C(O)OR.sup.A1, NR.sup.A1C(O)N(R.sup.A1).sub.2, NR.sup.A1S(O).sub.2R.sup.A1, NR.sup.A1S(O)R.sup.A1, OC(O)R.sup.A1, OC(O)OR.sup.A1, OC(O)N(R.sup.A1).sub.2, S(O)R.sup.A1, S(O)N(R.sup.A1).sub.2, S(O).sub.2R.sup.A1, or S(O).sub.2N(R.sup.A1).sub.2.

5. The compound of claim 1, wherein the compound is of Formula (A3): ##STR00716## or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof.

6. The compound of claim 5, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R.sup.D is selected from the group consisting of: ##STR00717##

7. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein at least one instance of R.sup.A is substituted or unsubstituted, C.sub.1-6 alkyl.

8. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein 1 is 1 or 2.

9. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein at least one instance of R.sup.B is substituted or unsubstituted, C.sub.1-6 alkyl.

10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein at least one instance of R.sup.B is substituted or unsubstituted CH.sub.2-(piperazinyl).

11. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein at least one instance of R.sup.B is C.sub.1-6 haloalkyl.

12. The compound of claim 1, wherein the compound is of the formula: ##STR00718## ##STR00719## ##STR00720## ##STR00721## ##STR00722## or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof.

13. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient.

14. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein -U-Q-is ##STR00723##

15. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R.sup.X is N(R.sup.A1)(R.sup.Xa).

16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R.sup.A1 is hydrogen.

17. The compound of claim 16, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R.sup.Xa is optionally substituted alkyl or optionally substituted acyl.

18. The compound of claim 16, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R.sup.Xa is optionally substituted heterocyclyl or optionally substituted heteroaryl.

19. The compound of claim 16, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R.sup.Xa is N(R.sup.A1).sub.2.

20. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein ##STR00724## is of the formula: ##STR00725##

21. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, provided that at least one instance of R.sup.B is optionally substituted (CH.sub.2)(heterocyclyl).

22. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein ##STR00726## is of the formula: ##STR00727##

23. The compound of claim 1, wherein the compound is of the formula: ##STR00728## or a pharmaceutically acceptable salt thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows isobolograms demonstrating the synergy between compound (A-17) and a BTK inhibitor. Points below the 1 to 1 line connecting the X and Y axes are synergistic, points near the line are additive, and points above it are antagonistic.

DETAILED DESCRIPTION OF THE INVENTION

(2) In an effort to identify novel treatments for Waldenstrm's macroglobulinemia, in vitro screens were carried out against several kinases (e.g., BTK, HCK, TAK1, HPK1). These kinases are involved in the regulation of aberrant cell growth associated with this condition. Cell-based screening was also carried out in several disease state model lines of Waldenstrm's macroglobulinemia (e.g., BCWM.1, MWCL-1). Based on these screening efforts and subsequent lead optimization, compounds of any one of Formulae (A), (I-11), (II), and (V) (e.g., compounds of Formula (A-1)-(A-18)) were identified.

(3) In one aspect, the present invention provides compounds of Formula (A):

(4) ##STR00012##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof;
wherein:

(5) each instance of R.sup.A is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, OR.sup.A1, N(R.sup.A1).sub.2, CN, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, NO.sub.2, NR.sup.A1C(O)R.sup.A1, NR.sup.A1C(O)OR.sup.A1, NR.sup.A1S(O).sub.2R.sup.A1, S(O).sub.2R.sup.A1, or S(O).sub.2N(R.sup.A1).sub.2;

(6) each instance of R.sup.B is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, OR.sup.A1, N(R.sup.A1).sub.2, CN, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, NO.sub.2, NR.sup.A1C(O)R.sup.A1, NR.sup.A1C(O)OR.sup.A1, NR.sup.A1S(O).sub.2R.sup.A1, S(O).sub.2R.sup.A1, or S(O).sub.2N(R.sup.A1).sub.2;

(7) each instance of R.sup.A1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R.sup.A1 groups are joined to form an optionally substituted heterocyclic ring;

(8) one instance of A that is included in Ring B is CR.sup.Y;

(9) the other instance of A that is included in Ring B is CR.sup.Y or N;

(10) each instance of R.sup.Y is independently H, halogen, or substituted or unsubstituted C.sub.1-6 alkyl;

(11) each instance of R.sup.X is independently selected from the group consisting of R.sup.D, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and N(R.sup.A1)(R.sup.Xa);

(12) each instance of R.sup.Xa is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, S(O)R.sup.A1, S(O)N(R.sup.A1).sub.2, S(O).sub.2R.sup.A1, S(O).sub.2OR.sup.A1, S(O).sub.2R.sup.A1, S(O).sub.2N(R.sup.A1).sub.2, N(R.sup.A1).sub.2, and a nitrogen protecting group;

(13) k is 0, 1, 2, 3, or 4;

(14) l is 1, 2, 3, 4, or 5;

(15) Q and U are taken together to be NR.sup.A(CO) or (CO)NR.sup.A; and

(16) R.sup.D is an electrophilic moiety as described herein.

(17) In certain embodiments, the present invention provides compounds from the group consisting of:

(18) ##STR00013## ##STR00014## ##STR00015## ##STR00016## ##STR00017##
and pharmaceutically acceptable salts thereof.

(19) In another aspect, the present invention provides methods for treating Waldenstrm's macroglobulinemia (WM) in a subject using compounds of the invention. The methods comprise administering to a subject in need thereof an effective amount of a compound of the invention. Also provided are methods to treat other B cell neoplasms using compounds of the invention in combination with inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase. In certain embodiments, one or more compounds of the invention are used in combination with an inhibitor of the phosphoinositide 3-kinase delta isoform (PI3K). In certain embodiments, combinations of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the agents described herein are used for treating WM. In certain embodiments, the agents described herein are used in combination with kinase inhibitors such as inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), and/or phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase.

(20) Waldenstrom's macroglobulinemia (WM) is a distinct clinicopathological entity resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphoplasmacytic cells which secrete a monoclonal IgM protein. This condition is considered to correspond to lymphoplasmacytic lymphoma (LPL) as defined by the World Health Organization classification system. Genetic factors play an important role in the pathogenesis of WM, with 25% of patients demonstrating a family history. IgM monoclonal gammopathy of unknown significance (MGUS) often precedes the development of WM.

(21) As used herein, a B cell neoplasm includes both Hodgkin's lymphoma and non-Hodgkin's lymphomas. Classical Hodgkin's lymphoma (HL) includes various subtypes such as Nodular sclerosing HL, Mixed-cellularity subtype, Lymphocyte-rich or Lymphocytic predominance and Lymphocyte depleted. Examples of B cell non-Hodgkin's lymphomas include, but are not limited to, Waldenstrm's macroglobulinemia, diffuse large B cell lymphoma, follicular lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT), small cell lymphocytic lymphoma (overlaps with chronic lymphocytic leukemia), mantle cell lymphoma (MCL), Burkitt lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), intravascular large B-cell lymphoma, primary effusion lymphoma, and lymphomatoid granulomatosis.

(22) In certain embodiments, the subject is administered a compound of Formula (A):

(23) ##STR00018##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof;
wherein:

(24) each instance of R.sup.A is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, OR.sup.A1, N(R.sup.A1).sub.2, CN, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, NO.sub.2, NR.sup.A1C(O)R.sup.A1, NR.sup.A1C(O)OR.sup.A1, NR.sup.A1S(O).sub.2R.sup.A1, S(O).sub.2R.sup.A1, or S(O).sub.2N(R.sup.A1).sub.2;

(25) each instance of R.sup.B is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, OR.sup.A1, N(R.sup.A1).sub.2, CN, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, NO.sub.2, NR.sup.A1C(O)R.sup.A1, NR.sup.A1C(O)OR.sup.A1, NR.sup.A1S(O).sub.2R.sup.A1, S(O).sub.2R.sup.A1, or S(O).sub.2N(R.sup.A1).sub.2;

(26) each instance of R.sup.A1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R.sup.A1 groups are joined to form an optionally substituted heterocyclic ring;

(27) each instance of R.sup.X is independently selected from the group consisting of R.sup.D, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and N(R.sup.A1)(R.sup.Xa);

(28) each instance of R.sup.Xa is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, S(O)R.sup.A1, S(O)N(R.sup.A1).sub.2, S(O).sub.2R.sup.A1, S(O).sub.2OR.sup.A1, S(O).sub.2N(R.sup.A1).sub.2, S(O).sub.2N(R.sup.A1).sub.2, N(R.sup.A1).sub.2, and a nitrogen protecting group;

(29) k is 0, 1, 2, 3, or 4;

(30) l is 1, 2, 3, 4, or 5;

(31) Q and U are taken together to be NR.sup.A(CO) or (CO)NR.sup.A; and

(32) R.sup.D is an electrophilic moiety as described herein.

(33) In certain embodiments, the subject is adminstered compound (A-1):

(34) ##STR00019##
or a pharmaceutically acceptable salt thereof.

(35) In certain embodiments, the subject is adminstered compound (A-2):

(36) ##STR00020##
or a pharmaceutically acceptable salt thereof.

(37) In certain embodiments, the subject is adminstered compound (A-3):

(38) ##STR00021##
or a pharmaceutically acceptable salt thereof.

(39) In certain embodiments, the subject is adminstered compound (A-4):

(40) ##STR00022##
or a pharmaceutically acceptable salt thereof.

(41) In certain embodiments, the subject is adminstered compound (A-5):

(42) ##STR00023##
or a pharmaceutically acceptable salt thereof.

(43) In certain embodiments, the subject is adminstered compound (A-6):

(44) ##STR00024##
or a pharmaceutically acceptable salt thereof.

(45) In certain embodiments, the subject is adminstered compound (A-7):

(46) ##STR00025##
or a pharmaceutically acceptable salt thereof.

(47) In certain embodiments, the subject is adminstered compound (A-8):

(48) ##STR00026##
or a pharmaceutically acceptable salt thereof.

(49) In certain embodiments, the subject is adminstered compound (A-9):

(50) ##STR00027##
or a pharmaceutically acceptable salt thereof.

(51) In certain embodiments, the subject is adminstered compound (A-10):

(52) ##STR00028##
or a pharmaceutically acceptable salt thereof.

(53) In certain embodiments, the subject is adminstered compound (A-11):

(54) ##STR00029##
or a pharmaceutically acceptable salt thereof.

(55) In certain embodiments, the subject is adminstered compound (A-12):

(56) ##STR00030##
or a pharmaceutically acceptable salt thereof.

(57) In certain embodiments, the subject is adminstered compound (A-13):

(58) ##STR00031##
or a pharmaceutically acceptable salt thereof.

(59) In certain embodiments, the subject is adminstered compound (A-14):

(60) ##STR00032##
or a pharmaceutically acceptable salt thereof.

(61) In certain embodiments, the subject is adminstered compound (A-15):

(62) ##STR00033##
or a pharmaceutically acceptable salt thereof.

(63) In certain embodiments, the subject is adminstered compound (A-16):

(64) ##STR00034##
or a pharmaceutically acceptable salt thereof.

(65) In certain embodiments, the subject is adminstered compound (A-17):

(66) ##STR00035##
or a pharmaceutically acceptable salt thereof.

(67) In certain embodiments, the subject is adminstered compound (A-18):

(68) ##STR00036##
or a pharmaceutically acceptable salt thereof.

(69) Compounds of Formula (A) include a phenyl Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, k is 0. In certain embodiments, Ring A is of the formula:

(70) ##STR00037##
In certain embodiments, Ring A is of the formula:

(71) ##STR00038##
In certain embodiments, Ring A is of the formula:

(72) ##STR00039##
In certain embodiments, Ring A is of the formula:

(73) ##STR00040##
In certain embodiments, Ring A is of the formula:

(74) ##STR00041##
In certain embodiments, k is 2. In certain embodiments, Ring A is of the formula:

(75) ##STR00042##
In certain embodiments, Ring A is of the formula:

(76) ##STR00043##
In certain embodiments, Ring A is of the formula:

(77) ##STR00044##
In certain embodiments, Ring A is of the formula:

(78) ##STR00045##
In certain embodiments, Ring A is of the formula:

(79) ##STR00046##
In certain embodiments, Ring A is of the formula:

(80) ##STR00047##
In certain embodiments, k is 3. In certain embodiments, Ring A is of the formula:

(81) ##STR00048##
In certain embodiments, Ring A is of the formula:

(82) ##STR00049##
In certain embodiments, Ring A is of the formula:

(83) ##STR00050##
In certain embodiments, k is 4. In certain embodiments, Ring A is of the formula:

(84) ##STR00051##

(85) In compounds of Formula (A), Ring A may be substituted with one or more R.sup.A groups. In certain embodiments, at least one R.sup.A is H. In certain embodiments, at least two R.sup.A groups are H. In certain embodiments, at least three R.sup.A groups are H. In certain embodiments, at least four R.sup.A groups are H. In certain embodiments, at least one R.sup.A is not H. In certain embodiments, at least two R.sup.A groups are not H. In certain embodiments, at least three R.sup.A groups are not H. In certain embodiments, at least one R.sup.A is halogen. In certain embodiments, at least one R.sup.A is F. In certain embodiments, at least one R.sup.A is Cl. In certain embodiments, at least one R.sup.A is Br. In certain embodiments, at least one R.sup.A is I (iodine). In certain embodiments, one R.sup.A is F. In certain embodiments, one R.sup.A is Cl. In certain embodiments, at least one R.sup.A is substituted alkyl. In certain embodiments, at least one R.sup.A is unsubstituted alkyl. In certain embodiments, at least one R.sup.A is substituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.A is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.A is methyl. In certain embodiments, at least one R.sup.A is ethyl. In certain embodiments, at least one R.sup.A is propyl. In certain embodiments, at least one R.sup.A is butyl. In certain embodiments, at least one R.sup.A is substituted carbocyclyl. In certain embodiments, at least one R.sup.A is unsubstituted carbocyclyl. In certain embodiments, at least one R.sup.A is OR.sup.A1. In certain embodiments, at least one R.sup.A is O(C.sub.1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R.sup.A is OMe. In certain embodiments, at least one R.sup.A is OH. In certain embodiments, at least one R.sup.A is N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.A is NH.sub.2. In certain embodiments, at least one R.sup.A is CN. In certain embodiments, at least one R.sup.A is C(O)R.sup.A1. In certain embodiments, at least one R.sup.A is acetyl. In certain embodiments, at least one R.sup.A is C(O)OR.sup.A1. In certain embodiments, at least one R.sup.A is C(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.A is C(O)NHR.sup.A1. In certain embodiments, at least one R.sup.A is C(O)NH(C.sub.1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R.sup.A is C(O)NHMe. In certain embodiments, at least one R.sup.A is C(O)NH.sub.2. In certain embodiments, at least one R.sup.A is NO.sub.2. In certain embodiments, at least one R.sup.A is NR.sup.A1C(O)R.sup.A1. In certain embodiments, at least one R.sup.A is NR.sup.A1C(O)OR.sup.A1. In certain embodiments, at least one R.sup.A is NR.sup.A1S(O).sub.2R.sup.A1. In certain embodiments, at least one R.sup.A is NHS(O).sub.2R.sup.A1. In certain embodiments, at least one R.sup.A is NHS(O).sub.2(C.sub.1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R.sup.A is NHS(O).sub.2Me. In certain embodiments, at least one R.sup.A is S(O).sub.2R.sup.A1. In certain embodiments, at least one R.sup.A is S(O).sub.2N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.A is S(O).sub.2N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.A is S(O).sub.2N(C.sub.1-6 alkyl).sub.2. In certain embodiments, at least one R.sup.A is S(O).sub.2NH(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.A is S(O).sub.2NH(t-Bu). In certain embodiments, at least one R.sup.A is S(O).sub.2NH.sub.2.

(86) In certain embodiments, R.sup.A is OR.sup.A1; and k is 1. In certain embodiments, R.sup.A is O(C.sub.1-6 alkyl); and k is 1. In certain embodiments, R.sup.A is OMe; and k is 1. In certain embodiments, R.sup.A is OH; and k is 1.

(87) In certain embodiments, R.sup.A is substituted C.sub.1-6 alkyl; and k is 1. In certain embodiments, R.sup.A is unsubstituted C.sub.1-6 alkyl; and k is 1. In certain embodiments, R.sup.A is methyl; and k is 1. In certain embodiments, R.sup.A is CF.sub.3; and k is 1. In certain embodiments, R.sup.A is ethyl; and k is 1. In certain embodiments, R.sup.A is propyl; and k is 1. In certain embodiments, R.sup.A is butyl; and k is 1. In certain embodiments, R.sup.A is propyl; and k is 1. In certain embodiments, R.sup.A is butyl; and k is 1.

(88) In certain embodiments, R.sup.A is halogen; and k is 1. In certain embodiments, R.sup.A is F; and k is 1. In certain embodiments, R.sup.A is Cl; and k is 1. In certain embodiments, R.sup.A is Br; and k is 1. In certain embodiments, R.sup.A is I (iodine); and k is 1.

(89) In certain embodiments, one instance of R.sup.A is halogen; another instance of R.sup.A is substituted C.sub.1-6 alkyl; and k is 2. In certain embodiments, one instance of R.sup.A is F; another instance of R.sup.A is substituted C.sub.1-6 alkyl; and k is 2. In certain embodiments, one instance of R.sup.A is Cl; another instance of R.sup.A is substituted C.sub.1-6 alkyl; and k is 2. In certain embodiments, one instance of R.sup.A is halogen; another instance of R.sup.A is unsubstituted C.sub.1-6 alkyl; and k is 2. In certain embodiments, one instance of R.sup.A is F; another instance of R.sup.A is unsubstituted C.sub.1-6 alkyl; and k is 2. In certain embodiments, one instance of R.sup.A is Cl; another instance of R.sup.A is unsubstituted C.sub.1-6 alkyl; and k is 2. In certain embodiments, one instance of R.sup.A is halogen; another instance of R.sup.A is methyl; and k is 2. In certain embodiments, one instance of R.sup.A is F; another instance of R.sup.A is methyl; and k is 2. In certain embodiments, one instance of R.sup.A is Cl; another instance of R.sup.A is methyl; and k is 2. In certain embodiments, one instance of R.sup.A is halogen; another instance of R.sup.A is CF.sub.3; and k is 2. In certain embodiments, one instance of R.sup.A is F; another instance of R.sup.A is CF.sub.3; and k is 2. In certain embodiments, one instance of R.sup.A is Cl; another instance of R.sup.A is CF.sub.3; and k is 2.

(90) In certain embodiments, at least one R.sup.A1 is H. In certain embodiments, at least one R.sup.A1 is substituted acyl. In certain embodiments, at least one R.sup.A1 is unsubstituted acyl. In certain embodiments, at least one R.sup.A1 is acetyl. In certain embodiments, at least one R.sup.A1 is substituted alkyl. In certain embodiments, at least one R.sup.A1 is unsubstituted alkyl. In certain embodiments, at least one R.sup.A1 is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.A1 is methyl. In certain embodiments, at least one R.sup.A1 is ethyl. In certain embodiments, at least one R.sup.A1 is propyl. In certain embodiments, at least one R.sup.A1 is butyl. In certain embodiments, at least one R.sup.A1 is substituted alkenyl. In certain embodiments, at least one R.sup.A1 is unsubstituted alkenyl. In certain embodiments, at least one R.sup.A1 is substituted alkynyl. In certain embodiments, at least one R.sup.A1 is unsubstituted alkynyl. In certain embodiments, at least one R.sup.A1 is substituted carbocyclyl. In certain embodiments, at least one R.sup.A1 is unsubstituted carbocyclyl. In certain embodiments, at least one R.sup.A1 is substituted heterocyclyl. In certain embodiments, at least one R.sup.A1 is unsubstituted heterocyclyl. In certain embodiments, at least one R.sup.A1 is substituted aryl. In certain embodiments, at least one R.sup.A1 is unsubstituted aryl. In certain embodiments, at least one R.sup.A1 is substituted phenyl. In certain embodiments, at least one R.sup.A1 is unsubstituted phenyl. In certain embodiments, at least one R.sup.A1 is substituted heteroaryl. In certain embodiments, at least one R.sup.A1 is unsubstituted heteroaryl. In certain embodiments, at least one R.sup.A1 is substituted pyridyl. In certain embodiments, at least one R.sup.A1 is unsubstituted pyridyl. In certain embodiments, at least one R.sup.A1 is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R.sup.A1 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R.sup.A1 is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.A1 is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R.sup.A1 is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R.sup.A1 is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom.

(91) In compounds of Formula (A), two R.sup.A1 groups may be joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring. In certain embodiments, two R.sup.A1 groups are joined to form a substituted carbocyclic ring. In certain embodiments, two R.sup.A1 groups are joined to form an unsubstituted carbocyclic ring. In certain embodiments, two R.sup.A1 groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R.sup.A1 groups are joined to form an unsubstituted heterocyclic ring. In certain embodiments, two R.sup.A1 groups are joined to form a substituted aryl ring. In certain embodiments, two R.sup.A1 groups are joined to form an unsubstituted aryl ring. In certain embodiments, two R.sup.A1 groups are joined to form a substituted phenyl ring. In certain embodiments, two R.sup.A1 groups are joined to form an unsubstituted phenyl ring. In certain embodiments, two R.sup.A1 groups are joined to form a substituted heteroaryl ring. In certain embodiments, two R.sup.A1 groups are joined to form an unsubstituted heteroaryl ring.

(92) Compounds of Formula (A) include a phenyl Ring C optionally substituted with one or more R.sup.B groups. In certain embodiments, l is 1. In certain embodiments, Ring C is of the formula:

(93) ##STR00052##
In certain embodiments, Ring C is of the formula:

(94) ##STR00053##
In certain embodiments, Ring C is of the formula:

(95) ##STR00054##
certain embodiments, l is 2. In certain embodiments, Ring C is of the formula:

(96) ##STR00055##
In certain embodiments, l is 2. In certain embodiments, Ring C is of the formula:

(97) ##STR00056##
In certain embodiments, Ring C is of the formula:

(98) ##STR00057##
In certain embodiments, Ring C is of the formula:

(99) ##STR00058##
In certain embodiments, Ring C is of the formula:

(100) ##STR00059##
In certain embodiments, Ring C is of the formula:

(101) ##STR00060##
In certain embodiments, 1 is 3. In certain embodiments, Ring C is of the formula:

(102) ##STR00061##
In certain embodiments, Ring C is of the formula:

(103) ##STR00062##
In certain embodiments, Ring C is of the formula:

(104) ##STR00063##
In certain embodiments, Ring C is of the formula:

(105) ##STR00064##
In certain embodiments, 1 is 4. In certain embodiments, Ring C is of the formula:

(106) ##STR00065##
In certain embodiments, Ring C is of the formula:

(107) ##STR00066##
In certain embodiments, Ring C is of the formula:

(108) ##STR00067##
In certain embodiments, 1 is 5. In certain embodiments, Ring C is of the formula:

(109) ##STR00068##

(110) In compounds of Formula (A), Ring C may be substituted with one or more R.sup.B groups. In certain embodiments, at least one R.sup.B is H. In certain embodiments, at least two R.sup.B groups are H. In certain embodiments, at least three R.sup.B groups are H. In certain embodiments, at least four R.sup.B groups are H. In certain embodiments, at least one R.sup.B is not H. In certain embodiments, at least two R.sup.B groups are not H. In certain embodiments, at least three R.sup.B groups are not H. In certain embodiments, at least one R.sup.B is halogen. In certain embodiments, at least one R.sup.B is F. In certain embodiments, at least one R.sup.B is Cl. In certain embodiments, at least one R.sup.B is Br. In certain embodiments, at least one R.sup.B is I (iodine). In certain embodiments, one R.sup.B is F. In certain embodiments, one R.sup.B is Cl. In certain embodiments, at least one R.sup.B is substituted alkyl. In certain embodiments, at least one R.sup.B is unsubstituted alkyl. In certain embodiments, at least one R.sup.B is substituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.B is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.B is methyl. In certain embodiments, at least one R.sup.B is ethyl. In certain embodiments, at least one R.sup.B is propyl. In certain embodiments, at least one R.sup.B is

(111) ##STR00069##
In certain embodiments, at least one R.sup.B is

(112) ##STR00070##
In certain embodiments, at least one R.sup.B is

(113) ##STR00071##
In certain embodiments, at least one R.sup.B is butyl. In certain embodiments, at least one R.sup.B is substituted carbocyclyl. In certain embodiments, at least one R.sup.B is unsubstituted carbocyclyl. In certain embodiments, at least one R.sup.B is substituted heterocyclyl. In certain embodiments, at least one R.sup.B is unsubstituted heterocyclyl. In certain embodiments, at least one R.sup.B is substituted piperidine. In certain embodiments, at least one R.sup.B is unsubstituted piperidine. In certain embodiments, at least one R.sup.B substituted piperizine. In certain embodiments, at least one R.sup.B unsubstituted piperizine. In certain embodiments, at least one R.sup.B substituted pyrrolidine. In certain embodiments, at least one R.sup.B unsubstituted pyrrolidine. In certain embodiments, at least one R.sup.B is substituted morpholine. In certain embodiments, at least one R.sup.B is unsubstituted morpholine. In certain embodiments, at least one R.sup.B is substituted diazepane. In certain embodiments, at least one R.sup.B is unsubstituted diazepane. In certain embodiments, at least one R.sup.B is

(114) ##STR00072##
In certain embodiments, at least one R.sup.B is

(115) ##STR00073##
In certain embodiments, at least one R.sup.B is

(116) ##STR00074##
In certain embodiments, at least one R.sup.B is

(117) ##STR00075##
In certain embodiments, at least one R.sup.B is substituted (CH.sub.2)(heterocyclyl). In certain embodiments, at least one R.sup.B is unsubstituted (CH.sub.2)(heterocyclyl). In certain embodiments, at least one R.sup.B is

(118) ##STR00076##
In certain embodiments, at least one R.sup.B is

(119) ##STR00077##
In certain embodiments, at least one R.sup.B is

(120) ##STR00078##
In certain embodiments, at least one R.sup.B is

(121) ##STR00079##
In certain embodiments, at least one R.sup.B is

(122) ##STR00080##
In certain embodiments, at least one R.sup.B is

(123) ##STR00081##
In certain embodiments, at least one R.sup.B is

(124) ##STR00082##
In certain embodiments, at least one R.sup.B is

(125) ##STR00083##
In certain embodiments, at least one R.sup.B is

(126) ##STR00084##
In certain embodiments, at least one R.sup.B is

(127) ##STR00085##
In certain embodiments, at least one R.sup.B is

(128) ##STR00086##
In certain embodiments, at least one R.sup.B is

(129) ##STR00087##
In certain embodiments, at least one R.sup.B is

(130) ##STR00088##
In certain embodiments, at least one R.sup.B is

(131) ##STR00089##
In certain embodiments, at least one R.sup.B is

(132) ##STR00090##
In certain embodiments, at least one R.sup.B is

(133) ##STR00091##
In certain embodiments, at least one R.sup.B is

(134) ##STR00092##
In certain embodiments, at least one R.sup.B is

(135) ##STR00093##
In certain embodiments, at least one R.sup.B is substituted (CH.sub.2).sub.2(heterocyclyl). In certain embodiments, at least one R.sup.B is unsubstituted (CH.sub.2).sub.2(heterocyclyl). In certain embodiments, at least one R.sup.B is

(136) ##STR00094##
In certain embodiments, at least one R.sup.B is substituted (CH.sub.2).sub.3(heterocyclyl). In certain embodiments, at least one R.sup.B is unsubstituted (CH.sub.2).sub.3(heterocyclyl). In certain embodiments, at least one R.sup.B is

(137) ##STR00095##
In certain embodiments, at least one R.sup.B is substituted aryl. In certain embodiments, at least one R.sup.B is unsubstituted aryl. In certain embodiments, at least one R.sup.B is substituted phenyl. In certain embodiments, at least one R.sup.B is unsubstituted phenyl. In certain embodiments, at least one R.sup.B is substituted heteroaryl. In certain embodiments, at least one R.sup.B is unsubstituted heteroaryl. In certain embodiments, at least one R.sup.B is substituted pyridyl. In certain embodiments, at least one R.sup.B is unsubstituted pyridyl. In certain embodiments, at least one R.sup.B is substituted imidazole. In certain embodiments, at least one R.sup.B is unsubstituted imidazole. In certain embodiments, at least one R.sup.B is

(138) ##STR00096##
In certain embodiments, at least one R.sup.B is

(139) ##STR00097##
In certain embodiments, at least one R.sup.B is OR.sup.A1. In certain embodiments, at least one R.sup.B is O(C.sub.1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R.sup.B is OMe. In certain embodiments, at least one R.sup.B is OPh. In certain embodiments, at least one R.sup.B is

(140) ##STR00098##
In certain embodiments, at least one R.sup.B is

(141) ##STR00099##
In certain embodiments, at least one R.sup.B is OH. In certain embodiments, at least one R.sup.B is N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.B is NEt.sub.2. In certain embodiments, at least one R.sup.B is NMe.sub.2. In certain embodiments, at least one R.sup.B is NHtBu. In certain embodiments, at least one R.sup.B is

(142) ##STR00100##
In certain embodiments, at least one R.sup.B is

(143) ##STR00101##
In certain embodiments, at least one R.sup.B is NH.sub.2. In certain embodiments, at least one R.sup.B certain embodiments, at least one R.sup.B is NH.sub.2. In certain embodiments, at least one R is CN. In certain embodiments, at least one R.sup.B is C(O)R.sup.A1. In certain embodiments, at least one R.sup.B is acetyl. In certain embodiments, at least one R.sup.B is C(O)OR.sup.A1. In certain embodiments, at least one R.sup.B is C(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.B is C(O)NHR.sup.A1. In certain embodiments, at least one R.sup.B is C(O)NH(C.sub.1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R.sup.B is C(O)NHMe. In certain embodiments, at least one R.sup.B is C(O)NH.sub.2. In certain embodiments, at least one R.sup.B is

(144) ##STR00102##
In certain embodiments, at least one R.sup.B is

(145) ##STR00103##
In certain embodiments, at least one R.sup.B is NO.sub.2. In certain embodiments, at least one R.sup.B is NR.sup.A1C(O)R.sup.A1. In certain embodiments, at least one R.sup.B is NR.sup.A1C(O)OR.sup.A1. In certain embodiments, at least one R.sup.B is NR.sup.A1S(O).sub.2R.sup.A1. In certain embodiments, at least one R.sup.B is NHS(O).sub.2R.sup.A1. In certain embodiments, at least one R.sup.B is NHS(O).sub.2(C.sub.1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R.sup.B is NHS(O).sub.2Me. In certain embodiments, at least one R.sup.B is S(O).sub.2R.sup.A1. In certain embodiments, at least one R.sup.B is S(O).sub.2N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.B is S(O).sub.2N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.B is S(O).sub.2N(C.sub.1-6 alkyl).sub.2. In certain embodiments, at least one R.sup.B is S(O).sub.2NH(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.B is S(O).sub.2NH(t-Bu). In certain embodiments, at least one R.sup.B is S(O).sub.2NH.sub.2.

(146) In certain embodiments, R.sup.B is substituted or unsubstituted C.sub.1-6alkyl; and l is 1. In certain embodiments, R.sup.B is substituted or unsubstituted C.sub.1-6alkyl; l is 1; and R.sup.B is meta to the point of attachment of U. In certain embodiments, R.sup.B is substituted or unsubstituted C.sub.1-6alkyl; l is 1; and R.sup.B is para to the point of attachment of U. In certain embodiments, R.sup.B is C.sub.1-6alkyl substituted with one CN group; and l is 1. In certain embodiments, R.sup.B is C.sub.1-6alkyl substituted with one CN group; l is 1; and R.sup.B is meta to the point of attachment of U. In certain embodiments, R.sup.B is C.sub.1-6alkyl substituted with one CN group; l is 1; and R.sup.B is para to the point of attachment of U. In certain embodiments, R.sup.B is

(147) ##STR00104##
and l is 1. In certain embodiments, R.sup.B is

(148) ##STR00105##
l is 1; and R.sup.B is meta to the point of attachment of U. In certain embodiments, R.sup.B is

(149) ##STR00106##
l is 1; and R.sup.B is para to the point of attachment of U. In certain embodiments, R.sup.B is substituted or unsubstituted CH.sub.2-(piperazinyl); and l is 1. In certain embodiments, R.sup.B is substituted or unsubstituted CH.sub.2-(piperazinyl); l is 1; and R.sup.B is meta to the point of attachment of U. In certain embodiments, R.sup.B is substituted or unsubstituted CH.sub.2-(piperazinyl); l is 1; and R.sup.B is para to the point of attachment of U. In certain embodiments, R.sup.B is

(150) ##STR00107##
and l is 1. In certain embodiments, R.sup.B is

(151) ##STR00108##
l is 1; and R.sup.B is meta to the point of attachment of U. In certain embodiments, R.sup.B is

(152) ##STR00109##
l is 1; and R.sup.B is para to the point of attachment of U. In certain embodiments, R.sup.B is haloalkyl; and l is 1. In certain embodiments, R.sup.B is haloalkyl; l is 1; and R.sup.B is meta to the point of attachment of U. In certain embodiments, R.sup.B is haloalkyl; l is 1; and R.sup.B is para to the point of attachment of U. In certain embodiments, R.sup.B is CF.sub.3; and l is 1. In certain embodiments, R.sup.B is CF.sub.3; l is 1; and R.sup.B is meta to the point of attachment of U. In certain embodiments, R.sup.B is CF.sub.3; l is 1; and R.sup.B is para to the point of attachment of U. In certain embodiments, R.sup.B is substituted or unsubstituted imidazoyl and l is 1. In certain embodiments, R.sup.B is substituted or unsubstituted imidazoyl l is 1; and R.sup.B is meta to the point of attachment of U. In certain embodiments, R.sup.B is substituted or unsubstituted imidazoyl; l is 1; and R.sup.B is para to the point of attachment of U. In certain embodiments, R.sup.B is

(153) ##STR00110##
and l is 1. In certain embodiments, R.sup.B is

(154) ##STR00111##
is 1; and R.sup.B is meta to the point of attachment of U. In certain embodiments, R.sup.B is

(155) ##STR00112##
l is 1; and R.sup.B is meta to the point of attachment of U. In certain embodiments, R.sup.B is 1; and R.sup.B is para to the point of attachment of U. In certain embodiments, R.sup.B is substituted or unsubstituted piperazinyl; and l is 1. In certain embodiments, R.sup.B is substituted or unsubstituted piperazinyl; l is 1; and R.sup.B is meta to the point of attachment of U. In certain embodiments, R.sup.B is substituted or unsubstituted piperazinyl; l is 1; and R.sup.B is para to the point of attachment of U. In certain embodiments, R.sup.B is

(156) ##STR00113##
and l is 1. In certain embodiments, R.sup.B is

(157) ##STR00114##
l is 1; and R.sup.B is meta to the point of attachment of U. In certain embodiments, R.sup.B is

(158) ##STR00115##
l is 1; and R.sup.B is para to the point of attachment of U. In certain embodiments, R.sup.B is substituted or unsubstituted morpholine; and l is 1. In certain embodiments, R.sup.B is substituted or unsubstituted morpholine; l is 1; and R.sup.B is meta to the point of attachment of U. In certain embodiments, R.sup.B is substituted or unsubstituted morpholine; l is 1; and R.sup.B is para to the point of attachment of U.

(159) In certain embodiments, at least one R.sup.B group is substituted or unsubstituted C.sub.1-6alkyl; and l is 2. In certain embodiments, at least one R.sup.B group is substituted or unsubstituted C.sub.1-6alkyl; l is 2; and at least one R.sup.B is meta to the point of attachment of U. In certain embodiments, at least one R.sup.B group is substituted or unsubstituted C.sub.1-6alkyl; l is 2; and one R.sup.B is para to the point of attachment of U. In certain embodiments, at least one R.sup.B group is C.sub.1-6alkyl substituted with one CN group; and l is 2. In certain embodiments, at least one R.sup.B group is C.sub.1-6alkyl substituted with one CN group; l is 2; and at least one R.sup.B is meta to the point of attachment of U. In certain embodiments, at least one R.sup.B group is C.sub.1-6alkyl substituted with one CN group; l is 2; and one R.sup.B is para to the point of attachment of U. In certain embodiments, at least one R.sup.B group is

(160) ##STR00116##
and l is 2. In certain embodiments, at least one R.sup.B group is

(161) ##STR00117##
l is 2; and at least one R.sup.B is meta to the point of attachment of U. In certain embodiments, at least one R.sup.B group is

(162) ##STR00118##
l is 2; and one R.sup.B is para to the point of attachment of U. In certain embodiments, at least one R.sup.B group is substituted or unsubstituted CH.sub.2-(piperazinyl); and l is 2. In certain embodiments, at least one R.sup.B group is substituted or unsubstituted CH.sub.2-(piperazinyl); l is 2; and at least one R.sup.B is meta to the point of attachment of U. In certain embodiments, at least one R.sup.B group is substituted or unsubstituted CH.sub.2-(piperazinyl); l is 2; and one R.sup.B is para to the point of attachment of U. In certain embodiments, at least one R.sup.B group is

(163) ##STR00119##
and l is 2. In certain embodiments, at least one R.sup.B group is

(164) ##STR00120##
l is 2; and at least one R.sup.B is meta to the point of attachment of U. In certain embodiments, at least one R.sup.B group is

(165) ##STR00121##
l is 2; and one R.sup.B is para to the point of attachment of U. In certain embodiments, at least one R.sup.B group is haloalkyl; and l is 2. In certain embodiments, at least one R.sup.B group is haloalkyl; l is 2; and at least one R.sup.B is meta to the point of attachment of U. In certain embodiments, at least one R.sup.B group is haloalkyl; l is 2; and one R.sup.B is para to the point of attachment of U. In certain embodiments, at least one R.sup.B group is CF.sub.3; and l is 2. In certain embodiments, at least one R.sup.B group is CF.sub.3; l is 2; and at least one R.sup.B is meta to the point of attachment of U. In certain embodiments, at least one R.sup.B group is CF.sub.3; l is 2; and one R.sup.B is para to the point of attachment of U. In certain embodiments, at least one R.sup.B group is substituted or unsubstituted imidazoyl; and l is 2. In certain embodiments, at least one R.sup.B group is substituted or unsubstituted imidazoyl; l is 2; and at least one R.sup.B is meta to the point of attachment of U. In certain embodiments, at least one R.sup.B group is substituted or unsubstituted imidazoyl; l is 2; and one R.sup.B is para to the point of attachment of U. In certain embodiments, at least one R.sup.B group is

(166) ##STR00122##
and l is 2. In certain embodiments, at least one R.sup.B group is

(167) ##STR00123##
l is 2; and at least one R.sup.B is meta to the point of attachment of U. In certain embodiments, at least one R.sup.B group is

(168) ##STR00124##
l is 2; and one R.sup.B is para to the point of attachment of U. In certain embodiments, at least one R.sup.B group is substituted or unsubstituted piperazinyl; and l is 2. In certain embodiments, at least one R.sup.B group is substituted or unsubstituted piperazinyl; l is 2; and at least one R.sup.B is meta to the point of attachment of U. In certain embodiments, at least one R.sup.B group is substituted or unsubstituted piperazinyl; l is 2; and one R.sup.B is para to the point of attachment of U. In certain embodiments, at least one R.sup.B group is

(169) ##STR00125##
and l is 2. In certain embodiments, at least one R.sup.B group is

(170) ##STR00126##
l is 2; and at least one R.sup.B is meta to the point of attachment of U. In certain embodiments, at least one R.sup.B group is

(171) ##STR00127##
l is 2; and one R.sup.B is para to the point of attachment of U. In certain embodiments, at least one R.sup.B group is substituted or unsubstituted morpholine; and l is 2. In certain embodiments, at least one R.sup.B group is substituted or unsubstituted morpholine; l is 2; and at least one R.sup.B is meta to the point of attachment of U. In certain embodiments, at least one R.sup.B group is substituted or unsubstituted morpholine; l is 2; and one R.sup.B is para to the point of attachment of U. In certain embodiments, two R.sup.B groups are substituted or unsubstituted morpholine; l is 2; and both R.sup.B groups are meta to the point of attachment of U.

(172) In compounds of Formula (A), Q and U are taken together to represent a divalent linker moiety. In certain embodiments, Q and U are taken together to represent

(173) ##STR00128##
In certain embodiments, Q and U are taken together to represent

(174) ##STR00129##
In certain embodiments, Q and U are taken together to represent

(175) ##STR00130##
In certain embodiments, Q and U are taken together to represent

(176) ##STR00131##

(177) Formula (A) includes a pyridine or pyrimidine ring as Ring B. In certain embodiments, each instance of A included in Ring B is carbon. In certain embodiments, one instance of A included in Ring B is carbon, and the other instance of A included in Ring B is nitrogen. In certain embodiments, Ring B is of the formula:

(178) ##STR00132##
In certain embodiments, Ring B is of the formula:

(179) ##STR00133##
In certain embodiments, Ring B is of the formula:

(180) ##STR00134##
In certain embodiments, Ring B is of the formula:

(181) ##STR00135##
In certain embodiments, Ring B is of the formula:

(182) ##STR00136##

(183) Formula (A) may include one or more R.sup.Y groups. When Formula (A) includes two instances of R.sup.Y, the two instances of R.sup.Y may be the same or different from each other. In certain embodiments, at least one instance of R.sup.Y is H. In certain embodiments, each instance of R.sup.Y is H. In certain embodiments, at least one instance of R.sup.Y is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.Y is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.Y is Me. In certain embodiments, at least one instance of R.sup.Y is substituted methyl (e.g., CF.sub.3 or Bn). In certain embodiments, at least one instance of R.sup.Y is Et, substituted ethyl (e.g., perfluoroethyl), Pr, substituted propyl (e.g., perfluoropropyl), Bu, or substituted butyl (e.g., perfluorobutyl).

(184) In compounds of Formula (A), the pyridine or pyrimidine ring may be substituted with one or more R.sup.X groups. When Formula (A) includes two instances of R.sup.X, the two instances of R.sup.X may be the same or different from each other. In certain embodiments, at least one R.sup.X is substituted carbocyclyl. In certain embodiments, at least one R.sup.X is unsubstituted carbocyclyl. In certain embodiments, at least one R.sup.X is

(185) ##STR00137##
In certain embodiments, at least one R.sup.X is

(186) ##STR00138##
In certain embodiments, at least one R.sup.X is

(187) ##STR00139##
In certain embodiments, at least one R.sup.X is substituted heterocyclyl. In certain embodiments, at least one R.sup.X is unsubstituted heterocyclyl. In certain embodiments, at least one R.sup.X is

(188) ##STR00140##
In certain embodiments, at least one R.sup.X is

(189) ##STR00141##
In certain embodiments, at least one R.sup.X is

(190) ##STR00142##
In certain embodiments, at least one R.sup.X is

(191) ##STR00143##
In certain embodiments, at least one R.sup.X is

(192) ##STR00144##
In certain embodiments, at least one R.sup.X is

(193) ##STR00145##
In certain embodiments, at least one R.sup.X is

(194) ##STR00146##
In certain embodiments, at least one R.sup.X is

(195) ##STR00147##
In certain embodiments, at least one R.sup.X is

(196) ##STR00148##
In certain embodiments, at least one R.sup.X is substituted aryl. In certain embodiments, at least one R.sup.X is unsubstituted aryl. In certain embodiments, at least one R.sup.X is substituted phenyl. In certain embodiments, at least one R.sup.X is unsubstituted phenyl. In certain embodiments, at least one R.sup.X is

(197) ##STR00149##
In certain embodiments, at least one R.sup.X is

(198) ##STR00150##
In certain embodiments, at least one R.sup.X is

(199) ##STR00151##
In certain embodiments, at least one R.sup.X is

(200) ##STR00152##
In certain embodiments, at least one R.sup.X is

(201) ##STR00153##
In certain embodiments, at least one R.sup.X is

(202) ##STR00154##
In certain embodiments, at least one R.sup.X is

(203) ##STR00155##
In certain embodiments, at least one R.sup.X is

(204) ##STR00156##
In certain embodiments, at least one R.sup.X is substituted heteroaryl. In certain embodiments, at least one R.sup.X is unsubstituted heteroaryl. In certain embodiments, at least one R.sup.X is

(205) ##STR00157##
In certain embodiments, at least one R.sup.X is

(206) ##STR00158##
In certain embodiments, at least one R.sup.X is

(207) ##STR00159##
In certain embodiments, at least one R.sup.X is

(208) ##STR00160##
In certain embodiments, at least one R.sup.X is

(209) ##STR00161##
In certain embodiments, at least one R.sup.X is

(210) ##STR00162##
In certain embodiments, at least one R.sup.X is

(211) ##STR00163##
In certain embodiments, at least one R.sup.X is

(212) ##STR00164##
In certain embodiments, at least one R.sup.X is

(213) ##STR00165##
In certain embodiments, at least one R.sup.X is

(214) ##STR00166##
In certain embodiments, at least one R.sup.X is

(215) ##STR00167##
In certain embodiments, at least one R.sup.X is

(216) ##STR00168##
In certain embodiments, at least one R is

(217) ##STR00169##
In certain embodiments, at least one R.sup.X is

(218) ##STR00170##
In certain embodiments, at least one R.sup.X is

(219) ##STR00171##
In certain embodiments, at least one R.sup.X is

(220) ##STR00172##
In certain embodiments, at least one R.sup.X is

(221) ##STR00173##
In certain embodiments, at least one R.sup.X is

(222) ##STR00174##
In certain embodiments, at least one R.sup.X is

(223) ##STR00175##
In certain embodiments, at least one R.sup.X is

(224) ##STR00176##
In certain embodiments, at least one R.sup.X is

(225) ##STR00177##
In certain embodiments, at least one R.sup.X is

(226) ##STR00178##
In certain embodiments, at least one R.sup.X is

(227) ##STR00179##
In certain embodiments, at least one R.sup.X is

(228) ##STR00180##
In certain embodiments, at least one R.sup.X is

(229) ##STR00181##
In certain embodiments, at least one R.sup.X is

(230) ##STR00182##
In certain embodiments, at least one R.sup.X is

(231) ##STR00183##
In certain embodiments, at least one R.sup.X is

(232) ##STR00184##
In certain embodiments, at least one R.sup.X is

(233) ##STR00185##
In certain embodiments, at least one R.sup.X is

(234) ##STR00186##
In certain embodiments, at least one R.sup.X is

(235) ##STR00187##
In certain embodiments, at least one R.sup.X is N(R.sup.A1)(R.sup.Xa). In certain embodiments, at least one R.sup.X is NH.sub.2. In certain embodiments, at least one R.sup.X is NH (3-6 membered cycloalkyl) where the cycloalkyl is substituted or unsubstituted. In certain embodiments, at least one R.sup.X is

(236) ##STR00188##
In certain embodiments, at least one R.sup.X is NH(C.sub.1-6alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R.sup.X is N(C.sub.1-6alkyl).sub.2 where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R.sup.X is

(237) ##STR00189##
In certain embodiments, at least one R.sup.X is NH(acyl). In certain embodiments, at least one R.sup.X is

(238) ##STR00190##
In certain embodiments, at least one R.sup.X is

(239) ##STR00191##
In certain embodiments, at least one R.sup.X is

(240) ##STR00192##
In certain embodiments, at least one R.sup.X is

(241) ##STR00193##
In certain embodiments, at least one R.sup.X is NHC(O)(3-6 membered cycloalkyl) where the cycloalkyl is substituted or unsubstituted. In certain embodiments, at least one R.sup.X is

(242) ##STR00194##
In certain embodiments, at least one R.sup.X is NHC(O)(C.sub.1-6alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R.sup.X is

(243) ##STR00195##
In certain embodiments, at least one R.sup.X is

(244) ##STR00196##
In certain embodiments, at least one R.sup.X is

(245) ##STR00197##
In certain embodiments, at least one R.sup.X is

(246) ##STR00198##
In certain embodiments, at least one R.sup.X is

(247) ##STR00199##
In certain embodiments, at least one R.sup.X is

(248) ##STR00200##
In certain embodiments, at least one R.sup.X is

(249) ##STR00201##
In certain embodiments, at least one R.sup.X is

(250) ##STR00202##
In certain embodiments, at least one R.sup.X is

(251) ##STR00203##
In certain embodiments, at least one R.sup.X is

(252) ##STR00204##
In certain embodiments, at least one R.sup.X is

(253) ##STR00205##
In certain embodiments, at least one R.sup.X is

(254) ##STR00206##
In certain embodiments, at least one R.sup.X is

(255) ##STR00207##
In certain embodiments, at least one R.sup.X is

(256) ##STR00208##
In certain embodiments, at least one R.sup.X is

(257) ##STR00209##
In certain embodiments, at least one R.sup.X is

(258) ##STR00210##
In certain embodiments, at least one R.sup.X is

(259) ##STR00211##
In certain embodiments, at least one R.sup.X is

(260) ##STR00212##
In certain embodiments, at least one R.sup.X is

(261) ##STR00213##
In certain embodiments, at least one R.sup.X is

(262) ##STR00214##
In certain embodiments, at least one R.sup.X is

(263) ##STR00215##
In certain embodiments, at least one R.sup.X is

(264) ##STR00216##
In certain embodiments, at least one R.sup.X is

(265) ##STR00217##
In certain embodiments, at least one R.sup.X is

(266) ##STR00218##
In certain embodiments, at least one R.sup.X is

(267) ##STR00219##
In certain embodiments, at least one R.sup.X is

(268) ##STR00220##
In certain embodiments, at least one R.sup.X is

(269) ##STR00221##
In certain embodiments, at least one R.sup.X is

(270) ##STR00222##
In certain embodiments, at least one R.sup.X is

(271) ##STR00223##
In certain embodiments, at least one R.sup.X is

(272) ##STR00224##
In certain embodiments, at least one R.sup.X is

(273) ##STR00225##
In certain embodiments, at least one R.sup.X is

(274) ##STR00226##
In certain embodiments, at least one R.sup.X is

(275) ##STR00227##
In certain embodiments, at least one R.sup.X is

(276) ##STR00228##
In certain embodiments, at least one R.sup.X is

(277) ##STR00229##
In certain embodiments, at least one R.sup.X is

(278) ##STR00230##
In certain embodiments, at least one R.sup.X is

(279) ##STR00231##
In certain embodiments, at least one R.sup.X is

(280) ##STR00232##
In certain embodiments, at least one R.sup.X is

(281) ##STR00233##
In certain embodiments, at least one R.sup.X is

(282) ##STR00234##
In certain embodiments, at least one R.sup.X is

(283) ##STR00235##
In certain embodiments, at least one R.sup.X is

(284) ##STR00236##
In certain embodiments, at least one R.sup.X is

(285) ##STR00237##
In certain embodiments, at least one R.sup.X is

(286) ##STR00238##
In certain embodiments, at least one R.sup.X is

(287) ##STR00239##
In certain embodiments, at least one R.sup.X is

(288) ##STR00240##
In certain embodiments, at least one R.sup.X is

(289) ##STR00241##
In certain embodiments, at least one R.sup.X is

(290) ##STR00242##
In certain embodiments, at least one R.sup.X is

(291) ##STR00243##
In certain embodiments, at least one R.sup.X is

(292) ##STR00244##
In certain embodiments, at least one R.sup.X is

(293) ##STR00245##
In certain embodiments, at least one R.sup.X is

(294) ##STR00246##
In certain embodiments, at least one R.sup.X is

(295) ##STR00247##
In certain embodiments, at least one R.sup.X is N(R.sup.A1)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.X is NHN(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.X is NHNH(acyl). In certain embodiments, at least one R.sup.X is NHNHC(O)Me. In certain embodiments, at least one R.sup.X is NHN(C.sub.1-6alkyl).sub.2 where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R.sup.X is NHNMe.sub.2.

(296) In compounds of Formula (A), R.sup.X may be substituted with one or more R.sup.Xa groups. Each instance of R.sup.Xa is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, S(O)R.sup.A1, S(O)N(R.sup.A1).sub.2, S(O).sub.2R.sup.A1S(O).sub.2OR.sup.A, S(O).sub.2R.sup.A1, S(O).sub.2N(R.sup.A1).sub.2, N(R.sup.A1).sub.2, and a nitrogen protecting group; wherein each occurrence of R.sup.A1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R.sup.A1 groups are joined to form an optionally substituted heterocyclic ring.

(297) In certain embodiments, at least one R.sup.Xa is H. In certain embodiments, all R.sup.Xa groups are H. In certain embodiments, at least one R.sup.Xa is substituted alkyl. In certain embodiments, at least one R.sup.Xa is substituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.Xa is substituted methyl. In certain embodiments, at least one R.sup.Xa is unsubstituted alkyl. In certain embodiments, at least one R.sup.Xa is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.Xa is methyl. In certain embodiments, at least one R.sup.Xa is ethyl. In certain embodiments, at least one R.sup.Xa is propyl. In certain embodiments, at least one R.sup.Xa is butyl. In certain embodiments, at least one R.sup.Xa is substituted alkenyl. In certain embodiments, at least one R.sup.Xa is unsubstituted alkenyl. In certain embodiments, at least one R.sup.Xa is substituted alkynyl. In certain embodiments, at least one R.sup.Xa is unsubstituted alkynyl. In certain embodiments, at least one R.sup.Xa is substituted carbocyclyl. In certain embodiments, at least one R.sup.Xa is unsubstituted carbocyclyl. In certain embodiments, at least one R.sup.Xa is substituted heterocyclyl. In certain embodiments, at least one R.sup.Xa is unsubstituted heterocyclyl. In certain embodiments, at least one R.sup.Xa is substituted aryl. In certain embodiments, at least one R.sup.Xa is unsubstituted aryl. In certain embodiments, at least one R.sup.Xa is substituted phenyl. In certain embodiments, at least one R.sup.Xa is unsubstituted phenyl. In certain embodiments, at least one R.sup.Xa is substituted heteroaryl. In certain embodiments, at least one R.sup.Xa is unsubstituted heteroaryl. In certain embodiments, at least one R.sup.Xa is C(O)R.sup.A1. In certain embodiments, at least one R.sup.Xa is C(O)H. In certain embodiments, at least one R.sup.Xa is acetyl. In certain embodiments, at least one R.sup.Xa is C(O)(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xa is C(O)OR.sup.A1. In certain embodiments, at least one R.sup.Xa is C(O)OH. In certain embodiments, at least one R.sup.Xa is C(O)O(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xa is C(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.Xa is C(O)NHR.sup.A1. In certain embodiments, at least one R.sup.Xa is C(O)N(C.sub.1-6 alkyl).sub.2. In certain embodiments, at least one R.sup.Xa is C(O)NH(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.Xa is C(O)NH.sub.2. In certain embodiments, at least one R.sup.Xa is S(O)R.sup.A1. In certain embodiments, at least one R.sup.Xa is S(O)(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xa is S(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.Xa is S(O)NH(R.sup.A1). In certain embodiments, at least one R.sup.Xa is S(O)NH.sub.2. In certain embodiments, at least one R.sup.Xa is S(O)N(C.sub.1-6alkyl).sub.2. In certain embodiments, at least one R.sup.Xa is S(O)NH(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xa is S(O).sub.2R.sup.A1. In certain embodiments, at least one R.sup.Xa is S(O).sub.2(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xa is S(O).sub.2OR.sup.A1. In certain embodiments, at least one R.sup.Xa is S(O).sub.2OH. In certain embodiments, at least one R.sup.Xa is S(O).sub.2N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.Xa is S(O).sub.2NH(R.sup.A1). In certain embodiments, at least one R.sup.Xa is S(O).sub.2NH.sub.2. In certain embodiments, at least one R.sup.Xa is S(O).sub.2N(C.sub.1-6alkyl).sub.2. In certain embodiments, at least one R.sup.Xa is S(O).sub.2NH(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xa is N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.Xa is NH(R.sup.A1). In certain embodiments, at least one R.sup.Xa is NH(acyl). In certain embodiments, at least one R.sup.Xa is NHC(O)Me. In certain embodiments, at least one R.sup.Xa is N(C.sub.1-6alkyl).sub.2 where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R.sup.Xa is NMe.sub.2.

(298) In compounds of Formula (A), R.sup.X may be substituted with one or more R.sup.Xc groups. Each instance of R.sup.Xc is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, OR.sup.A1, N(R.sup.A1).sub.2, SR.sup.A1, CN, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)N(R.sup.A1).sub.2, NO.sub.2, N.sub.3, NR.sup.A1C(O)R.sup.A1, NR.sup.A1C(O)OR.sup.A1, NR.sup.A1C(O)N(R.sup.A1).sub.2, NR.sup.A1S(O).sub.2R.sup.A1, NR.sup.A1S(O)R.sup.A1, OC(O)R.sup.A1, OC(O)OR.sup.A1, OC(O)N(R.sup.A1).sub.2, S(O)R.sup.A1, S(O)N(R.sup.A1).sub.2, S(O).sub.2R.sup.A1, S(O).sub.2N(R.sup.A1).sub.2; wherein each occurrence of R.sup.A1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R.sup.A1 groups are joined to form an optionally substituted heterocyclic ring.

(299) In certain embodiments, at least one R.sup.Xc is H. In certain embodiments, all R.sup.Xc groups are H. In certain embodiments, at least one R.sup.Xc is substituted alkyl. In certain embodiments, at least one R.sup.Xc is substituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.Xc is substituted methyl. In certain embodiments, at least one R.sup.Xc is unsubstituted alkyl. In certain embodiments, at least one R.sup.Xc is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.Xc is methyl. In certain embodiments, at least one R.sup.Xc is ethyl. In certain embodiments, at least one R.sup.Xc is propyl. In certain embodiments, at least one R.sup.Xc is butyl. In certain embodiments, at least one R.sup.Xc is substituted alkenyl. In certain embodiments, at least one R.sup.Xc is unsubstituted alkenyl. In certain embodiments, at least one R.sup.Xc is substituted alkynyl. In certain embodiments, at least one R.sup.Xc is unsubstituted alkynyl. In certain embodiments, at least one R.sup.Xc is substituted carbocyclyl. In certain embodiments, at least one R.sup.Xc is unsubstituted carbocyclyl. In certain embodiments, at least one R.sup.Xc is substituted heterocyclyl. In certain embodiments, at least one R.sup.Xc is unsubstituted heterocyclyl. In certain embodiments, at least one R.sup.Xc is substituted aryl. In certain embodiments, at least one R.sup.Xc is unsubstituted aryl. In certain embodiments, at least one R.sup.Xc is substituted phenyl. In certain embodiments, at least one R.sup.Xc is unsubstituted phenyl. In certain embodiments, at least one R.sup.Xc is substituted heteroaryl. In certain embodiments, at least one R.sup.Xc is unsubstituted heteroaryl. In certain embodiments, at least one R.sup.Xc is OR.sup.A1. In certain embodiments, at least one R.sup.Xc is OH. In certain embodiments, at least one R.sup.Xc is O(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xc is N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.Xc is NH(R.sup.A1). In certain embodiments, at least one R.sup.Xc is N(C.sub.1-6alkyl).sub.2. In certain embodiments, at least one R.sup.Xc is NH(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xc is NH.sub.2. In certain embodiments, at least one R.sup.Xc is SR.sup.A1. In certain embodiments, at least one R.sup.Xc is SH. In certain embodiments, at least one R.sup.Xc is S(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xc is CN. In certain embodiments, at least one R.sup.Xc is NO.sub.2. In certain embodiments, at least one R.sup.Xc is N.sub.3. In certain embodiments, at least one R.sup.Xc is NR.sup.A1C(O)R.sup.A1. In certain embodiments, at least one R.sup.Xc is NHC(O)R.sup.A1. In certain embodiments, at least one R.sup.Xc is NHC(O)(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xc is NR.sup.A1C(O)OR.sup.A1. In certain embodiments, at least one R.sup.Xc is NHC(O)OR.sup.A1. In certain embodiments, at least one R.sup.Xc is NR.sup.A1C(O)O(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xc is NR.sup.A1C(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.Xc is NHC(O)N(C.sub.1-6alkyl).sub.2. In certain embodiments, at least one R.sup.Xc is NHC(O)NH.sub.2. In certain embodiments, at least one R.sup.Xc is NR.sup.A1S(O).sub.2R.sup.A1. In certain embodiments, at least one R.sup.Xc is NHS(O).sub.2R.sup.A1. In certain embodiments, at least one R.sup.Xc is NHS(O).sub.2(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xc is NR.sup.A1S(O)R.sup.A1. In certain embodiments, at least one R.sup.Xc is NR.sup.A1S(O)(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xc is NHS(O)(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xc is OC(O)R.sup.A1. In certain embodiments, at least one R.sup.Xc is OC(O)(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xc is OC(O)OR.sup.A1 In certain embodiments, at least one R.sup.Xc is OC(O)O(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xc is OC(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.Xc is OC(O)NH(R.sup.A1). In certain embodiments, at least one R.sup.Xc is OC(O)N(C.sub.1-6alkyl).sub.2. In certain embodiments, at least one R.sup.Xc is C(O)R.sup.A1. In certain embodiments, at least one R.sup.Xc is C(O)H. In certain embodiments, at least one R.sup.Xc is acetyl. In certain embodiments, at least one R.sup.Xc is C(O)(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xc is C(O)OR.sup.A1 In certain embodiments, at least one R.sup.Xc is C(O)OH. In certain embodiments, at least one R.sup.Xc is C(O)O(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xc is C(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.Xc is C(O)NHR.sup.A1. In certain embodiments, at least one R.sup.Xc is C(O)N(C.sub.1-6 alkyl).sub.2. In certain embodiments, at least one R.sup.Xc is C(O)NH(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.Xc is C(O)NH.sub.2. In certain embodiments, at least one R.sup.Xc is S(O)R.sup.A1. In certain embodiments, at least one R.sup.Xc is S(O)(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xc is S(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.Xc is S(O)NH(R.sup.A1). In certain embodiments, at least one R.sup.Xc is S(O)NH.sub.2. In certain embodiments, at least one R.sup.Xc is S(O)N(C.sub.1-6alkyl).sub.2. In certain embodiments, at least one R.sup.Xc is S(O)NH(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xc is S(O).sub.2R.sup.A1. In certain embodiments, at least one R.sup.Xc is S(O).sub.2(C.sub.1-6alkyl). In certain embodiments, at least one R.sup.Xc is S(O).sub.2OR.sup.A1. In certain embodiments, at least one R.sup.Xc is S(O).sub.2OH. In certain embodiments, at least one R.sup.Xc is S(O).sub.2N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.Xc is S(O).sub.2NH(R.sup.A1). In certain embodiments, at least one R.sup.Xc is S(O).sub.2NH.sub.2. In certain embodiments, at least one R.sup.Xc is S(O).sub.2N(C.sub.1-6alkyl).sub.2. In certain embodiments, at least one R.sup.Xc is S(O).sub.2NH(C.sub.1-6alkyl).

(300) In compounds of Formula (A), R.sup.D is an optional electrophilic moiety that is attached to the pyridyl ring. In certain embodiments, R.sup.D is any one of Formulae (i-1)-(i-18):

(301) ##STR00248## ##STR00249##

(302) R.sup.D1 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, NO.sub.2, OR.sup.D1a, N(R.sup.D1a).sub.2, SR.sup.D1a, CH.sub.2OR.sup.D1a, CH.sub.2N(R.sup.D1a).sub.2, CH.sub.2SR.sup.D1a, C(O)R.sup.D1a, C(O)OR.sup.D1a, C(O)SR.sup.D1a, C(O)N(R.sup.D1a).sub.2, C(S)R.sup.D1a, C(S)OR.sup.D1a, C(S)SR.sup.D1a, C(S)N(R.sup.D1a).sub.2, C(NR.sup.D1a)R.sup.D1a, C(NR.sup.D1a)OR.sup.D1a, C(NR.sup.D1a)SR.sup.D1a, and C(NR.sup.D1a)N(R.sup.D1a).sub.2 wherein each occurrence of R.sup.D1a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.D1a groups are joined to form an optionally substituted heterocyclic ring;

(303) R.sup.D2 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, NO.sub.2, OR.sup.D2a, N(R.sup.D2a).sub.2, SR.sup.D2a, CH.sub.2OR.sup.D2a, CH.sub.2N(R.sup.D2a).sub.2, CH.sub.2SR.sup.D2a, C(O)R.sup.D2a, C(O)OR.sup.D2a, C(O)SR.sup.D2a, C(O)N(R.sup.D2a).sub.2, C(S)R.sup.D2a, C(S)OR.sup.D2a, C(S)SR.sup.D2a, C(S)N(R.sup.D2a).sub.2, C(NR.sup.D2a)R.sup.D2a, C(NR.sup.D2a)OR.sup.D2a, C(NR.sup.D2a)SR.sup.D2a, and C(NR.sup.D2a)N(R.sup.D2a).sub.2, wherein each occurrence of R.sup.D2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.D2a groups are joined to form an optionally substituted heterocyclic ring;

(304) R.sup.D3 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, NO.sub.2, OR.sup.D3a, N(R.sup.D3a).sub.2, SR.sup.D3a, CH.sub.2OR.sup.D3a, CH.sub.2N(R.sup.D3a).sub.2, CH.sub.2SR.sup.D3a, C(O)R.sup.D3a, C(O)OR.sup.D3a, C(O)SR.sup.D3a, C(O)N(R.sup.D3a).sub.2, C(S)R.sup.D3a, C(S)OR.sup.D3a, C(S)SR.sup.D3a, C(S)N(R.sup.D3a).sub.2, C(NR.sup.D3a)R.sup.D3a, C(NR.sup.D3a)OR.sup.D3a, C(NR.sup.D3a)SR.sup.D3a, and C(NR.sup.D3a)N(R.sup.D3a).sub.2, wherein each occurrence of R.sup.D3a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.D3a groups are joined to form an optionally substituted heterocyclic ring;

(305) optionally R.sup.D1 and R.sup.D3, or R.sup.D2 and R.sup.D3, or R.sup.D1 and R.sup.D2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;

(306) R.sup.D4 is a leaving group;

(307) R.sup.D5 is hydrogen, C.sub.1-6 alkyl, or a nitrogen protecting group;

(308) Y.sup.Z is O, S, or NR.sup.D6, wherein R.sup.D6 is hydrogen, C.sub.1-6 alkyl, or a nitrogen protecting group;

(309) a is 1 or 2;

(310) z is 0, 1, 2, 3, 4, 5, or 6; and

(311) optionally R.sup.D5 and one R.sup.C are joined to form an optionally substituted heterocyclic ring.

(312) In certain embodiments, R.sup.D comprises a Michael acceptor moiety. This Michael acceptor moiety may react with a cysteine or other nucleophilic residue to allow covalent attachment of the compound to the target. In certain embodiments, the covalent attachment is irreversible. In other embodiments, the covalent attachment is reversible. In certain embodiments, R.sup.D is of Formula (i-1). In certain embodiments, R.sup.D is of Formula (i-2). In certain embodiments, R.sup.D is of Formula (i-3). In certain embodiments, R.sup.D is of Formula (i-4). In certain embodiments, R.sup.D is of Formula (i-5). In certain embodiments, R.sup.D is of Formula (i-6). In certain embodiments, R.sup.D is of Formula (i-7). In certain embodiments, R.sup.D is of Formula (i-8). In certain embodiments, R.sup.D is of Formula (i-9). In certain embodiments, R.sup.D is of Formula (i-10). In certain embodiments, R.sup.D is of Formula (i-11). In certain embodiments, R.sup.D is of Formula (i-12). In certain embodiments, R.sup.D is of Formula (i-13). In certain embodiments, R.sup.D is of Formula (i-14). In certain embodiments, R.sup.D is of Formula (i-15). In certain embodiments, R.sup.D is of Formula (i-16). In certain embodiments, R.sup.D is of Formula (i-17).

(313) In compounds of Formula (A), R.sup.D may include a substituent R.sup.D1. In certain embodiments, R.sup.D1 is H. In certain embodiments, R.sup.D1 is halogen. In certain embodiments, R.sup.D1 is F. In certain embodiments, R.sup.D1 is Cl. In certain embodiments, R.sup.D1 is Br. In certain embodiments, R.sup.D1 is I (iodine). In certain embodiments, R.sup.D1 is substituted acyl. In certain embodiments, R.sup.D1 is unsubstituted acyl. In certain embodiments, R.sup.D1 is acetyl. In certain embodiments, R.sup.D1 is substituted alkyl. In certain embodiments, R.sup.D1 is unsubstituted alkyl. In certain embodiments, R.sup.D1 is C.sub.1-6 alkyl. In certain embodiments, R.sup.D1 is methyl. In certain embodiments, R.sup.D1 is ethyl. In certain embodiments, R.sup.D1 is propyl. In certain embodiments, R.sup.D1 is butyl. In certain embodiments, R.sup.D1 is substituted alkenyl. In certain embodiments, R.sup.D1 is unsubstituted alkenyl. In certain embodiments, R.sup.D1 is substituted alkynyl. In certain embodiments, R.sup.D1 is unsubstituted alkynyl. In certain embodiments, R.sup.D1 is substituted carbocyclyl. In certain embodiments, R.sup.D1 is unsubstituted carbocyclyl. In certain embodiments, R.sup.D1 is substituted heterocyclyl. In certain embodiments, R.sup.D1 is unsubstituted heterocyclyl. In certain embodiments, R.sup.D1 is substituted aryl. In certain embodiments, R.sup.D1 is unsubstituted aryl. In certain embodiments, R.sup.D1 is substituted phenyl. In certain embodiments, R.sup.D1 is unsubstituted phenyl. In certain embodiments, R.sup.D1 is substituted heteroaryl. In certain embodiments, R.sup.D1 is unsubstituted heteroaryl. In certain embodiments, R.sup.D1 is substituted pyridyl. In certain embodiments, R.sup.D1 is unsubstituted pyridyl. In certain embodiments, R.sup.D1 is CN. In certain embodiments, R.sup.D1 is NO.sub.2. In certain embodiments, R.sup.D1 is OR.sup.D1a. In certain embodiments, R.sup.D1 is N(R.sup.D1a).sub.2. In certain embodiments, R.sup.D1 is SR.sup.D1a. In certain embodiments, R.sup.D1 is CH.sub.2OR.sup.D1a. In certain embodiments, R.sup.D1 is CH.sub.2N(R.sup.D1a).sub.2. In certain embodiments, R.sup.D1 is CH.sub.2SR.sup.D1a.

(314) In certain embodiments, at least one R.sup.D1a is H. In certain embodiments, at least one R.sup.D1a is substituted acyl. In certain embodiments, at least one R.sup.D1a is unsubstituted acyl. In certain embodiments, at least one R.sup.D1a is acetyl. In certain embodiments, at least one R.sup.D1a is substituted alkyl. In certain embodiments, at least one R.sup.D1a is unsubstituted alkyl. In certain embodiments, at least one R.sup.D1a is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.D1a is methyl. In certain embodiments, at least one R.sup.D1a is ethyl. In certain embodiments, at least one R.sup.D1a is propyl. In certain embodiments, at least one R.sup.D1a is butyl. In certain embodiments, at least one R.sup.D1a is substituted alkenyl. In certain embodiments, at least one R.sup.D1a is unsubstituted alkenyl. In certain embodiments, at least one R.sup.D1a is substituted alkynyl. In certain embodiments, at least one R.sup.D1a is unsubstituted alkynyl. In certain embodiments, at least one R.sup.D1a is substituted carbocyclyl. In certain embodiments, at least one R.sup.D1a is unsubstituted carbocyclyl. In certain embodiments, at least one R.sup.D1a is substituted heterocyclyl. In certain embodiments, at least one R.sup.D1a is unsubstituted heterocyclyl. In certain embodiments, at least one R.sup.D1a is substituted aryl. In certain embodiments, at least one R.sup.D1a is unsubstituted aryl. In certain embodiments, at least one R.sup.D1a is substituted phenyl. In certain embodiments, at least one R.sup.D1a is unsubstituted phenyl. In certain embodiments, at least one R.sup.D1a is substituted heteroaryl. In certain embodiments, at least one R.sup.D1a is unsubstituted heteroaryl. In certain embodiments, at least one R.sup.D1a is substituted pyridyl. In certain embodiments, at least one R.sup.D1a is unsubstituted pyridyl. In certain embodiments, at least one R.sup.D1a is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R.sup.D1a is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R.sup.D1a is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.D1a is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R.sup.D1a is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R.sup.D1a is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R.sup.D1a groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R.sup.D1a groups are joined to form an unsubstituted heterocyclic ring.

(315) In compounds of Formula (A), R.sup.D may include a substituent R.sup.D2. In certain embodiments, R.sup.D2 is H. In certain embodiments, R.sup.D2 is halogen. In certain embodiments, R.sup.D2 is F. In certain embodiments, R.sup.D2 is Cl. In certain embodiments, R.sup.D2 is Br. In certain embodiments, R.sup.D2 is I (iodine). In certain embodiments, R.sup.D2 is substituted acyl. In certain embodiments, R.sup.D2 is unsubstituted acyl. In certain embodiments, R.sup.D2 is acetyl. In certain embodiments, R.sup.D2 is substituted alkyl. In certain embodiments, R.sup.D2 is unsubstituted alkyl. In certain embodiments, R.sup.D2 is C.sub.1-6 alkyl. In certain embodiments, R.sup.D2 is methyl. In certain embodiments, R.sup.D2 is ethyl. In certain embodiments, R.sup.D2 is propyl. In certain embodiments, R.sup.D2 is butyl. In certain embodiments, R.sup.D2 is substituted alkenyl. In certain embodiments, R.sup.D2 is unsubstituted alkenyl. In certain embodiments, R.sup.D2 is substituted alkynyl. In certain embodiments, R.sup.D2 is unsubstituted alkynyl. In certain embodiments, R.sup.D2 is substituted carbocyclyl. In certain embodiments, R.sup.D2 is unsubstituted carbocyclyl. In certain embodiments, R.sup.D2 is substituted heterocyclyl. In certain embodiments, R.sup.D2 is unsubstituted heterocyclyl. In certain embodiments, R.sup.D2 is substituted aryl. In certain embodiments, R.sup.D2 is unsubstituted aryl. In certain embodiments, R.sup.D2 is substituted phenyl. In certain embodiments, R.sup.D2 is unsubstituted phenyl. In certain embodiments, R.sup.D2 is substituted heteroaryl. In certain embodiments, R.sup.D2 is unsubstituted heteroaryl. In certain embodiments, R.sup.D2 is substituted pyridyl. In certain embodiments, R.sup.D2 is unsubstituted pyridyl. In certain embodiments, R.sup.D2 is CN. In certain embodiments, R.sup.D2 is NO.sub.2. In certain embodiments, R.sup.D2 is OR.sup.D2a. In certain embodiments, R.sup.D2 is N(R.sup.D2a).sub.2. In certain embodiments, R.sup.D2 is SR.sup.D2a. In certain embodiments, R.sup.D2 is CH.sub.2OR.sup.D2a. In certain embodiments, R.sup.D2 is CH.sub.2N(R.sup.D2a).sub.2. In certain embodiments, R.sup.D2 is CH.sub.2SR.sup.D2a.

(316) In certain embodiments, at least one R.sup.D2a is H. In certain embodiments, at least one R.sup.D2a is substituted acyl. In certain embodiments, at least one R.sup.D2a is unsubstituted acyl. In certain embodiments, at least one R.sup.D2a is acetyl. In certain embodiments, at least one R.sup.D2a is substituted alkyl. In certain embodiments, at least one R.sup.D2a is unsubstituted alkyl. In certain embodiments, at least one R.sup.D2a is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.D2a is methyl. In certain embodiments, at least one R.sup.D2a is ethyl. In certain embodiments, at least one R.sup.D2a is propyl. In certain embodiments, at least one R.sup.D2a is butyl. In certain embodiments, at least one R.sup.D2a is substituted alkenyl. In certain embodiments, at least one R.sup.D2a is unsubstituted alkenyl. In certain embodiments, at least one R.sup.D2a is substituted alkynyl. In certain embodiments, at least one R.sup.D2a is unsubstituted alkynyl. In certain embodiments, at least one R.sup.D2a is substituted carbocyclyl. In certain embodiments, at least one R.sup.D2a is unsubstituted carbocyclyl. In certain embodiments, at least one R.sup.D2a is substituted heterocyclyl. In certain embodiments, at least one R.sup.D2a is unsubstituted heterocyclyl. In certain embodiments, at least one R.sup.D2a is substituted aryl. In certain embodiments, at least one R.sup.D2a is unsubstituted aryl. In certain embodiments, at least one R.sup.D2a is substituted phenyl. In certain embodiments, at least one R.sup.D2a is unsubstituted phenyl. In certain embodiments, at least one R.sup.D2a is substituted heteroaryl. In certain embodiments, at least one R.sup.D2a is unsubstituted heteroaryl. In certain embodiments, at least one R.sup.D2a is substituted pyridyl. In certain embodiments, at least one R.sup.D2a is unsubstituted pyridyl. In certain embodiments, at least one R.sup.D2a is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R.sup.D2a is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R.sup.D2a is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.D2a is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R.sup.D2a is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R.sup.D2a is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R.sup.D2a groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R.sup.D2a groups are joined to form an unsubstituted heterocyclic ring.

(317) In compounds of Formula (A), R.sup.D may include a substituent R.sup.D3. In certain embodiments, R.sup.D3 is H. In certain embodiments, R.sup.D3 is halogen. In certain embodiments, R.sup.D3 is F. In certain embodiments, R.sup.D3 is Cl. In certain embodiments, R.sup.D3 is Br. In certain embodiments, R.sup.D3 is I (iodine). In certain embodiments, R.sup.D3 is substituted acyl. In certain embodiments, R.sup.D3 is unsubstituted acyl. In certain embodiments, R.sup.D3 is acetyl. In certain embodiments, R.sup.D3 is substituted alkyl. In certain embodiments, R.sup.D3 is unsubstituted alkyl. In certain embodiments, R.sup.D3 is C.sub.1-6 alkyl. In certain embodiments, R.sup.D3 is methyl. In certain embodiments, R.sup.D3 is ethyl. In certain embodiments, R.sup.D3 is propyl. In certain embodiments, R.sup.D3 is butyl. In certain embodiments, R.sup.D3 is substituted alkenyl. In certain embodiments, R.sup.D3 is unsubstituted alkenyl. In certain embodiments, R.sup.D3 is substituted alkynyl. In certain embodiments, R.sup.D3 is unsubstituted alkynyl. In certain embodiments, R.sup.D3 is substituted carbocyclyl. In certain embodiments, R.sup.D3 is unsubstituted carbocyclyl. In certain embodiments, R.sup.D3 is substituted heterocyclyl. In certain embodiments, R.sup.D3 is unsubstituted heterocyclyl. In certain embodiments, R.sup.D3 is substituted aryl. In certain embodiments, R.sup.D3 is unsubstituted aryl. In certain embodiments, R.sup.D3 is substituted phenyl. In certain embodiments, R.sup.D3 is unsubstituted phenyl. In certain embodiments, R.sup.D3 is substituted heteroaryl. In certain embodiments, R.sup.D3 is unsubstituted heteroaryl. In certain embodiments, R.sup.D3 is substituted pyridyl. In certain embodiments, R.sup.D3 is unsubstituted pyridyl. In certain embodiments, R.sup.D3 is CN. In certain embodiments, R.sup.D3 is NO.sub.2. In certain embodiments, R.sup.D3 is OR.sup.D3a. In certain embodiments, R.sup.D3 is N(R.sup.D3a).sub.2. In certain embodiments, R.sup.D3 is SR.sup.D3a. In certain embodiments, R.sup.D3 is CH.sub.2OR.sup.D3a. In certain embodiments, R.sup.D3 is CH.sub.2N(R.sup.D3a).sub.2. In certain embodiments, R.sup.D3 is CH.sub.2SR.sup.D3a.

(318) In certain embodiments, at least one R.sup.D3a is H. In certain embodiments, at least one R.sup.D3a is substituted acyl. In certain embodiments, at least one R.sup.D3a is unsubstituted acyl. In certain embodiments, at least one R.sup.D3a is acetyl. In certain embodiments, at least one R.sup.D3a is substituted alkyl. In certain embodiments, at least one R.sup.D3a is unsubstituted alkyl. In certain embodiments, at least one R.sup.D3a is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.D3a is methyl. In certain embodiments, at least one R.sup.D3a is ethyl. In certain embodiments, at least one R.sup.D3a is propyl. In certain embodiments, at least one R.sup.D3a is butyl. In certain embodiments, at least one R.sup.D3a is substituted alkenyl. In certain embodiments, at least one R.sup.D3a is unsubstituted alkenyl. In certain embodiments, at least one R.sup.D3a is substituted alkynyl. In certain embodiments, at least one R.sup.D3a is unsubstituted alkynyl. In certain embodiments, at least one R.sup.D3a is substituted carbocyclyl. In certain embodiments, at least one R.sup.D3a is unsubstituted carbocyclyl. In certain embodiments, at least one R.sup.D3a is substituted heterocyclyl. In certain embodiments, at least one R.sup.D3a is unsubstituted heterocyclyl. In certain embodiments, at least one R.sup.D3a is substituted aryl. In certain embodiments, at least one R.sup.D3a is unsubstituted aryl. In certain embodiments, at least one R.sup.D3a is substituted phenyl. In certain embodiments, at least one R.sup.D3a is unsubstituted phenyl. In certain embodiments, at least one R.sup.D3a is substituted heteroaryl. In certain embodiments, at least one R.sup.D3a is unsubstituted heteroaryl. In certain embodiments, at least one R.sup.D3a is substituted pyridyl. In certain embodiments, at least one R.sup.D3a is unsubstituted pyridyl. In certain embodiments, at least one R.sup.D3a is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R.sup.D3a is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R.sup.D3a is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.D3a is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R.sup.D3 is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R.sup.D3a is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R.sup.D3a groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R.sup.D3a groups are joined to form an unsubstituted heterocyclic ring.

(319) In compounds of Formula (A), R.sup.D may include a substituent R.sup.D4. In certain embodiments, R.sup.D4 is a leaving group. In certain embodiments, R.sup.D4 is halogen. In certain embodiments, R.sup.D4 is F. In certain embodiments, R.sup.D4 is Cl. In certain embodiments, R.sup.D4 is Br. In certain embodiments, R.sup.D4 is I (iodine). In certain embodiments, R.sup.D4 is OS(O).sub.wR.sup.D4a. In certain embodiments, w is 1. In certain embodiments, w is 2. In certain embodiments, R.sup.D4 is OMs. In certain embodiments, R.sup.D4 is OTf. In certain embodiments, R.sup.D4 is OTs. In certain embodiments, R.sup.D4 is OBs. In certain embodiments, R.sup.D4 is 2-nitrobenzenesulfonyloxy. In certain embodiments, R.sup.D4 is OR.sup.D4a. In certain embodiments, R.sup.D4 is OMe. In certain embodiments, R.sup.D4 is OCF.sub.3. In certain embodiments, R.sup.D4 is OPh. In certain embodiments, R.sup.D4 is OC(O)R.sup.D4a. In certain embodiments, R.sup.D4 is OC(O)Me. In certain embodiments, R.sup.D4 is OC(O)CF.sub.3. In certain embodiments, R.sup.D4 is OC(O)Ph. In certain embodiments, R.sup.D4 is OC(O)Cl. In certain embodiments, R.sup.D4 is OC(O)OR.sup.D4a. In certain embodiments, R.sup.D4 is OC(O)OMe. In certain embodiments, R.sup.D4 is OC(O)O(t-Bu).

(320) In certain embodiments, R.sup.D4a is substituted alkyl. In certain embodiments, R.sup.D4a is unsubstituted alkyl. In certain embodiments, R.sup.D4a is C.sub.1-6 alkyl. In certain embodiments, R.sup.D4a is methyl. In certain embodiments, R.sup.D4a is ethyl. In certain embodiments, R.sup.D4a is propyl. In certain embodiments, R.sup.D4a is butyl. In certain embodiments, R.sup.D4a is substituted alkenyl. In certain embodiments, R.sup.D4a is unsubstituted alkenyl. In certain embodiments, R.sup.D4a is vinyl. In certain embodiments, R.sup.D4a is substituted alkynyl. In certain embodiments, R.sup.D4a is unsubstituted alkynyl. In certain embodiments, R.sup.D4a is ethynyl. In certain embodiments, R.sup.D4a is substituted carbocyclyl. In certain embodiments, R.sup.D4a is unsubstituted carbocyclyl. In certain embodiments, R.sup.D4a is substituted heterocyclyl. In certain embodiments, R.sup.D4a is unsubstituted heterocyclyl. In certain embodiments, R.sup.D4a is substituted aryl. In certain embodiments, R.sup.D4a is unsubstituted aryl. In certain embodiments, R.sup.D4a is substituted phenyl. In certain embodiments, R.sup.D4a is unsubstituted phenyl. In certain embodiments, R.sup.D4a is substituted heteroaryl. In certain embodiments, R.sup.D4a is unsubstituted heteroaryl. In certain embodiments, R.sup.D4a is substituted pyridyl. In certain embodiments, R.sup.D4a is unsubstituted pyridyl.

(321) In compounds of Formula (A), R.sup.D may include a substituent R.sup.D5. In certain embodiments, R.sup.D5 is H. In certain embodiments, R.sup.D5 is substituted alkyl. In certain embodiments, R.sup.D5 is unsubstituted alkyl. In certain embodiments, R.sup.D5 is C.sub.1-6 alkyl. In certain embodiments, R.sup.D5 is methyl. In certain embodiments, R.sup.D5 is ethyl. In certain embodiments, R.sup.D5 is propyl. In certain embodiments, R.sup.D5 is butyl. In certain embodiments, R.sup.D5 is a nitrogen protecting group. In certain embodiments, R.sup.D5 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.

(322) In certain embodiments, R.sup.D1 and R.sup.D2 are each hydrogen. In certain embodiments, R.sup.D1 and R.sup.D3 are each hydrogen. In certain embodiments, R.sup.D2 and R.sup.D3 are each hydrogen. In certain embodiments, R.sup.D1, R.sup.D2, and R.sup.D3 are each hydrogen. In certain embodiments, R.sup.D1, R.sup.D2, and R.sup.D3, and R.sup.D5 are each hydrogen.

(323) In certain embodiments, a is 1. In certain embodiments, a is 2.

(324) In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, z is 4. In certain embodiments, z is 5. In certain embodiments, z is 6.

(325) In certain embodiments, Y is O. In certain embodiments, Y is C(O). In certain embodiments, Y is S. In certain embodiments, Y is C(S). In certain embodiments, Y is NR.sup.D6, wherein R.sup.D6 is hydrogen, C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, Y is NH. In certain embodiments, Y is NCH.sub.3. In certain embodiments, Y is N(BOC). In certain embodiments, Y is N(Fmoc)-. In certain embodiments, Y is N(Cbz)-. In certain embodiments, Y is N(Bn)-. In certain embodiments, Y is C(NR.sup.D6), wherein R.sup.D6 is hydrogen, C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, Y is C(NH). In certain embodiments, Y is C(NCH.sub.3). In certain embodiments, Y is C(NTs)-. In certain embodiments, Y is C(NBn)-. In certain embodiments, Y is C(NCH(Ph).sub.2)-.

(326) In certain embodiments, R.sup.D is of the formula:

(327) ##STR00250##
In certain embodiments, R.sup.D is of the formula:

(328) ##STR00251##
In certain embodiments, R.sup.D is of the formula:

(329) ##STR00252##
In certain embodiments, R.sup.D is of the formula:

(330) ##STR00253##
In certain embodiments, R.sup.D is of the formula:

(331) ##STR00254##
In certain embodiments, R.sup.D is of the formula:

(332) ##STR00255##
In certain embodiments, R.sup.D is of the formula:

(333) ##STR00256##
In certain embodiments, R.sup.D is of the formula:

(334) ##STR00257##
In certain embodiments, R.sup.D is of the formula:

(335) ##STR00258##
In certain embodiments, R.sup.D is of the formula:

(336) ##STR00259##
In certain embodiments, R.sup.D is of the formula:

(337) ##STR00260##
In certain embodiments, R.sup.D is of the formula:

(338) ##STR00261##
In certain embodiments, R.sup.D is of the formula:

(339) ##STR00262##
In certain embodiments, R.sup.D is of the formula:

(340) ##STR00263##
In certain embodiments, R.sup.D is of the formula:

(341) ##STR00264##
In certain embodiments, R.sup.D is of the formula:

(342) ##STR00265##
In certain embodiments, R.sup.D is of the formula:

(343) ##STR00266##
In certain embodiments, R.sup.D is of the formula:

(344) ##STR00267##
In certain embodiments, R.sup.D is of the formula:

(345) ##STR00268##
In certain embodiments, R.sup.D is of the formula:

(346) ##STR00269##
In certain embodiments, R.sup.D is of the formula:

(347) ##STR00270##
In certain embodiments, R.sup.D is of the formula:

(348) ##STR00271##
In certain embodiments, R.sup.D is of the formula:

(349) ##STR00272##
In certain embodiments, R.sup.D is of the formula:

(350) ##STR00273##
In certain embodiments, R.sup.D is of the formula:

(351) ##STR00274##
In certain embodiments, R.sup.D is of the formula:

(352) ##STR00275##
In certain embodiments, R.sup.D is of the formula:

(353) ##STR00276##
In certain embodiments, R.sup.D is of the formula:

(354) ##STR00277##

(355) Various combinations of certain embodiments of Formula (A) are further contemplated herein.

(356) For example, in certain embodiments, a compound of Formula (A) is a compound of Formula (A1) or (A2):

(357) ##STR00278##
wherein R.sup.X, R.sup.A, R.sup.B, and l are defined herein. In certain embodiments R.sup.A is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R.sup.B is meta to the point of attachment of the amide linker. In certain embodiments, l is 2. In certain embodiments, l is 2; and the two R.sup.B groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R.sup.B group is meta to the point of attachment of the amide linker; and the second R.sup.B group is para to the point of attachment of the amide linker. In certain embodiments, one R.sup.B group is substituted or unsubstituted C.sub.1-6alkyl. In certain embodiments, one R.sup.B group is C.sub.1-6alkyl substituted with one CN group. In certain embodiments, one R.sup.B group is

(358) ##STR00279##
In certain embodiments, one R.sup.B group is substituted or unsubstituted CH.sub.2-(piperazinyl). In certain embodiments, one R.sup.B group is

(359) ##STR00280##
where the alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(360) ##STR00281##
where the alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(361) ##STR00282##
In certain embodiments, one R.sup.B group is haloalkyl. In certain embodiments, one R.sup.B group is CF.sub.3. In certain embodiments, one R.sup.B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R.sup.B group is

(362) ##STR00283##
where the alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(363) ##STR00284##
where the alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(364) ##STR00285##
In certain embodiments, one R.sup.B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R.sup.B group is

(365) ##STR00286##
where there alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(366) ##STR00287##
where there alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(367) ##STR00288##
In certain embodiments, one R.sup.B group is substituted or unsubstituted morpholine. In certain embodiments, two R.sup.B groups are substituted or unsubstituted morpholine. In certain embodiments, R.sup.X is N(R.sup.A1)N(R.sup.A1).sub.2. In certain embodiments, R.sup.X is N(R.sup.A1)N(R.sup.A1).sub.2; and each instance of R.sup.A is hydrogen, methyl, or acetyl. In certain embodiments, R.sup.X is NHNMe.sub.2 or NHNHAc. In certain embodiments, Rx is NH.sub.2. In certain embodiments, R.sup.X is NH(R.sup.A1). In certain embodiments, R.sup.X is NH(R.sup.A1); and R.sup.A1 is substituted or unsubstituted C.sub.1-6alkyl. In certain embodiments, R.sup.X is NH(R.sup.A1); and R.sup.A1 is substituted or unsubstituted methyl. In certain embodiments, R.sup.X is NH(R.sup.A1); and R.sup.A1 is acyl. In certain embodiments, R.sup.X is NH(R.sup.A1); and R.sup.A1 is substituted or unsubstituted C(O)(C.sub.1-6alkyl). In certain embodiments, R.sup.X is NH(R.sup.A1); and R.sup.A1 is acetyl or propionyl. In certain embodiments, R.sup.X is NH(R.sup.A1); and R.sup.A1 is substituted or unsubstituted C(O)-(carbocyclyl). In certain embodiments, R.sup.X is NH(R.sup.A); and R.sup.A1 is substituted or unsubstituted C(O)-(cyclopropyl). In certain embodiments, R.sup.X is NH(R.sup.A1); and R.sup.A1 is substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.X is NH(R.sup.A1); and R.sup.A1 is substituted or unsubstituted pyrazole. In certain embodiments, R.sup.X is NH(R.sup.A1); and R.sup.A1 is substituted or unsubstituted isoxazole. In certain embodiments, R.sup.X is NH(R.sup.A); and R.sup.A1 is substituted or unsubstituted pyrimidine. In certain embodiments, R.sup.X is NH(R.sup.A1); and R.sup.A1 is substituted or unsubstituted heterocyclyl. In certain embodiments, R.sup.X is NH(R.sup.A1); and R.sup.A1 is substituted or unsubstituted azetidine. In certain embodiments, R.sup.X is NH(R.sup.A1); and R.sup.A1 is substituted or unsubstituted oxetane.

(368) In certain embodiments, a compound of Formula (A1) is a compound of Formula (A1-a), (A1-b), (A1-c), or (A1-d):

(369) ##STR00289##
wherein R.sup.Xa, R.sup.Xc, R.sup.A, R.sup.B, and l are defined herein. In certain embodiments R.sup.A is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R.sup.B is meta to the point of attachment of the amide linker. In certain embodiments, l is 2. In certain embodiments, l is 2; and the two R.sup.B groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R.sup.B group is meta to the point of attachment of the amide linker; and the second R.sup.B group is para to the point of attachment of the amide linker. In certain embodiments, one R.sup.B group is substituted or unsubstituted C.sub.1-6alkyl. In certain embodiments, one R.sup.B group is C.sub.1-6alkyl substituted with one CN group. In certain embodiments, one R.sup.B group is

(370) ##STR00290##
In certain embodiments, one R.sup.B group is substituted or unsubstituted CH.sub.2-(piperazinyl). In certain embodiments, one R.sup.B group is

(371) ##STR00291##
where the alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(372) ##STR00292##
where the alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(373) ##STR00293##
In certain embodiments, one R.sup.B group is haloalkyl. In certain embodiments, one R.sup.B group is CF.sub.3. In certain embodiments, one R.sup.B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R.sup.B group is

(374) ##STR00294##
where the alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(375) ##STR00295##
where the alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(376) ##STR00296##
In certain embodiments, one R.sup.B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R.sup.B group is

(377) ##STR00297##
where there alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(378) ##STR00298##
where there alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(379) ##STR00299##
In certain embodiments, one R.sup.B group is substituted or unsubstituted morpholine. In certain embodiments, two R.sup.B groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of R.sup.Xc are hydrogen. In certain embodiments, R.sup.Xa is substituted or unsubstituted C.sub.1-6alkyl. In certain embodiments, R.sup.Xa is methyl or ethyl.

(380) In certain embodiments, a compound of Formula (A2) is a compound of Formula (A2-a), (A2-b), (A2-c), or (A2-d):

(381) ##STR00300##
wherein R.sup.Xa, R.sup.Xc, R.sup.A, R.sup.B, and l are defined herein. In certain embodiments R.sup.A is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R.sup.B is meta to the point of attachment of the amide linker. In certain embodiments, l is 2. In certain embodiments, l is 2; and the two R.sup.B groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R.sup.B group is meta to the point of attachment of the amide linker; and the second R.sup.B group is para to the point of attachment of the amide linker. In certain embodiments, one R.sup.B group is substituted or unsubstituted C.sub.1-6alkyl. In certain embodiments, one R.sup.B group is C.sub.1-6alkyl substituted with one CN group. In certain embodiments, one R.sup.B group is

(382) ##STR00301##
In certain embodiments, one R.sup.B group is substituted or unsubstituted CH.sub.2-(piperazinyl). In certain embodiments, one R.sup.B group is

(383) ##STR00302##
where the alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(384) ##STR00303##
where the alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(385) ##STR00304##
In certain embodiments, one R.sup.B group is haloalkyl. In certain embodiments, one R.sup.B group is CF.sub.3. In certain embodiments, one R.sup.B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R.sup.B group is

(386) ##STR00305##
where the alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(387) ##STR00306##
where the alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(388) ##STR00307##
In certain embodiments, one R.sup.B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R.sup.B group is

(389) ##STR00308##
where there alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(390) ##STR00309##
where there alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(391) ##STR00310##
In certain embodiments, one R.sup.B group is substituted or unsubstituted morpholine. In certain embodiments, two R.sup.B groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of R.sup.Xc are hydrogen. In certain embodiments, R.sup.Xa is substituted or unsubstituted C.sub.1-6alkyl. In certain embodiments, R.sup.Xa is methyl or ethyl.

(392) In certain embodiments, a compound of Formula (A1) is a compound of Formula (A1-e)-(A1-p):

(393) ##STR00311## ##STR00312##
wherein R.sup.Xa, R.sup.Xc, R.sup.A, and R.sup.B are defined herein. In certain embodiments R.sup.A is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A is methyl. In certain embodiments, one R.sup.B group is substituted or unsubstituted C.sub.1-6alkyl. In certain embodiments, one R.sup.B group is C.sub.1-6alkyl substituted with one CN group. In certain embodiments, one R.sup.B group is

(394) ##STR00313##
In certain embodiments, one R.sup.B group is substituted or unsubstituted CH.sub.2-(piperazinyl). In certain embodiments, one R.sup.B group is

(395) ##STR00314##
where the alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(396) ##STR00315##
where the alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(397) ##STR00316##
In certain embodiments, one R.sup.B group is haloalkyl. In certain embodiments, one R.sup.B group is CF.sub.3. In certain embodiments, one R.sup.B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R.sup.B group is

(398) ##STR00317##
where the alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(399) ##STR00318##
where the alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(400) ##STR00319##
In certain embodiments, one R.sup.B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R.sup.B group is

(401) ##STR00320##
where there alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(402) ##STR00321##
where there alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(403) ##STR00322##
In certain embodiments, one R.sup.B group is substituted or unsubstituted morpholine. In certain embodiments, two R.sup.B groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of R.sup.Xc are hydrogen. In certain embodiments, R.sup.Xa is substituted or unsubstituted C.sub.1-6alkyl. In certain embodiments, R.sup.Xa is methyl or ethyl.

(404) In certain embodiments, a compound of Formula (A2) is a compound of Formula (A2-e)-(A2-p):

(405) ##STR00323## ##STR00324##
wherein R.sup.Xa, R.sup.Xc, R.sup.A, and R.sup.B are defined herein. In certain embodiments R.sup.A is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A is methyl. In certain embodiments, one R.sup.B group is substituted or unsubstituted C.sub.1-6alkyl. In certain embodiments, one R.sup.B group is

(406) ##STR00325##
C.sub.1-6alkyl substituted with one CN group. In certain embodiments, one R.sup.B group is NC In certain embodiments, one R.sup.B group is substituted or unsubstituted CH.sub.2-(piperazinyl). In certain embodiments, one R.sup.B group is

(407) ##STR00326##
where the alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(408) ##STR00327##
where the alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(409) ##STR00328##
In certain embodiments, one R.sup.B group is haloalkyl. In certain embodiments, one R.sup.B group is CF.sub.3. In certain embodiments, one R.sup.B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R.sup.B group is

(410) ##STR00329##
where the alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(411) ##STR00330##
where the alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(412) ##STR00331##
In certain embodiments, one R.sup.B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R.sup.B group is

(413) ##STR00332##
where there alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(414) ##STR00333##
where there alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(415) ##STR00334##
In certain embodiments, one R.sup.B group is substituted or unsubstituted morpholine. In certain embodiments, two R.sup.B groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of R.sup.Xc are hydrogen. In certain embodiments, R.sup.Xa is substituted or unsubstituted C.sub.1-6alkyl. In certain embodiments, R.sup.Xa is methyl or ethyl.

(416) In certain embodiments, a compound of Formula (A) is a compound of Formula (A3) or (A4):

(417) ##STR00335##
wherein R.sup.D, R.sup.A, R.sup.B, and l are defined herein. In certain embodiments R.sup.A is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R.sup.B is meta to the point of attachment of the amide linker. In certain embodiments, l is 2. In certain embodiments, l is 2; and the two R.sup.B groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R.sup.B group is meta to the point of attachment of the amide linker; and the second R.sup.B group is para to the point of attachment of the amide linker. In certain embodiments, one R.sup.B group is substituted or unsubstituted C.sub.1-6alkyl. In certain embodiments, one R.sup.B group is C.sub.1-6alkyl substituted with one CN group. In certain embodiments, one R.sup.B group is

(418) ##STR00336##
In certain embodiments, one R.sup.B group is substituted or unsubstituted CH.sub.2-(piperazinyl). In certain embodiments, one R.sup.B group is

(419) ##STR00337##
where the alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(420) ##STR00338##
where the alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(421) ##STR00339##
In certain embodiments, one R.sup.B group is haloalkyl. In certain embodiments, one R.sup.B group is CF.sub.3. In certain embodiments, one R.sup.B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R.sup.B group is

(422) ##STR00340##
where the alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(423) ##STR00341##
where the alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(424) ##STR00342##
In certain embodiments, one R.sup.B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R.sup.B group is

(425) ##STR00343##
where there alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(426) ##STR00344##
alkyl where there alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(427) ##STR00345##
In certain embodiments, one R.sup.B group is substituted or unsubstituted morpholine. In certain embodiments, two R.sup.B groups are substituted or unsubstituted morpholine. In certain embodiments, R.sup.D is R.sup.D is

(428) ##STR00346##
In certain embodiments, R.sup.D is

(429) ##STR00347##
In certain embodiments, R.sup.D is

(430) ##STR00348##
In certain embodiments, R.sup.D is

(431) ##STR00349##

(432) In certain embodiments, a compound of Formula (A3) is a compound of Formula (A3-a), (A3-b), or (A3-c):

(433) ##STR00350##
wherein R.sup.D, R.sup.A, R.sup.B, and l are defined herein. In certain embodiments R.sup.A is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R.sup.B is meta to the point of attachment of the amide linker. In certain embodiments, l is 2. In certain embodiments, l is 2; and the two R.sup.B groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R.sup.B group is meta to the point of attachment of the amide linker; and the second R.sup.B group is para to the point of attachment of the amide linker. In certain embodiments, one R.sup.B group is substituted or unsubstituted C.sub.1-6alkyl. In certain embodiments, one R.sup.B group is C.sub.1-6alkyl substituted with one CN group. In certain embodiments, one R.sup.B group is

(434) ##STR00351##
In certain embodiments, one R.sup.B group is substituted or unsubstituted CH.sub.2-(piperazinyl). In certain embodiments, one R.sup.B group is

(435) ##STR00352##
where the alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(436) ##STR00353##
where the alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(437) ##STR00354##
In certain embodiments, one R.sup.B group is haloalkyl. In certain embodiments, one R.sup.B group is CF.sub.3. In certain embodiments, one R.sup.B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R.sup.B group is

(438) ##STR00355##
where the alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(439) ##STR00356##
where the alkyl where the alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(440) ##STR00357##
In certain embodiments, one R.sup.B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R.sup.B group is

(441) ##STR00358##
where there alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(442) ##STR00359##
where there alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(443) ##STR00360##
In certain embodiments, one R.sup.B group is substituted or unsubstituted morpholine. In certain embodiments, two R.sup.B groups are substituted or unsubstituted morpholine. In certain embodiments, R.sup.D is

(444) ##STR00361##
In certain embodiments, R.sup.D is

(445) ##STR00362##
In certain embodiments, R.sup.D is

(446) ##STR00363##
In certain embodiments, R.sup.D is

(447) ##STR00364##

(448) In certain embodiments, a compound of Formula (A4) is a compound of Formula (A4-a), (A4-b), or (A4-c):

(449) ##STR00365##
wherein R.sup.D, R.sup.A, R.sup.B, and l are defined herein. In certain embodiments R.sup.A is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R.sup.B is meta to the point of attachment of the amide linker. In certain embodiments, l is 2. In certain embodiments, l is 2; and the two R.sup.B groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R.sup.B group is meta to the point of attachment of the amide linker; and the second R.sup.B group is para to the point of attachment of the amide linker. In certain embodiments, one R.sup.B group is substituted or unsubstituted C.sub.1-6alkyl. In certain embodiments, one R.sup.B group is C.sub.1-6alkyl substituted with one CN group. In certain embodiments, one R.sup.B group is

(450) ##STR00366##
In certain embodiments, one R.sup.B group is substituted or unsubstituted CH.sub.2-(piperazinyl). In certain embodiments, one R.sup.B group is

(451) ##STR00367##
where the alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(452) ##STR00368##
where the alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(453) ##STR00369##
In certain embodiments, one R.sup.B group is haloalkyl. In certain embodiments, one R.sup.B group is CF.sub.3. In certain embodiments, one R.sup.B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R.sup.B group is

(454) ##STR00370##
where the alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(455) ##STR00371##
where the alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(456) ##STR00372##
In certain embodiments, one R.sup.B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R.sup.B group is

(457) ##STR00373##
where there alkyl is optionally substituted. In certain embodiments, one R.sup.B group is

(458) ##STR00374##
where there alkyl is unsubstituted. In certain embodiments, one R.sup.B group is

(459) ##STR00375##
In certain embodiments, one R.sup.B group is substituted or unsubstituted morpholine. In certain embodiments, two R.sup.B groups are substituted or unsubstituted morpholine. In certain embodiments, R.sup.D is

(460) ##STR00376##
In certain embodiments, R.sup.D is

(461) ##STR00377##
In certain embodiments, R.sup.D is

(462) ##STR00378##
In certain embodiments, R.sup.D is

(463) ##STR00379##

(464) Another aspect of the invention relates to the compound of Formula (I-11):

(465) ##STR00380##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

(466) In another aspect, provided are compounds of Formula (V):

(467) ##STR00381##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof; wherein:

(468) each instance of each instance of R.sup.A, R.sup.B, and R.sup.X are independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, OR.sup.A1, N(R.sup.A1).sub.2, SR.sup.A1, CN, C(O)R.sup.A1, C(O)OR.sup.A1, C(O)SR.sup.A1, C(O)N(R.sup.A1).sub.2, C(S)R.sup.A1, C(S)OR.sup.A1, C(S)SR.sup.A1, C(S)N(R.sup.A1).sub.2, C(NR.sup.A1)R.sup.A1, C(NR.sup.A1)OR.sup.A1, C(NR.sup.A1)SR.sup.A1, C(NR.sup.A1)N(R.sup.A1).sub.2, NO.sub.2, N.sub.3, N(R.sup.A1).sub.3.sup.+X.sup., wherein X.sup. is a counterion, N(OR.sup.A1)R.sup.A1, NR.sup.A1C(O)R.sup.A1, NR.sup.A1C(O)OR.sup.A1, NR.sup.A1C(O)SR.sup.A1, NR.sup.A1C(O)N(R.sup.A1).sub.2, NR.sup.A1C(S)R.sup.A1, NR.sup.A1C(S)OR.sup.A1, NR.sup.A1C(S)SR.sup.A1, NR.sup.A1C(S)N(R.sup.A1).sub.2, NR.sup.A1C(NR.sup.A1)R.sup.A1, NR.sup.A1C(NR.sup.A1)OR.sup.A1, NR.sup.A1C(NR.sup.A1)SR.sup.A1, NR.sup.A1C(NR.sup.A1)N(R.sup.A1).sub.2, NR.sup.A1S(O).sub.2R.sup.A1, NR.sup.A1S(O).sub.2OR.sup.A1, NR.sup.A1S(O).sub.2SR.sup.A1, NR.sup.A1S(O).sub.2N(R.sup.A1).sub.2, NR.sup.A1S(O)R.sup.A1, NR.sup.A1S(O)OR.sup.A1, NR.sup.A1S(O)SR.sup.A1, NR.sup.A1S(O)N(R.sup.A1).sub.2, NR.sup.A1P(O), NR.sup.A1P(O).sub.2, NR.sup.A1P(O)(R.sup.A1).sub.2, NR.sup.A1P(O)R.sup.A1(OR.sup.A1), NR.sup.A1P(O)(OR.sup.A1).sub.2, OC(O)R.sup.A1, OC(O)OR.sup.A1, OC(O)SR.sup.A1, OC(O)N(R.sup.A1).sub.2, OC(NR.sup.A1)R.sup.A1, OC(NR.sup.A1)OR.sup.A1, OC(NR.sup.A1)N(R.sup.A1).sub.2, OC(S)R.sup.A1, OC(S)OR.sup.A1, OC(S)SR.sup.A1, OC(S)N(R.sup.A1).sub.2, ON(R.sup.A1).sub.2, OS(O)R.sup.A1, OS(O)OR.sup.A1, OS(O)SR.sup.A1, OS(O)N(R.sup.A1).sub.2, OS(O).sub.2R.sup.A1, OS(O).sub.2OR.sup.A1, OS(O).sub.2SR.sup.A1, OS(O).sub.2N(R.sup.A1).sub.2, OP(O).sub.2, OP(O)(R.sup.A1).sub.2, OP(O)R.sup.A1(OR.sup.A1), OP(O)(OR.sup.A1).sub.2, OP(O), OP(R.sup.A1).sub.2, OPR.sup.A1(OR.sup.A1), OP(OR.sup.A1).sub.2, OSi(R.sup.A1).sub.3, OSi(R.sup.A1).sub.2OR.sup.A1, OSi(R.sup.A1)(OR.sup.A1).sub.2, OSi(OR.sup.A1).sub.3, SSR.sup.A1, S(O)R.sup.A1, S(O)OR.sup.A1, S(O)N(R.sup.A1).sub.2, S(O).sub.2R.sup.A1, S(O).sub.2OR.sup.A1, S(O).sub.2N(R.sup.A1).sub.2, SC(O)R.sup.A1, SC(O)OR.sup.A1, SC(O)SR.sup.A1, SC(O)N(R.sup.A1).sub.2, SC(S)R.sup.A1, SC(S)OR.sup.A1, SC(S)SR.sup.A1, SC(S)N(R.sup.A1).sub.2, P(R.sup.A1).sub.2, PR.sup.A1(OR.sup.A1), P(OR.sup.A1).sub.2, P(O), P(O)(R.sup.A1).sub.2, P(O)(OR.sup.A1).sub.2, P(O)R.sup.A1(OR.sup.A1), P(O).sub.2, B(R.sup.A1).sub.2, B(OR.sup.A1).sub.2, BR.sup.A1(OR.sup.A1), Si(R.sup.A1).sub.3, Si(R.sup.A1).sub.2OR.sup.A1, SiR.sup.A1(OR.sup.A1).sub.2, and Si(OR.sup.A1).sub.3, two R.sup.A or R.sup.B groups are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring, or R.sup.A or R.sup.B forms an optional 5 to 8 membered ring with any one of X, Y, Z, Q, U, or Cy; wherein each occurrence of R.sup.A1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R.sup.A1 groups are joined to form an optionally substituted heterocyclic ring;

(469) k and l are each independently 0, 1, 2, 3, 4, or 5;

(470) X, Y, Z are each independently CH.sub.2, CHR.sup.A, CH, C(R.sup.A).sub.2, C, N, NR.sup.A, O, S or CO, or bond and may optionally form a 5 to 8 membered ring with R.sup.A or R.sup.B;

(471) Q and U are each independently NR.sup.A, O, CO, NR.sup.ACO, or bond;

(472) Ring A is an optionally substituted aryl, or optionally substituted heteroaryl ring

(473) Ring C is an optionally substituted aryl ring; and

(474) Cy is an optionally substituted aryl ring, optionally substituted heteroaryl ring, bond, or hydrogen.

(475) Compounds of Formula (V) include an aryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is naphthyl, the invention provides compounds of Formula (V-a):

(476) ##STR00382##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.X, k, and l are as defined herein.

(477) Compounds of Formula (V) include an aryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, Ring A is naphthyl, the invention provides compounds of Formula (V-b):

(478) ##STR00383##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.X, k, and l are as defined herein.

(479) Compounds of Formula (V) include an aryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is phenyl, the invention provides compounds of Formula (V-c):

(480) ##STR00384##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.X, k, and l are as defined herein.

(481) Compounds of Formula (V) include an aryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is phenyl, the invention provides compounds of Formula (V-d):

(482) ##STR00385##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.X, k, and l are as defined herein.

(483) Compounds of Formula (V) include an heteroaryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is pyrrolopyrimidine, the invention provides compounds of Formula (V-e):

(484) ##STR00386##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.X, k, and l are as defined herein.

(485) Compounds of Formula (V) include an heteroaryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is a pyrimidine, the invention provides compounds of Formula (V-e.sup.A):

(486) ##STR00387##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.X, k, and l are as defined herein.

(487) Compounds of Formula (V) include an heteroaryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is a 1H-pyrazolo[3,4-d]pyrimidin-4-amine, the invention provides compounds of Formula (V-e.sup.B):

(488) ##STR00388##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.X, k, and l are as defined herein.

(489) Compounds of Formula (V) include an heteroaryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is a furo[2,3-c]pyridin-7-amine, the invention provides compounds of Formula (V-e.sup.C):

(490) ##STR00389##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.X, k, and l are as defined herein.

(491) Compounds of Formula (V) include an heteroaryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is a quinazoline, the invention provides compounds of Formula (V-e.sup.D):

(492) ##STR00390##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.X, k, and l are as defined herein.

(493) Compounds of Formula (V) include an heteroaryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is phenyl, and at least one R.sup.A group links to Cy forming an optional 5 to 8 membered ring, the invention provides compounds of Formula (V-f):

(494) ##STR00391##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.X, k, and l are as defined herein.

(495) Compounds of Formula (V) include an heteroaryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is phenyl, and at least one R.sup.A group links to Cy forming an optional 5 to 8 membered ring, the invention provides compounds of Formula (V-g):

(496) ##STR00392##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.X, k, and l are as defined herein.

(497) In another aspect, provided herein are compounds of Formula (II):

(498) ##STR00393##
and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof; wherein:

(499) each instance of R.sup.D is independently an optional electrophilic moiety that can be attached to Cy, Ring A, or Ring C;

(500) each instance of m is independently 0 or 1; and

(501) Ring A, Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.X, k, and l are as defined herein.

(502) In certain embodiments, R.sup.D is an optional electrophilic moiety that can be attached to Cy, Ring A, or Ring C; and m is 0 or 1. In compounds of Formula (II), R.sup.D is an optional electrophilic moiety that can be attached to Cy, Ring A, or Ring C. In certain embodiments, R.sup.D is any one of Formulae (i-1)-(i-17):

(503) ##STR00394## ##STR00395##
wherein:

(504) R.sup.D1 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, NO.sub.2, OR.sup.D1a, N(R.sup.D1a).sub.2, SR.sup.D1a, CH.sub.2OR.sup.D1a, CH.sub.2N(R.sup.D1a).sub.2, CH.sub.2SR.sup.D1a, C(O)R.sup.D1a, C(O)OR.sup.D1a, C(O)SR.sup.D1a, C(O)N(R.sup.D1a).sub.2, C(S)R.sup.D1a, C(S)OR.sup.D1a, C(S)SR.sup.D1a, C(S)N(R.sup.D1a).sub.2, C(NR.sup.D1a)R.sup.D1a, C(NR.sup.D1a)OR.sup.D1a, C(NR.sup.D1a)SR.sup.D1a, and C(NR.sup.D1a)N(R.sup.D1a).sub.2, wherein each occurrence of R.sup.D1a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.D1a groups are joined to form an optionally substituted heterocyclic ring;

(505) R.sup.D2 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, NO.sub.2, OR.sup.D2a, N(R.sup.D2a).sub.2, SR.sup.D2a, CH.sub.2OR.sup.D2a, CH.sub.2N(R.sup.D2a).sub.2, CH.sub.2SR.sup.D2a, C(O)R.sup.D2a, C(O)OR.sup.D2a, C(O)SR.sup.D2a, C(O)N(R.sup.D2a).sub.2, C(S)R.sup.D2a, C(S)OR.sup.D2a, C(S)SR.sup.D2a, C(S)N(R.sup.D2a).sub.2, C(NR.sup.D2a)R.sup.D2a, C(NR.sup.D2a)OR.sup.D2a, C(NR.sup.D2a)SR.sup.D2a, and C(NR.sup.D2a)N(R.sup.D2a).sub.2, wherein each occurrence of R.sup.D2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.D2a groups are joined to form an optionally substituted heterocyclic ring;

(506) R.sup.D3 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, NO.sub.2, OR.sup.D3a, N(R.sup.D3a).sub.2, SR.sup.D3a, CH.sub.2OR.sup.D3a, CH.sub.2N(R.sup.D3a).sub.2, CH.sub.2SR.sup.D3a, C(O)R.sup.D3a, C(O)OR.sup.D3a, C(O)SR.sup.D3a, C(O)N(R.sup.D3a).sub.2, C(S)R.sup.D3a, C(S)OR.sup.D3a, C(S)SR.sup.D3a, C(S)N(R.sup.D3a).sub.2, C(NR.sup.D3a)R.sup.D3a, C(NR.sup.D3a)OR.sup.D3a, C(NR.sup.D3a)SR.sup.D3a, and C(NR.sup.D3a)N(R.sup.D3a).sub.2, wherein each occurrence of R.sup.D3a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R.sup.D3a groups are joined to form an optionally substituted heterocyclic ring;

(507) optionally R.sup.D1, and R.sup.D3, or R.sup.D2 and R.sup.D3, or R.sup.D1 and R.sup.D2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;

(508) R.sup.D4 is a leaving group;

(509) R.sup.D5 is hydrogen, C.sub.1-6 alkyl, or a nitrogen protecting group;

(510) Y.sup.Z is O, S, or NR.sup.D6, wherein R.sup.D6 is hydrogen, C.sub.1-6 alkyl, or a nitrogen protecting group;

(511) a is 1 or 2; and

(512) z is 0, 1, 2, 3, 4, 5, or 6.

(513) Compounds of Formula (II) include an aryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is naphthyl, the invention provides compounds of Formula (II-a):

(514) ##STR00396##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.D, R.sup.X, k, l, and m are as defined herein.

(515) Compounds of Formula (II) include an aryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is naphthyl, the invention provides compounds of Formula (II-b):

(516) ##STR00397##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.D, R.sup.X, k, l, and m are as defined herein.

(517) Compounds of Formula (II) include an aryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is phenyl, the invention provides compounds of Formula (II-c):

(518) ##STR00398##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.D, R.sup.X, k, l, and m are as defined herein.

(519) Compounds of Formula (II) include an aryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is phenyl, the invention provides compounds of Formula (II-d):

(520) ##STR00399##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.D, R.sup.X, k, l, and m are as defined herein.

(521) Compounds of Formula (II) include an heteroaryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is pyrrolopyrimidine, the invention provides compounds of Formula (II-e):

(522) ##STR00400##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.D, R.sup.X, k, l, and m are as defined herein.

(523) Compounds of Formula (II) include an heteroaryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is pyrimidine, the invention provides compounds of Formula (II-e.sup.A):

(524) ##STR00401##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.D, R.sup.X, k, l, and m are as defined herein.

(525) Compounds of Formula (II) include an heteroaryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is pyrimidine, the invention provides compounds of Formula (II-e.sup.B):

(526) ##STR00402##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.D, R.sup.X, k, l, and m are as defined herein.

(527) Compounds of Formula (II) include an heteroaryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is a furo[2,3-c]pyridin-7-amine, the invention provides compounds of Formula (II-e.sup.C):

(528) ##STR00403##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.X, k, and l are as defined herein.

(529) Compounds of Formula (II) include an heteroaryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is a quinazoline, the invention provides compounds of Formula (II-e.sup.D):

(530) ##STR00404##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.X, k, and l are as defined herein.

(531) Compounds of Formula (II) include an heteroaryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is phenyl, and at least one R.sup.A group links to Cy forming an optional 5 to 8 membered ring, the invention provides compounds of Formula (II-f):

(532) ##STR00405##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.D, R.sup.X, k, l, and m are as defined herein.

(533) Compounds of Formula (II) include an heteroaryl group for Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, when Ring A is phenyl, and at least one R.sup.A group links to Cy forming an optional 5 to 8 membered ring, the invention provides compounds of Formula (II-g):

(534) ##STR00406##
wherein Ring C, Cy, Q, U, X, Y, Z, R.sup.A, R.sup.B, R.sup.D, R.sup.X, k, l, and m are as defined herein.

(535) In compounds of Formula (II), R.sup.D is a substituent on Ring A, Ring C, or Cy. In certain embodiments, R.sup.D comprises a Michael acceptor moiety. This Michael acceptor moiety may react with a cysteine or other nucleophilic residue to allow covalent attachment of the compound to the target. In certain embodiments, the covalent attachment is irreversible. In other embodiments, the covalent attachment is reversible. In certain embodiments, R.sup.D is of Formula (i-1). In certain embodiments, R.sup.D is of Formula (i-2). In certain embodiments, R.sup.D is of Formula (i-3). In certain embodiments, R.sup.D is of Formula (i-4). In certain embodiments, R.sup.D is of Formula (i-5). In certain embodiments, R.sup.D is of Formula (i-6). In certain embodiments, R.sup.D is of Formula (i-7). In certain embodiments, R.sup.D is of Formula (i-8). In certain embodiments, R.sup.D is of Formula (i-9). In certain embodiments, R.sup.D is of Formula (i-10). In certain embodiments, R.sup.D is of Formula (i-11). In certain embodiments, R.sup.D is of Formula (i-12). In certain embodiments, R.sup.D is of Formula (i-13). In certain embodiments, R.sup.D is of Formula (i-14). In certain embodiments, R.sup.D is of Formula (i-15). In certain embodiments, R.sup.D is of Formula (i-16). In certain embodiments, R.sup.D is of Formula (i-17).

(536) In compounds of Formula (II), R.sup.D may include a substituent R.sup.D1. In certain embodiments, R.sup.D1 is H. In certain embodiments, R.sup.D1 is halogen. In certain embodiments, R.sup.D1 is F. In certain embodiments, R.sup.D1, is Cl. In certain embodiments, R.sup.D, is Br. In certain embodiments, R.sup.D1 is I (iodine). In certain embodiments, R.sup.D1, is substituted acyl. In certain embodiments, R.sup.D1 is unsubstituted acyl. In certain embodiments, R.sup.D1, is acetyl. In certain embodiments, R.sup.D1 is substituted alkyl. In certain embodiments, R.sup.D1, is unsubstituted alkyl. In certain embodiments, R.sup.D1 is C.sub.1-6 alkyl. In certain embodiments, R.sup.D1 is methyl. In certain embodiments, R.sup.D1 is ethyl. In certain embodiments, R.sup.D1 is propyl. In certain embodiments, R.sup.D1 is butyl. In certain embodiments, R.sup.D1 is substituted alkenyl. In certain embodiments, R.sup.D1 is unsubstituted alkenyl. In certain embodiments, R.sup.D1 is substituted alkynyl. In certain embodiments, R.sup.D1 is unsubstituted alkynyl. In certain embodiments, R.sup.D1 is substituted carbocyclyl. In certain embodiments, R.sup.D1 is unsubstituted carbocyclyl. In certain embodiments, R.sup.D1 is substituted heterocyclyl. In certain embodiments, R.sup.D1 is unsubstituted heterocyclyl. In certain embodiments, R.sup.D1 is substituted aryl. In certain embodiments, R.sup.D1 is unsubstituted aryl. In certain embodiments, R.sup.D1 is substituted phenyl. In certain embodiments, R.sup.D1 is unsubstituted phenyl. In certain embodiments, R.sup.D1 is substituted heteroaryl. In certain embodiments, R.sup.D1 is unsubstituted heteroaryl. In certain embodiments, R.sup.D1 is substituted pyridyl. In certain embodiments, R.sup.D1 is unsubstituted pyridyl. In certain embodiments, R.sup.D1 is CN. In certain embodiments, R.sup.D1 is NO.sub.2. In certain embodiments, R.sup.D1 is OR.sup.D1a. In certain embodiments, R.sup.D1 is N(R.sup.D1a).sub.2. In certain embodiments, R.sup.D1 is SR.sup.D1a. In certain embodiments, R.sup.D1, is CH.sub.2OR.sup.D1a. In certain embodiments, R.sup.D1 is CH.sub.2N(R.sup.D1a).sub.2. In certain embodiments, R.sup.D1 is CH.sub.2SR.sup.D1a.

(537) In certain embodiments, at least one R.sup.D1a is H. In certain embodiments, at least one R.sup.D1a is substituted acyl. In certain embodiments, at least one R.sup.D1a is unsubstituted acyl. In certain embodiments, at least one R.sup.D1a is acetyl. In certain embodiments, at least one R.sup.D1a, is substituted alkyl. In certain embodiments, at least one R.sup.D1a is unsubstituted alkyl. In certain embodiments, at least one R.sup.D1a is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.D1a is methyl. In certain embodiments, at least one R.sup.D1a is ethyl. In certain embodiments, at least one R.sup.D1a is propyl. In certain embodiments, at least one R.sup.D1a is butyl. In certain embodiments, at least one R.sup.D1a is substituted alkenyl. In certain embodiments, at least one R.sup.D1a is unsubstituted alkenyl. In certain embodiments, at least one R.sup.D1a is substituted alkynyl. In certain embodiments, at least one R.sup.D1a is unsubstituted alkynyl. In certain embodiments, at least one R.sup.D1a is substituted carbocyclyl. In certain embodiments, at least one R.sup.D1a is unsubstituted carbocyclyl. In certain embodiments, at least one R.sup.D1a is substituted heterocyclyl. In certain embodiments, at least one R.sup.D1a is unsubstituted heterocyclyl. In certain embodiments, at least one R.sup.D1a is substituted aryl. In certain embodiments, at least one R.sup.D1a is unsubstituted aryl. In certain embodiments, at least one R.sup.D1a is substituted phenyl. In certain embodiments, at least one R.sup.D1a is unsubstituted phenyl. In certain embodiments, at least one R.sup.D1a is substituted heteroaryl. In certain embodiments, at least one R.sup.D1a is unsubstituted heteroaryl. In certain embodiments, at least one R.sup.D1a is substituted pyridyl. In certain embodiments, at least one R.sup.D1a is unsubstituted pyridyl. In certain embodiments, at least one R.sup.D1a is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R.sup.D1a is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R.sup.D1a is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.D1a is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R.sup.D1a is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R.sup.D1a is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R.sup.D1a groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R.sup.D1a groups are joined to form an unsubstituted heterocyclic ring.

(538) In compounds of Formula (II), R.sup.D may include a substituent R.sup.D2. In certain embodiments, R.sup.D2 is H. In certain embodiments, R.sup.D2 is halogen. In certain embodiments, R.sup.D2, is F. In certain embodiments, R.sup.D2 is Cl. In certain embodiments, R.sup.D2 is Br. In certain embodiments, R.sup.D2 is I (iodine). In certain embodiments, R.sup.D2 is substituted acyl. In certain embodiments, R.sup.D2 is unsubstituted acyl. In certain embodiments, R.sup.D2 is acetyl. In certain embodiments, R.sup.D2 is substituted alkyl. In certain embodiments, R.sup.D2 is unsubstituted alkyl. In certain embodiments, R.sup.D2 is C.sub.1-6 alkyl. In certain embodiments, R.sup.D2 is methyl. In certain embodiments, R.sup.D2 is ethyl. In certain embodiments, R.sup.D2 is propyl. In certain embodiments, R.sup.D2 is butyl. In certain embodiments, R.sup.D2 is substituted alkenyl. In certain embodiments, R.sup.D2 is unsubstituted alkenyl. In certain embodiments, R.sup.D2 is substituted alkynyl. In certain embodiments, R.sup.D2 is unsubstituted alkynyl. In certain embodiments, R.sup.D2 is substituted carbocyclyl. In certain embodiments, R.sup.D2 is unsubstituted carbocyclyl. In certain embodiments, R.sup.D2 is substituted heterocyclyl. In certain embodiments, R.sup.D2 is unsubstituted heterocyclyl. In certain embodiments, R.sup.D2 is substituted aryl. In certain embodiments, R.sup.D2 is unsubstituted aryl. In certain embodiments, R.sup.D2 is substituted phenyl. In certain embodiments, R.sup.D2 is unsubstituted phenyl. In certain embodiments, R.sup.D2 is substituted heteroaryl. In certain embodiments, R.sup.D2 is unsubstituted heteroaryl. In certain embodiments, R.sup.D2, is substituted pyridyl. In certain embodiments, R.sup.D2 is unsubstituted pyridyl. In certain embodiments, R.sup.D2 is CN. In certain embodiments, R.sup.D2 is NO.sub.2. In certain embodiments, R.sup.D2 is OR.sup.D2a. In certain embodiments, R.sup.D2 is N(R.sup.D2a).sub.2. In certain embodiments, R.sup.D2 is SR.sup.D2a. In certain embodiments, R.sup.D2 is CH.sub.2OR.sup.D2a. In certain embodiments, R.sup.D2 is CH.sub.2N(R.sup.D2a).sub.2. In certain embodiments, R.sup.D2 is CH.sub.2SR.sup.D2a.

(539) In certain embodiments, at least one R.sup.D2a is H. In certain embodiments, at least one R.sup.D2a is substituted acyl. In certain embodiments, at least one R.sup.D2a is unsubstituted acyl. In certain embodiments, at least one R.sup.D2a is acetyl. In certain embodiments, at least one R.sup.D2a is substituted alkyl. In certain embodiments, at least one R.sup.D2a is unsubstituted alkyl. In certain embodiments, at least one R.sup.D2a is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.D2a is methyl. In certain embodiments, at least one R.sup.D2a is ethyl. In certain embodiments, at least one R.sup.D2a is propyl. In certain embodiments, at least one R.sup.D2a is butyl. In certain embodiments, at least one R.sup.D2a is substituted alkenyl. In certain embodiments, at least one R.sup.D2a is unsubstituted alkenyl. In certain embodiments, at least one R.sup.D2a is substituted alkynyl. In certain embodiments, at least one R.sup.D2a is unsubstituted alkynyl. In certain embodiments, at least one R.sup.D2a is substituted carbocyclyl. In certain embodiments, at least one R.sup.D2a is unsubstituted carbocyclyl. In certain embodiments, at least one R.sup.D2a is substituted heterocyclyl. In certain embodiments, at least one R.sup.D2a is unsubstituted heterocyclyl. In certain embodiments, at least one R.sup.D2a is substituted aryl. In certain embodiments, at least one R.sup.D2a is unsubstituted aryl. In certain embodiments, at least one R.sup.D2a is substituted phenyl. In certain embodiments, at least one R.sup.D2a is unsubstituted phenyl. In certain embodiments, at least one R.sup.D2a is substituted heteroaryl. In certain embodiments, at least one R.sup.D2a is unsubstituted heteroaryl. In certain embodiments, at least one R.sup.D2a is substituted pyridyl. In certain embodiments, at least one R.sup.D2a is unsubstituted pyridyl. In certain embodiments, at least one R.sup.D2a is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R.sup.D2a is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R.sup.D2a is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.D2a is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R.sup.D2a is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R.sup.D2a is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R.sup.D2a groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R.sup.D2a groups are joined to form an unsubstituted heterocyclic ring.

(540) In compounds of Formula (II), R.sup.D may include a substituent R.sup.D3. In certain embodiments, R.sup.D3 is H. In certain embodiments, R.sup.D3 is halogen. In certain embodiments, R.sup.D3 is F. In certain embodiments, R.sup.D3 is Cl. In certain embodiments, R.sup.D3 is Br. In certain embodiments, R.sup.D3 is I (iodine). In certain embodiments, R.sup.D3 is substituted acyl. In certain embodiments, R.sup.D3 is unsubstituted acyl. In certain embodiments, R.sup.D3 is acetyl. In certain embodiments, R.sup.D3 is substituted alkyl. In certain embodiments, R.sup.D3 is unsubstituted alkyl. In certain embodiments, R.sup.D3 is C.sub.1-6 alkyl. In certain embodiments, R.sup.D3 is methyl. In certain embodiments, R.sup.D3 is ethyl. In certain embodiments, R.sup.D3 is propyl. In certain embodiments, R.sup.D3 is butyl. In certain embodiments, R.sup.D3 is substituted alkenyl. In certain embodiments, R.sup.D3 is unsubstituted alkenyl. In certain embodiments, R.sup.D3 is substituted alkynyl. In certain embodiments, R.sup.D3 is unsubstituted alkynyl. In certain embodiments, R.sup.D3 is substituted carbocyclyl. In certain embodiments, R.sup.D3 is unsubstituted carbocyclyl. In certain embodiments, R.sup.D3 is substituted heterocyclyl. In certain embodiments, R.sup.D3 is unsubstituted heterocyclyl. In certain embodiments, R.sup.D3 is substituted aryl. In certain embodiments, R.sup.D3 is unsubstituted aryl. In certain embodiments, R.sup.D3 is substituted phenyl. In certain embodiments, R.sup.D3 is unsubstituted phenyl. In certain embodiments, R.sup.D3 is substituted heteroaryl. In certain embodiments, R.sup.D3 is unsubstituted heteroaryl. In certain embodiments, R.sup.D3 is substituted pyridyl. In certain embodiments, R.sup.D3 is unsubstituted pyridyl. In certain embodiments, R.sup.D3 is CN. In certain embodiments, R.sup.D3 is NO.sub.2. In certain embodiments, R.sup.D3 is OR.sup.D3a. In certain embodiments, R.sup.D3 is N(R.sup.D3a).sub.2. In certain embodiments, R.sup.D3 is SR.sup.D3a. In certain embodiments, R.sup.D3 is CH.sub.2OR.sup.D3a. In certain embodiments, R.sup.D3 is CH.sub.2N(R.sup.D3a).sub.2. In certain embodiments, R.sup.D3 is CH.sub.2SR.sup.D3a.

(541) In certain embodiments, at least one R.sup.D3a is H. In certain embodiments, at least one R.sup.D3a is substituted acyl. In certain embodiments, at least one R.sup.D3a is unsubstituted acyl. In certain embodiments, at least one R.sup.D3a is acetyl. In certain embodiments, at least one R.sup.D3a is substituted alkyl. In certain embodiments, at least one R.sup.D3a is unsubstituted alkyl. In certain embodiments, at least one R.sup.D3a is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.D3a is methyl. In certain embodiments, at least one R.sup.D3a is ethyl. In certain embodiments, at least one R.sup.D3a is propyl. In certain embodiments, at least one R.sup.D3a is butyl. In certain embodiments, at least one R.sup.D3a is substituted alkenyl. In certain embodiments, at least one R.sup.D3a is unsubstituted alkenyl. In certain embodiments, at least one R.sup.D3a is substituted alkynyl. In certain embodiments, at least one R.sup.D3a is unsubstituted alkynyl. In certain embodiments, at least one R.sup.D3a is substituted carbocyclyl. In certain embodiments, at least one R.sup.D3a is unsubstituted carbocyclyl. In certain embodiments, at least one R.sup.D3a is substituted heterocyclyl. In certain embodiments, at least one R.sup.D3a is unsubstituted heterocyclyl. In certain embodiments, at least one R.sup.D3a is substituted aryl. In certain embodiments, at least one R.sup.D3a is unsubstituted aryl. In certain embodiments, at least one R.sup.D3a is substituted phenyl. In certain embodiments, at least one R.sup.D3a is unsubstituted phenyl. In certain embodiments, at least one R.sup.D3a, is substituted heteroaryl. In certain embodiments, at least one R.sup.D3a is unsubstituted heteroaryl. In certain embodiments, at least one R.sup.D3a is substituted pyridyl. In certain embodiments, at least one R.sup.D3a is unsubstituted pyridyl. In certain embodiments, at least one R.sup.D3a is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R.sup.D3a is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R.sup.D3a is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.D3a is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R.sup.D3a is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R.sup.D3a is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R.sup.D3a groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R.sup.D3a groups are joined to form an unsubstituted heterocyclic ring.

(542) In compounds of Formula (II), R.sup.D may include a substituent R.sup.D4. In certain embodiments, R.sup.D4 is a leaving group. In certain embodiments, R.sup.D4 is halogen. In certain embodiments, R.sup.D4 is F. In certain embodiments, R.sup.D4 is Cl. In certain embodiments, R.sup.D4 is Br. In certain embodiments, R.sup.D4 is I (iodine). In certain embodiments, R.sup.D4 is OS(O).sub.wR.sup.D4a. In certain embodiments, w is 1. In certain embodiments, w is 2. In certain embodiments, R.sup.D4 is OMs. In certain embodiments, R.sup.D4 is OTf. In certain embodiments, R.sup.D4 is OTs. In certain embodiments, R.sup.D4 is OBs. In certain embodiments, R.sup.D4 is 2-nitrobenzenesulfonyloxy. In certain embodiments, R.sup.D4 is OR.sup.D4a. In certain embodiments, R.sup.D4 is OMe. In certain embodiments, R.sup.D4 is OCF.sub.3. In certain embodiments, R.sup.D4 is OPh. In certain embodiments, R.sup.D4 is OC(O)R.sup.D4a. In certain embodiments, R.sup.D4 is OC(O)Me. In certain embodiments, R.sup.D4 is OC(O)CF.sub.3. In certain embodiments, R.sup.D4 is OC(O)Ph. In certain embodiments, R.sup.D4 is OC(O)Cl. In certain embodiments, R.sup.D4 is OC(O)OR.sup.D4a. In certain embodiments, R.sup.D4 is OC(O)OMe. In certain embodiments, R.sup.D4 is OC(O)O(t-Bu).

(543) In certain embodiments, R.sup.D4a is substituted alkyl. In certain embodiments, R.sup.D4a is unsubstituted alkyl. In certain embodiments, R.sup.D4a is C.sub.1-6 alkyl. In certain embodiments, R.sup.D4a is methyl. In certain embodiments, R.sup.D4a is ethyl. In certain embodiments, R.sup.D4a is propyl. In certain embodiments, R.sup.D4a is butyl. In certain embodiments, R.sup.D4a is substituted alkenyl. In certain embodiments, R.sup.D4a is unsubstituted alkenyl. In certain embodiments, R.sup.D4a is vinyl. In certain embodiments, R.sup.D4a is substituted alkynyl. In certain embodiments, R.sup.D4a is unsubstituted alkynyl. In certain embodiments, R.sup.D4a is ethynyl. In certain embodiments, R.sup.D4a is substituted carbocyclyl. In certain embodiments, R.sup.D4a is unsubstituted carbocyclyl. In certain embodiments, R.sup.D4a is substituted heterocyclyl. In certain embodiments, R.sup.D4a is unsubstituted heterocyclyl. In certain embodiments, R.sup.D4a is substituted aryl. In certain embodiments, R.sup.D4a is unsubstituted aryl. In certain embodiments, R.sup.D4a is substituted phenyl. In certain embodiments, R.sup.D4a is unsubstituted phenyl. In certain embodiments, R.sup.D4a is substituted heteroaryl. In certain embodiments, R.sup.D4a is unsubstituted heteroaryl. In certain embodiments, R.sup.D4a is substituted pyridyl. In certain embodiments, R.sup.D4a is unsubstituted pyridyl.

(544) In compounds of Formula (II), R.sup.D may include a substituent R.sup.D5. In certain embodiments, R.sup.D5 is H. In certain embodiments, R.sup.D5 is substituted alkyl. In certain embodiments, R.sup.D5 is unsubstituted alkyl. In certain embodiments, R.sup.D5 is C.sub.1-6 alkyl. In certain embodiments, R.sup.D5 is methyl. In certain embodiments, R.sup.D5 is ethyl. In certain embodiments, R.sup.D5 is propyl. In certain embodiments, R.sup.D5 is butyl. In certain embodiments, R.sup.D5 is a nitrogen protecting group. In certain embodiments, R.sup.D5 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.

(545) In certain embodiments, R.sup.D1 and R.sup.D2 are each hydrogen. In certain embodiments, R.sup.D1 and R.sup.D3 are each hydrogen. In certain embodiments, R.sup.D2 and R.sup.D3 are each hydrogen. In certain embodiments, R.sup.D1, R.sup.D2, and R.sup.D3 are each hydrogen. In certain embodiments, R.sup.D1, R.sup.D2, and R.sup.D3, and R.sup.D5 are each hydrogen.

(546) In certain embodiments, A is 1. In certain embodiments, A is 2.

(547) In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, Z is 3. In certain embodiments, z is 4. In certain embodiments, z is 5. In certain embodiments, z is 6.

(548) In certain embodiments, Y.sup.Z is O. In certain embodiments, Y.sup.Z is O. In certain embodiments, Y.sup.Z is S. In certain embodiments, Y.sup.Z is S. In certain embodiments, Y.sup.Z is NR.sup.D6, wherein R.sup.D6 is hydrogen, C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, Y.sup.Z is NH. In certain embodiments, Y.sup.Z is NCH.sub.3. In certain embodiments, Y.sup.Z is N(BOC). In certain embodiments, Y.sup.Z is N(Fmoc)-. In certain embodiments, Y.sup.Z is N(Cbz)-. In certain embodiments, Y.sup.Z is N(Bn)-. In certain embodiments, Y.sup.Z is NR.sup.D6, wherein R.sup.D6 is hydrogen, C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, Y.sup.Z is NH. In certain embodiments, Y.sup.Z is NCH.sub.3. In certain embodiments, Y.sup.Z is NTs. In certain embodiments, Y.sup.Z is NBn. In certain embodiments, Y.sup.Z is NCH(Ph).sub.2.

(549) In certain embodiments, R.sup.D is of the formula:

(550) ##STR00407##
In certain embodiments, R.sup.D is of the formula:

(551) ##STR00408##
In certain embodiments, R.sup.D is of the formula:

(552) ##STR00409##
In certain embodiments, R.sup.D is of the formula:

(553) ##STR00410##
In certain embodiments, R.sup.D is of the formula:

(554) ##STR00411##
In certain embodiments, R.sup.D is of the formula:

(555) ##STR00412##
In certain embodiments, R.sup.D is of the formula:

(556) ##STR00413##
In certain embodiments, R.sup.D is of the formula:

(557) ##STR00414##
In certain embodiments, R.sup.D is of the formula:

(558) ##STR00415##
In certain embodiments, R.sup.D is of the formula:

(559) ##STR00416##
In certain embodiments, R.sup.D is of the formula:

(560) ##STR00417##
In certain embodiments, R.sup.D is of the formula:

(561) ##STR00418##
In certain embodiments, R.sup.D is of the formula:

(562) ##STR00419##
In certain embodiments, R.sup.D is of the formula:

(563) ##STR00420##
In certain embodiments, R.sup.D is of the formula:

(564) ##STR00421##
In certain embodiments, R.sup.D is of the formula:

(565) ##STR00422##
In certain embodiments, R.sup.D is of the formula:

(566) ##STR00423##
In certain embodiments, R.sup.D is of the formula:

(567) ##STR00424##
In certain embodiments, R.sup.D is of the formula:

(568) ##STR00425##
In certain embodiments, R.sup.D is of the formula:

(569) ##STR00426##
In certain embodiments, R.sup.D is of the formula:

(570) ##STR00427##
In certain embodiments, R.sup.D is of the formula:

(571) ##STR00428##
In certain embodiments, R.sup.D is of the formula:

(572) ##STR00429##
In certain embodiments, R.sup.D is of the formula:

(573) ##STR00430##
In certain embodiments, R.sup.D is of the formula:

(574) ##STR00431##
In certain embodiments, R.sup.D is of the formula:

(575) ##STR00432##

(576) Compounds of Formula (II) or (V) include an aryl Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, k is 0. In certain embodiments, Ring A is of the formula:

(577) ##STR00433##
In certain embodiments, Ring A is of the formula:

(578) ##STR00434##
In certain embodiments, k is 1. In certain embodiments, Ring A is of the formula:

(579) ##STR00435##
In certain embodiments, Ring A is of the formula:

(580) ##STR00436##
In certain embodiments, Ring A is of the formula:

(581) ##STR00437##
In certain embodiments, Ring A is of the formula:

(582) ##STR00438##
In certain embodiments, Ring A is of the formula:

(583) ##STR00439##
In certain embodiments, Ring A is of the formula:

(584) ##STR00440##
In certain embodiments, k is 2. In certain embodiments, Ring A is of the formula:

(585) ##STR00441##
In certain embodiments, Ring A is of the formula:

(586) ##STR00442##
In certain embodiments, Ring A is of the formula:

(587) ##STR00443##
In certain embodiments, Ring A is of the formula:

(588) ##STR00444##
In certain embodiments, Ring A is of the formula:

(589) ##STR00445##
In certain embodiments, Ring A is of the formula:

(590) ##STR00446##
In certain embodiments, Ring A is of the formula:

(591) ##STR00447##
In certain embodiments, Ring A is of the formula:

(592) ##STR00448##
In certain embodiments, Ring A is of the formula:

(593) ##STR00449##
In certain embodiments, Ring A is of the formula:

(594) ##STR00450##
In certain embodiments, k is 3. In certain embodiments, Ring A is of the formula:

(595) ##STR00451##
In certain embodiments, Ring A is of the formula:

(596) ##STR00452##
In certain embodiments, Ring A is of the formula:

(597) ##STR00453##
In certain embodiments, Ring A is of the formula:

(598) ##STR00454##
In certain embodiments, Ring A is of the formula:

(599) ##STR00455##
In certain embodiments, k is 4. In certain embodiments, Ring A is of the formula:

(600) ##STR00456##
In certain embodiments, Ring A is of the formula:

(601) ##STR00457##

(602) Compounds of Formula (II) or (V) include an aryl Ring A optionally substituted with one or more R.sup.A groups. In certain embodiments, X, Y, and Z are bonds, and Cy is hydrogen. In certain embodiments, k is 0. In certain embodiments, Ring A is of the formula:

(603) ##STR00458##
In certain embodiments, k is 1. In certain embodiments, Ring A is of the formula:

(604) ##STR00459##
In certain embodiments, Ring A is of the formula:

(605) ##STR00460##
In certain embodiments, Ring A is of the formula:

(606) ##STR00461##
In certain embodiments, k is 2. In certain embodiments, Ring A is of the formula:

(607) ##STR00462##
In certain embodiments, Ring A is of the formula:

(608) ##STR00463##
In certain embodiments, Ring A is of the formula:

(609) ##STR00464##
In certain embodiments, Ring A is of the formula:

(610) ##STR00465##
In certain embodiments, Ring A is of the formula:

(611) ##STR00466##
In certain embodiments, Ring A is of the formula:

(612) ##STR00467##
In certain embodiments, Ring A is of the formula:

(613) ##STR00468##
In certain embodiments, Ring A is of the formula:

(614) ##STR00469##

(615) In compounds of Formula (II) or (V), Ring A may be substituted with one or more R.sup.A groups. In certain embodiments, at least one R.sup.A is H. In certain embodiments, at least two R.sup.A groups are H. In certain embodiments, at least three R.sup.A groups are H. In certain embodiments, at least four R.sup.A groups are H. In certain embodiments, at least one R.sup.A is halogen. In certain embodiments, at least one R.sup.A is F. In certain embodiments, at least one R.sup.A is Cl. In certain embodiments, at least one R.sup.A is Br. In certain embodiments, at least one R.sup.A is I (iodine). In certain embodiments, at least one R.sup.A is substituted acyl. In certain embodiments, at least one R.sup.A is C(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.A is C(O)NHR.sup.A1. In certain embodiments, at least one R.sup.A is C(O)NH(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.A is C(O)NHMe. In certain embodiments, at least one R.sup.A is C(O)NH.sub.2. In certain embodiments, at least one R.sup.A is unsubstituted acyl. In certain embodiments, at least one R.sup.A is acetyl. In certain embodiments, at least one R.sup.A is substituted alkyl. In certain embodiments, at least one R.sup.A is substituted methyl. In certain embodiments, at least one R.sup.A is unsubstituted alkyl. In certain embodiments, at least one R.sup.A is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.A is methyl. In certain embodiments, at least one R.sup.A is ethyl. In certain embodiments, at least one R.sup.A is propyl. In certain embodiments, at least one R.sup.A is butyl. In certain embodiments, at least one R.sup.A is substituted alkenyl. In certain embodiments, at least one R.sup.A is unsubstituted alkenyl. In certain embodiments, at least one R.sup.A is substituted alkynyl. In certain embodiments, at least one R.sup.A is unsubstituted alkynyl. In certain embodiments, at least one R.sup.A is substituted carbocyclyl. In certain embodiments, at least one R.sup.A is unsubstituted carbocyclyl. In certain embodiments, at least one R.sup.A is substituted heterocyclyl. In certain embodiments, at least one R.sup.A is unsubstituted heterocyclyl. In certain embodiments, at least one R.sup.A is

(616) ##STR00470##
In certain embodiments, at least one R.sup.A is substituted aryl. In certain embodiments, at least one R.sup.A is unsubstituted aryl. In certain embodiments, at least one R.sup.A is substituted phenyl. In certain embodiments, at least one R.sup.A is unsubstituted phenyl. In certain embodiments, at least one R.sup.A is substituted heteroaryl. In certain embodiments, at least one R.sup.A is unsubstituted heteroaryl. In certain embodiments, at least one R.sup.A is substituted pyridyl. In certain embodiments, at least one R.sup.A is unsubstituted pyridyl. In certain embodiments, at least one R.sup.A is OR.sup.A1. In certain embodiments, at least one R.sup.A is O(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.A is OMe. In certain embodiments, at least one R.sup.A is OH. In certain embodiments, at least one R.sup.A is N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.A is NH.sub.2. In certain embodiments, at least one R.sup.A is SR.sup.A1. In certain embodiments, at least one R.sup.A is SH. In certain embodiments, at least one R.sup.A is NR.sup.A1C(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.A is NHC(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.A is NHC(O)NHR.sup.A1. In certain embodiments, at least one R.sup.A is NHC(O)NH(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.A is NHC(O)NHMe. In certain embodiments, at least one R.sup.A is NHC(O)NH.sub.2. In certain embodiments, at least one R.sup.A is NR.sup.A1C(O)NHR.sup.A1. In certain embodiments, at least one R.sup.A is NR.sup.A1C(O)NH.sub.2. In certain embodiments, at least one R.sup.A is NR.sup.A1S(O).sub.2R.sup.A1. In certain embodiments, at least one R.sup.A is NHS(O).sub.2R.sup.A1. In certain embodiments, at least one R.sup.A is NHS(O).sub.2(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.A is NHS(O).sub.2Me. In certain embodiments, at least one R.sup.A is S(O).sub.2N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.A is S(O).sub.2N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.A is S(O).sub.2N(C.sub.1-6 alkyl).sub.2. In certain embodiments, at least one R.sup.A is S(O).sub.2NH(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.A is S(O).sub.2NH(t-Bu). In certain embodiments, at least one R.sup.A is S(O).sub.2NH.sub.2.

(617) In compounds of Formula (II) or (V), Ring C may be substituted with one or more R.sup.B groups. In certain embodiments, at least one R.sup.B is H. In certain embodiments, at least two R.sup.B groups are H. In certain embodiments, at least three R.sup.B groups are H. In certain embodiments, at least four R.sup.B groups are H. In certain embodiments, at least one R.sup.B is halogen. In certain embodiments, at least one R.sup.B is F. In certain embodiments, at least one R.sup.B is Cl. In certain embodiments, at least one R.sup.B is Br. In certain embodiments, at least one R.sup.B is I (iodine). In certain embodiments, at least one R.sup.B is substituted acyl. In certain embodiments, at least one R.sup.B is C(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.B is C(O)NHR.sup.A1. In certain embodiments, at least one R.sup.B is C(O)NH(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.B is C(O)NHMe. In certain embodiments, at least one R.sup.B is C(O)NH.sub.2. In certain embodiments, at least one R.sup.B is unsubstituted acyl. In certain embodiments, at least one R.sup.B is acetyl. In certain embodiments, at least one R.sup.B is substituted alkyl. In certain embodiments, at least one R.sup.B is substituted methyl. In certain embodiments, at least one R.sup.B is unsubstituted alkyl. In certain embodiments, at least one R.sup.B is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.B is methyl. In certain embodiments, at least one R.sup.B is ethyl. In certain embodiments, at least one R.sup.B is propyl. In certain embodiments, at least one R.sup.B is butyl. In certain embodiments, at least one R.sup.B is CF.sub.3. In certain embodiments, at least one R.sup.B is substituted alkenyl. In certain embodiments, at least one R.sup.B is unsubstituted alkenyl. In certain embodiments, at least one R.sup.B is substituted alkynyl. In certain embodiments, at least one R.sup.B is unsubstituted alkynyl. In certain embodiments, at least one R.sup.B is substituted carbocyclyl. In certain embodiments, at least one R.sup.B is unsubstituted carbocyclyl. In certain embodiments, at least one R.sup.B is substituted heterocyclyl. In certain embodiments, at least one R.sup.B is unsubstituted heterocyclyl. In certain embodiments, at least one R.sup.B is substituted aryl. In certain embodiments, at least one R.sup.B is unsubstituted aryl. In certain embodiments, at least one R.sup.B is substituted phenyl. In certain embodiments, at least one R.sup.B is unsubstituted phenyl. In certain embodiments, at least one R.sup.B is substituted heteroaryl. In certain embodiments, at least one R.sup.B is unsubstituted heteroaryl. In certain embodiments, at least one R.sup.B is substituted pyridyl. In certain embodiments, at least one R.sup.B is unsubstituted pyridyl. In certain embodiments, at least one R.sup.B is O.sup.A1. In certain embodiments, at least one R.sup.B is O(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.B is OMe. In certain embodiments, at least one R.sup.B is OH. In certain embodiments, at least one R.sup.B is N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.B is NH.sub.2. In certain embodiments, at least one R.sup.B is SR.sup.A1. In certain embodiments, at least one R.sup.B is SH. In certain embodiments, at least one R.sup.B is NR.sup.A1C(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.B is NHC(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.B is NHC(O)NHR.sup.A1. In certain embodiments, at least one R.sup.B is NHC(O)NH(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.B is NHC(O)NHMe. In certain embodiments, at least one R.sup.B is NHC(O)NH.sub.2. In certain embodiments, at least one R.sup.B is NR.sup.A1C(O)NHR.sup.A1. In certain embodiments, at least one R.sup.B is NR.sup.A1C(O)NH.sub.2. In certain embodiments, at least one R.sup.B is NR.sup.A1S(O).sub.2R.sup.A1. In certain embodiments, at least one R.sup.B is NHS(O).sub.2R.sup.A1. In certain embodiments, at least one R.sup.B is NHS(O).sub.2(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.B is NHS(O).sub.2Me. In certain embodiments, at least one R.sup.B is S(O).sub.2N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.B is S(O).sub.2N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.B is S(O).sub.2N(C.sub.1-6 alkyl).sub.2. In certain embodiments, at least one R.sup.B is S(O).sub.2NH(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.B is S(O).sub.2NH(t-Bu). In certain embodiments, at least one R.sup.B is S(O).sub.2NH.sub.2. In certain embodiments, at least one R.sup.B is substituted imidazole. In certain embodiments, at least one R.sup.B is substituted piperidine. In certain embodiments, at least one R.sup.B substituted piperizine. In certain embodiments, at least one R.sup.B substituted pyrrolidine. In certain embodiments, at least one R.sup.B is substituted morpholine. In certain embodiments, at least one R.sup.B is substituted diazepane. In certain embodiments, at least one R.sup.B is

(618) ##STR00471##
In certain embodiments, at least one R.sup.B is

(619) ##STR00472##
In certain embodiments, at least one R.sup.B is

(620) ##STR00473##
In certain embodiments, at least one R.sup.B is

(621) ##STR00474##
In certain embodiments, at least one R.sup.B is

(622) ##STR00475##
In certain embodiments, at least one R.sup.B is

(623) ##STR00476##
In certain embodiments, at least one R.sup.B is

(624) ##STR00477##
In certain embodiments, at least one R.sup.B is

(625) ##STR00478##
In certain embodiments, at least one R.sup.B is

(626) ##STR00479##
In certain embodiments, at least one R.sup.B is

(627) ##STR00480##
In certain embodiments, at least one R.sup.B is

(628) ##STR00481##
In certain embodiments, at least one R.sup.B is

(629) ##STR00482##
In certain embodiments, at least one R.sup.B is

(630) ##STR00483##
In certain embodiments, at least one R.sup.B is

(631) ##STR00484##
In certain embodiments, at least one R.sup.B is

(632) ##STR00485##
In certain embodiments, at least one R.sup.B is

(633) ##STR00486##
In certain embodiments, at least one R.sup.B is

(634) ##STR00487##
In certain embodiments, at least one R.sup.B is

(635) ##STR00488##
In certain embodiments, at least one R.sup.B is

(636) ##STR00489##
In certain embodiments, at least one R.sup.B is

(637) ##STR00490##
In certain embodiments, at least one R.sup.B is

(638) ##STR00491##
In certain embodiments, at least one R.sup.B is

(639) ##STR00492##
In certain embodiments, at least one R.sup.B is

(640) ##STR00493##
In certain embodiments, at least one R.sup.B is

(641) ##STR00494##
In certain embodiments, at least one R.sup.B is

(642) ##STR00495##
In certain embodiments, at least one R.sup.B is

(643) ##STR00496##
In certain embodiments, at least one R.sup.B is

(644) ##STR00497##
In certain embodiments, at least one R.sup.B is

(645) ##STR00498##
In certain embodiments, at least one R.sup.B is

(646) ##STR00499##
In certain embodiments at least one R.sup.B is

(647) ##STR00500##
In certain embodiments, at least one R.sup.B is

(648) ##STR00501##
In certain embodiments, at least one R.sup.B is

(649) ##STR00502##
In certain embodiments, at least one R.sup.B is

(650) ##STR00503##
In certain embodiments, at least one R.sup.B is

(651) ##STR00504##
In certain embodiments, at least one R.sup.B is

(652) ##STR00505##
In certain embodiments, at least one R.sup.B is

(653) ##STR00506##
In certain embodiments, at least one R.sup.B is

(654) ##STR00507##
In certain embodiments, at least one R.sup.B is

(655) ##STR00508##
In certain embodiments, at least one R.sup.B is

(656) ##STR00509##
In certain embodiments, at least one R.sup.B is

(657) ##STR00510##
In certain embodiments, at least one R.sup.B is

(658) ##STR00511##

(659) In certain embodiments, two R.sup.B groups are joined to form a 1,3 dioxolane. In certain embodiments, two R.sup.B groups are joined to form a 1,3 dioxolane which is fused to aryl Ring C, together comprising an optionally substituted benzodioxolane. In certain embodiments, two R.sup.B groups are joined to form a 1,2,3-thiadiazole. In certain embodiments, two R.sup.B groups are joined to form a 1,2,3-thiadiazole which is fused to aryl Ring C, together comprising an optionally substituted. benzo[d][1,2,3]thiadiazole.

(660) In certain embodiments, at least one R.sup.A1 is H. In certain embodiments, at least one R.sup.A1 is substituted acyl. In certain embodiments, at least one R.sup.A1 is unsubstituted acyl. In certain embodiments, at least one R.sup.A1 is acetyl. In certain embodiments, at least one R.sup.A1 is substituted alkyl. In certain embodiments, at least one R.sup.A1 is unsubstituted alkyl. In certain embodiments, at least one R.sup.A1 is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.A1 is methyl. In certain embodiments, at least one R.sup.A1 is ethyl. In certain embodiments, at least one R.sup.A1 is propyl. In certain embodiments, at least one R.sup.A1 is butyl. In certain embodiments, at least one R.sup.A1 is substituted alkenyl. In certain embodiments, at least one R.sup.A1 is unsubstituted alkenyl. In certain embodiments, at least one R.sup.A1 is substituted alkynyl. In certain embodiments, at least one R.sup.A1 is unsubstituted alkynyl. In certain embodiments, at least one R.sup.A1 is substituted carbocyclyl. In certain embodiments, at least one R.sup.A1 is unsubstituted carbocyclyl. In certain embodiments, at least one R.sup.A1 is substituted heterocyclyl. In certain embodiments, at least one R.sup.A1 is unsubstituted heterocyclyl. In certain embodiments, at least one R.sup.A1 is substituted aryl. In certain embodiments, at least one R.sup.A1 is unsubstituted aryl. In certain embodiments, at least one R.sup.A1 is substituted phenyl. In certain embodiments, at least one R.sup.A1 is unsubstituted phenyl. In certain embodiments, at least one R.sup.A1 is substituted heteroaryl. In certain embodiments, at least one R.sup.A1 is unsubstituted heteroaryl. In certain embodiments, at least one R.sup.A1 is substituted pyridyl. In certain embodiments, at least one R.sup.A1 is unsubstituted pyridyl. In certain embodiments, at least one R.sup.A1 is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R.sup.A1 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R.sup.A1 is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.A1 is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R.sup.A1 is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R.sup.A1 is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom.

(661) In compounds of Formula (II) or (V), two R.sup.A1 groups may be joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring. In certain embodiments, two R.sup.A1 groups are joined to form a substituted carbocyclic ring. In certain embodiments, two R.sup.A1 groups are joined to form an unsubstituted carbocyclic ring. In certain embodiments, two R.sup.A1 groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R.sup.A1 groups are joined to form an unsubstituted heterocyclic ring. In certain embodiments, two R.sup.A1 groups are joined to form a substituted aryl ring. In certain embodiments, two R.sup.A1 groups are joined to form an unsubstituted aryl ring. In certain embodiments, two R.sup.A1 groups are joined to form a substituted phenyl ring. In certain embodiments, two R.sup.A1 groups are joined to form an unsubstituted phenyl ring. In certain embodiments, two R.sup.A1 groups are joined to form a substituted heteroaryl ring. In certain embodiments, two R.sup.A1 groups are joined to form an unsubstituted heteroaryl ring.

(662) In certain embodiments, R.sup.A is OR.sup.A1 and k is 1. In certain embodiments, R.sup.A is O(C.sub.1-6 alkyl) and k is 1. In certain embodiments, R.sup.A is OMe and k is 1. In certain embodiments, R.sup.A is OH and k is 1.

(663) In certain embodiments, R.sup.A is substituted C.sub.1-6 alkyl; and k is 1. In certain embodiments, R.sup.A is unsubstituted C.sub.1-6 alkyl; and k is 1. In certain embodiments, R.sup.A is methyl; and k is 1. In certain embodiments, R.sup.A is CF.sub.3; and k is 1. In certain embodiments, R.sup.A, is ethyl; and k is 1. In certain embodiments, R.sup.A is propyl; and k is 1. In certain embodiments, R.sup.A is butyl; and k is 1. In certain embodiments, R.sup.A is propyl; and k is 1. In certain embodiments, R.sup.A is butyl; and k is 1.

(664) In certain embodiments, R.sup.A is halogen; and k is 1. In certain embodiments, R.sup.A is F; and k is 1. In certain embodiments, R.sup.A is Cl; and k is 1. In certain embodiments, R.sup.A is Br; and k is 1. In certain embodiments, R.sup.A is I (iodine); and k is 1.

(665) In certain embodiments, one instance of R.sup.A is halogen, another instance of R.sup.A is substituted C.sub.1-6 alkyl; and k is 2. In certain embodiments, one instance of R.sup.A is F, another instance of R.sup.A is substituted C.sub.1-6 alkyl; and k is 2. In certain embodiments, one instance of R.sup.A is Cl, another instance of R.sup.A is substituted C.sub.1-6 alkyl; and k is 2. In certain embodiments, one instance of R.sup.A is halogen, another instance of R.sup.A is unsubstituted C.sub.1-6 alkyl; and k is 2. In certain embodiments, one instance of R.sup.A is F, another instance of R.sup.A is unsubstituted C.sub.1-6 alkyl; and k is 2. In certain embodiments, one instance of R.sup.A is Cl, another instance of R.sup.A is unsubstituted C.sub.1-6 alkyl; and k is 2. In certain embodiments, one instance of R.sup.A is halogen, another instance of R.sup.A is methyl; and k is 2. In certain embodiments, one instance of R.sup.A is F, another instance of R.sup.A is methyl; and k is 2. In certain embodiments, one instance of R.sup.A is Cl, another instance of R.sup.A is methyl; and k is 2. In certain embodiments, one instance of R.sup.A is halogen, another instance of R.sup.A is CF.sub.3; and k is 2. In certain embodiments, one instance of R.sup.A is F, another instance of R.sup.A is CF.sub.3; and k is 2. In certain embodiments, one instance of R.sup.A is Cl, another instance of R.sup.A is CF.sub.3; and k is 2.

(666) In compounds of Formula (II) or (V), linker X, Y, and Z are divalent linker moieties. In certain embodiments, X is a bond. In certain embodiments, X is a single bond. In certain embodiments, X is CH.sub.2. In certain embodiments, X is CHR.sup.A. In certain embodiments, X is CH. In certain embodiments, X is C(R.sup.A).sub.2. In certain embodiments, X is C. In certain embodiments, X is N. In certain embodiments, X is NR.sup.A. In certain embodiments, X is O. In certain embodiments, X is CO. In certain embodiments, X is O. In certain embodiments, X is S. In certain embodiments, X may optionally form a 5 to 8 membered ring with R.sup.A or R.sup.B. In certain embodiments, Y is a bond. In certain embodiments, Y is a single bond. In certain embodiments, Y is CH.sub.2. In certain embodiments, Y is CHR.sup.A. In certain embodiments, Y is CH. In certain embodiments, Y is C(R.sup.A).sub.2. In certain embodiments, Y is C. In certain embodiments, Y is N. In certain embodiments, Y is NR.sup.A. In certain embodiments, Y is O. In certain embodiments, Y is CO. In certain embodiments, Y is S. In certain embodiments, Y may optionally form a 5 to 8 membered ring with R.sup.A or R.sup.B. In certain embodiments, Z is a bond. In certain embodiments, Z is a single bond. In certain embodiments, Z is CH.sub.2. In certain embodiments, Z is CHR.sup.A. In certain embodiments, Z is CH. In certain embodiments, Z is C(R.sup.A).sub.2. In certain embodiments, Z is C. In certain embodiments, Z is N. In certain embodiments, Z is NR.sup.A. In certain embodiments, Z is O. In certain embodiments, Z is CO. In certain embodiments, Z is S. In certain embodiments, Z may optionally form a 5 to 8 membered ring with R.sup.A or R.sup.B.

(667) In compounds of Formula (II) or (V), linker X, Y, and Z can be taken together to represent specific linking groups. In certain embodiments, X, Y, and Z together represent

(668) ##STR00512##
In certain embodiments, X, Y, and Z together represent

(669) ##STR00513##
In certain embodiments, X, Y, and Z together represent

(670) ##STR00514##
In certain embodiments, X, Y, and Z together represent

(671) ##STR00515##
In certain embodiments, X, Y, and Z together represent

(672) ##STR00516##
In certain embodiments, X, Y, and Z together represent

(673) ##STR00517##
In certain embodiments, X, Y, and Z together represent

(674) ##STR00518##
In certain embodiments, X, Y, and Z together represent

(675) ##STR00519##
In certain embodiments, X, Y, and Z together represent

(676) ##STR00520##
In certain embodiments, X, Y, and Z together represent

(677) ##STR00521##
In certain embodiments, X, Y, and Z together represent

(678) ##STR00522##
In certain embodiments, X, Y, and Z together represent

(679) ##STR00523##
In certain embodiments, X, Y, and Z together represent

(680) ##STR00524##
In certain embodiments, X, Y, and Z together represent

(681) ##STR00525##
In certain embodiments, X, Y, and Z together represent

(682) ##STR00526##
In certain embodiments, X, Y, and Z together represent

(683) ##STR00527##
In certain embodiments, X, Y, and Z together represent

(684) ##STR00528##
In certain embodiments, X, Y, and Z together represent

(685) ##STR00529##
In certain embodiments, X, Y, and Z together represent

(686) ##STR00530##
In certain embodiments, X, Y, and Z together represent

(687) ##STR00531##
In certain embodiments, X, Y, and Z together represent

(688) ##STR00532##
In certain embodiments, X, Y, and Z together represent

(689) ##STR00533##
In certain embodiments, X, Y, and Z together represent

(690) ##STR00534##
In certain embodiments, X, Y, and Z together represent

(691) ##STR00535##
In certain embodiments, X, Y, and Z together represent

(692) ##STR00536##
In certain embodiments, X, Y, and Z together represent

(693) ##STR00537##
In certain embodiments, X, Y, and Z together represent

(694) ##STR00538##
In certain embodiments, X, Y, and Z together represent

(695) ##STR00539##
In certain embodiments, X, Y, and Z together represent

(696) ##STR00540##
In certain embodiments, X, Y, and Z together represent

(697) ##STR00541##
In certain embodiments, X, Y, and Z together represent

(698) ##STR00542##
In certain embodiments, X, Y, and Z together represent

(699) ##STR00543##
In certain embodiments, X, Y, and Z together represent

(700) ##STR00544##
In certain embodiments, X, Y, and Z together represent

(701) ##STR00545##
In certain embodiments, X, Y, and Z together represent

(702) ##STR00546##
In certain embodiments, X, Y, and Z together represent

(703) ##STR00547##
In certain embodiments, X, Y, and Z together represent a single bond.

(704) In compounds of Formula (II) or (V), linker Q and U are divalent linker moieties. In certain embodiments, Q is NR.sup.A. In certain embodiments, Q is NH. In certain embodiments, Q is CO. In certain embodiments, Q is NR.sup.ACO. In certain embodiments, Q is a bond. In certain embodiments, X may optionally form a 5 to 8 membered ring with R.sup.A or R.sup.B. In certain embodiments, U is NR.sup.A. In certain embodiments, U is NH. In certain embodiments, U is CO. In certain embodiments, U is NR.sup.ACO. In certain embodiments, U is a bond. In certain embodiments, U may optionally form a 5 to 8 membered ring with R.sup.A or R.sup.B.

(705) In compounds of Formula (II) or (V), linker Q and U can be taken together to represent specific linking groups. In certain embodiments, Q and U together represent

(706) ##STR00548##
In certain embodiments, Q and U together represent

(707) ##STR00549##
In certain embodiments, Q and U together represent

(708) ##STR00550##
In certain embodiments, Q and U together represent

(709) ##STR00551##
In certain embodiments, Q and U together represent

(710) ##STR00552##
In certain embodiments, Q and U together represent

(711) ##STR00553##
In certain embodiments, Q and U together represent

(712) ##STR00554##
In certain embodiments, Q and U together represent

(713) ##STR00555##
In certain embodiments, Q and U together represent

(714) ##STR00556##
In certain embodiments, Q and U together represent

(715) ##STR00557##
In certain embodiments, Q and U together represent

(716) ##STR00558##
In certain embodiments, Q and U together represent

(717) ##STR00559##

(718) Cy of Formula (II) or (V) may be an optionally substituted aryl ring. In certain embodiments, Ring Cy is a substituted aryl ring. In certain embodiments, Cy is an unsubstituted aryl ring. In certain embodiments, Cy is a monocyclic aryl ring. In certain embodiments, Cy is substituted phenyl. In certain embodiments, Cy is unsubstituted phenyl. In certain embodiments, Cy is a bicyclic aryl ring. In certain embodiments, Cy is substituted naphthyl. In certain embodiments, Cy is unsubstituted naphthyl. In certain embodiments, Cy is an optionally substituted aryl ring fused with one or more optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl groups wherein the point of attachment is on the aryl ring.

(719) Cy of Formula (II) or (V) may also be an optionally substituted heteroaryl ring. In certain embodiments, Cy is a substituted heteroaryl ring. In certain embodiments, Cy is an unsubstituted heteroaryl ring. In certain embodiments, Cy is a monocyclic heteroaryl ring. In certain embodiments, Cy is a 5-membered monocyclic heteroaryl ring. In certain embodiments, Cy is a 5-membered monocyclic heteroaryl ring with one heteroatom selected from the group consisting of S, N, and O. In certain embodiments, Cy is a 5-membered monocyclic heteroaryl ring with two heteroatoms selected from the group consisting of S, N, and O. In certain embodiments, Cy is a 5-membered monocyclic heteroaryl ring with three heteroatoms selected from the group consisting of S, N, and O. In certain embodiments, Cy is substituted pyrrolyl. In certain embodiments, Cy is unsubstituted pyrrolyl. In certain embodiments, Cy is substituted furanyl. In certain embodiments, Cy is unsubstituted furanyl. In certain embodiments, Cy is substituted thienyl. In certain embodiments, Cy is unsubstituted thienyl. In certain embodiments, Cy is substituted pyrazolyl. In certain embodiments, Cy is unsubstituted pyrazolyl. In certain embodiments, Cy is substituted imidazolyl. In certain embodiments, Cy is unsubstituted imidazolyl. In certain embodiments, Cy is substituted oxazolyl. In certain embodiments, Cy is unsubstituted oxazolyl. In certain embodiments, Cy is substituted isoxazolyl. In certain embodiments, Cy is unsubstituted isoxazolyl. In certain embodiments, Cy is substituted thiazolyl. In certain embodiments, Cy is unsubstituted thiazolyl. In certain embodiments, Cy is substituted isothiazolyl. In certain embodiments, Cy is unsubstituted isothiazolyl. In certain embodiments, Cy is substituted triazolyl. In certain embodiments, Cy is unsubstituted triazolyl. In certain embodiments, Cy is substituted oxadiazolyl. In certain embodiments, Cy is unsubstituted oxadiazolyl. In certain embodiments, Cy is substituted thiadiazolyl. In certain embodiments, Cy is unsubstituted thiadiazolyl. In certain embodiments, Cy is a 6-membered monocyclic heteroaryl ring. In certain embodiments, Cy is a 6-membered monocyclic heteroaryl ring with one heteroatom selected from the group consisting of S, N, and O. In certain embodiments, Cy is a 6-membered monocyclic heteroaryl ring with two heteroatoms selected from the group consisting of S, N, and O. In certain embodiments, Cy is a 6-membered monocyclic heteroaryl ring with three heteroatoms selected from the group consisting of S, N, and O. In certain embodiments, Cy is substituted pyridyl. In certain embodiments, Cy is unsubstituted pyridyl. In certain embodiments, Cy is substituted pyridazinyl. In certain embodiments, Cy is unsubstituted pyridazinyl. In certain embodiments, Cy is substituted pyrimidinyl. In certain embodiments, Cy is unsubstituted pyrimidinyl. In certain embodiments, Cy is substituted pyrazinyl. In certain embodiments, Cy is unsubstituted pyrazinyl. In certain embodiments, Cy is substituted triazinyl. In certain embodiments, Cy is unsubstituted triazinyl. In certain embodiments, Cy is an optionally substituted heteroaryl ring fused with one or more optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl groups wherein the point of attachment is on any one of the heteroaryl ring, or carbocyclic, heterocyclic, aryl, or heteroaryl groups, as valency permits. In certain embodiments, Cy is a bicyclic heteroaryl ring. In certain embodiments, Cy is an optionally substituted heteroaryl ring fused with an optionally substituted phenyl ring. In certain embodiments, Cy is substituted indolyl. In certain embodiments, Cy is unsubstituted indolyl. In certain embodiments, Cy is substituted isoindolyl. In certain embodiments, Cy is unsubstituted isoindolyl. In certain embodiments, Cy is substituted indazolyl. In certain embodiments, Cy is unsubstituted indazolyl. In certain embodiments, Cy is substituted benzothienyl. In certain embodiments, Cy is unsubstituted benzothienyl. In certain embodiments, Cy is substituted isobenzothienyl. In certain embodiments, Cy is unsubstituted isobenzothienyl. In certain embodiments, Cy is substituted benzofuranyl. In certain embodiments, Cy is unsubstituted benzofuranyl. In certain embodiments, Cy is substituted benzoisofuranyl. In certain embodiments, Cy is unsubstituted benzoisofuranyl. In certain embodiments, Cy is substituted benzimidazolyl. In certain embodiments, Cy is unsubstituted benzimidazolyl. In certain embodiments, Cy is substituted benzoxazolyl. In certain embodiments, Cy is unsubstituted benzoxazolyl. In certain embodiments, Cy is substituted benzisoxazolyl. In certain embodiments, Cy is unsubstituted benzisoxazolyl. In certain embodiments, Cy is substituted benzothiazolyl. In certain embodiments, Cy is unsubstituted benzothiazolyl. In certain embodiments, Cy is substituted benzisothiazolyl. In certain embodiments, Cy is unsubstituted benzisothiazolyl. In certain embodiments, Cy is substituted benzotriazolyl. In certain embodiments, Cy is unsubstituted benzotriazolyl. In certain embodiments, Cy is substituted benzoxadiazolyl. In certain embodiments, Cy is unsubstituted benzoxadiazolyl. In certain embodiments, Cy is substituted quinolinyl. In certain embodiments, Cy is unsubstituted quinolinyl. In certain embodiments, Cy is substituted isoquinolinyl. In certain embodiments, Cy is unsubstituted isoquinolinyl. In certain embodiments, Cy is substituted cinnolinyl. In certain embodiments, Cy is unsubstituted cinnolinyl. In certain embodiments, Cy is substituted quinoxalinyl. In certain embodiments, Cy is unsubstituted quinoxalinyl. In certain embodiments, Cy is substituted phthalazinyl. In certain embodiments, Cy is unsubstituted phthalazinyl. In certain embodiments, Cy is substituted quinazolinyl. In certain embodiments, Cy is unsubstituted quinazolinyl. In certain embodiments, Cy is

(720) ##STR00560##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(721) ##STR00561##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(722) ##STR00562##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(723) ##STR00563##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(724) ##STR00564##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(725) ##STR00565##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(726) ##STR00566##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(727) ##STR00567##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(728) ##STR00568##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(729) ##STR00569##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(730) ##STR00570##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(731) ##STR00571##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(732) ##STR00572##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(733) ##STR00573##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(734) ##STR00574##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(735) ##STR00575##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(736) ##STR00576##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(737) ##STR00577##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(738) ##STR00578##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(739) ##STR00579##
wherein X may link to any freely valent position. In certain embodiments, Cy

(740) ##STR00580##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(741) ##STR00581##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(742) ##STR00582##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(743) ##STR00583##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(744) ##STR00584##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(745) ##STR00585##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(746) ##STR00586##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(747) ##STR00587##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(748) ##STR00588##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(749) ##STR00589##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(750) ##STR00590##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(751) ##STR00591##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(752) ##STR00592##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(753) ##STR00593##
wherein X may link to any freely valent position. In certain embodiments, Cy is

(754) ##STR00594##
wherein X may link to any freely valent position.

(755) In compounds of Formula (II) or (V), Cy may be substituted with one or more R.sup.X groups. In certain embodiments, at least one R.sup.X is H. In certain embodiments, at least two R.sup.X groups are H. In certain embodiments, at least three R.sup.X groups are H. In certain embodiments, at least four R.sup.X groups are H. In certain embodiments, at least one R.sup.X is halogen. In certain embodiments, at least one R.sup.X is F. In certain embodiments, at least one R.sup.X is Cl. In certain embodiments, at least one R.sup.X is Br. In certain embodiments, at least one R.sup.X is I (iodine). In certain embodiments, at least one R.sup.X is substituted acyl. In certain embodiments, at least one R.sup.X is C(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.X is C(O)NHR.sup.A1. In certain embodiments, at least one R.sup.X is C(O)NH(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.X is C(O)NHMe. In certain embodiments, at least one R.sup.X is C(O)NH.sub.2. In certain embodiments, at least one R.sup.X is unsubstituted acyl. In certain embodiments, at least one R.sup.X is acetyl. In certain embodiments, at least one R.sup.X is substituted alkyl. In certain embodiments, at least one R.sup.X is substituted methyl. In certain embodiments, at least one R.sup.X is unsubstituted alkyl. In certain embodiments, at least one R.sup.X is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.X is methyl. In certain embodiments, at least one R.sup.X is ethyl. In certain embodiments, at least one R.sup.X is propyl. In certain embodiments, at least one R.sup.X is butyl. In certain embodiments, at least one R.sup.X is substituted alkenyl. In certain embodiments, at least one R.sup.X is unsubstituted alkenyl. In certain embodiments, at least one R.sup.X is substituted alkynyl. In certain embodiments, at least one R.sup.X is unsubstituted alkynyl. In certain embodiments, at least one R.sup.X is substituted carbocyclyl. In certain embodiments, at least one R.sup.X is unsubstituted carbocyclyl. In certain embodiments, at least one R.sup.X is substituted heterocyclyl. In certain embodiments, at least one R.sup.X is unsubstituted heterocyclyl. In certain embodiments, at least one R.sup.X is substituted aryl. In certain embodiments, at least one R.sup.X is unsubstituted aryl. In certain embodiments, at least one R.sup.X is substituted phenyl. In certain embodiments, at least one R.sup.X is unsubstituted phenyl. In certain embodiments, at least one R.sup.X is substituted heteroaryl. In certain embodiments, at least one R.sup.X is unsubstituted heteroaryl. In certain embodiments, at least one R.sup.X is substituted pyridyl. In certain embodiments, at least one R.sup.X is unsubstituted pyridyl. In certain embodiments, at least one R.sup.X is OR.sup.A1. In certain embodiments, at least one R.sup.X is O(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.X is OMe. In certain embodiments, at least one R.sup.X is OH. In certain embodiments, at least one R.sup.X is N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.X is NH.sub.2. In certain embodiments, at least one R.sup.X is SR.sup.A1. In certain embodiments, at least one R.sup.X is SH. In certain embodiments, at least one R.sup.X is NR.sup.A1C(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.X is NHC(O)N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.X is NHC(O)NHR.sup.A1. In certain embodiments, at least one R.sup.X is NHC(O)NH(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.X is NHC(O)NHMe. In certain embodiments, at least one R.sup.X is NHC(O)NH.sub.2. In certain embodiments, at least one R.sup.X is NR.sup.A1C(O)NHR.sup.A1. In certain embodiments, at least one R.sup.X is NR.sup.A1C(O)NH.sub.2. In certain embodiments, at least one R.sup.X is NR.sup.A1S(O).sub.2R.sup.A1. In certain embodiments, at least one R.sup.X is NHS(O).sub.2R.sup.A1. In certain embodiments, at least one R.sup.X is NHS(O).sub.2(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.X is NHS(O).sub.2Me. In certain embodiments, at least one R.sup.X is S(O).sub.2N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.X is S(O).sub.2N(R.sup.A1).sub.2. In certain embodiments, at least one R.sup.X is S(O).sub.2N(C.sub.1-6 alkyl).sub.2. In certain embodiments, at least one R.sup.X is S(O).sub.2NH(C.sub.1-6 alkyl). In certain embodiments, at least one R.sup.X is S(O).sub.2NH(t-Bu). In certain embodiments, at least one R.sup.X is S(O).sub.2NH.sub.2. In certain embodiments, at least one R.sup.X is

(756) ##STR00595##
In certain embodiments, at least one R.sup.X is

(757) ##STR00596##
In certain embodiments, at least one R.sup.X is

(758) ##STR00597##
In certain embodiments, at least one R.sup.X is

(759) ##STR00598##
In certain embodiments, at least one R.sup.X is

(760) ##STR00599##
In certain embodiments, at least one R.sup.X is

(761) ##STR00600##
In certain embodiments, at least one R.sup.X is

(762) ##STR00601##
In certain embodiments, at least one R.sup.X is

(763) ##STR00602##
In certain embodiments, at least one R.sup.X is

(764) ##STR00603##
In certain embodiments, at least one R.sup.X is

(765) ##STR00604##
In certain embodiments, at least one R.sup.X is

(766) ##STR00605##
In certain embodiments, at least one R.sup.X is

(767) ##STR00606##
In certain embodiments, at least one R.sup.X is

(768) ##STR00607##
In certain embodiments, at least one R.sup.X is

(769) ##STR00608##
In certain embodiments, at least one R.sup.X is

(770) ##STR00609##
In certain embodiments at least one R.sup.X is

(771) ##STR00610##
In certain embodiments, at least one R.sup.X is

(772) ##STR00611##
In certain embodiments, at least one R.sup.X is

(773) ##STR00612##
In certain embodiments, at least one R.sup.X is

(774) ##STR00613##
In certain embodiments, at least one R.sup.X is

(775) ##STR00614##
In certain embodiments, at least one R.sup.X is

(776) ##STR00615##
In certain embodiments, at least one R.sup.X is

(777) ##STR00616##
In certain embodiments, at least one R.sup.X is

(778) ##STR00617##
In certain embodiments, at least one R.sup.X is

(779) ##STR00618##
In certain embodiments, at least one R.sup.X is

(780) ##STR00619##
In certain embodiments, at least one R.sup.X is

(781) ##STR00620##
In certain embodiments, at least one R.sup.X is

(782) ##STR00621##
In certain embodiments, at least one R.sup.X is

(783) ##STR00622##
In certain embodiments, at least one R.sup.X is

(784) ##STR00623##
In certain embodiments, at least one R.sup.X is

(785) ##STR00624##
In certain embodiments, at least one R.sup.X is

(786) ##STR00625##
In certain embodiments, at least one R.sup.X is

(787) ##STR00626##
In certain embodiments, at least one R.sup.X is

(788) ##STR00627##
n certain embodiments, at least one R.sup.X is

(789) ##STR00628##
In certain embodiments, at least one R.sup.X is

(790) ##STR00629##
In certain embodiments, at least one R.sup.X is

(791) ##STR00630##
In certain embodiments, at least one R.sup.X is

(792) ##STR00631##
In certain embodiments, at least one R.sup.X is

(793) ##STR00632##
In certain embodiments, at least one R.sup.X is

(794) ##STR00633##
In certain embodiments, at least one R.sup.X is

(795) ##STR00634##
In certain embodiments, at least one R.sup.X is

(796) ##STR00635##
In certain embodiments, at least one R.sup.X is

(797) ##STR00636##
In certain embodiments, at least one R.sup.X is

(798) ##STR00637##
In certain embodiments, at least one R.sup.X is

(799) ##STR00638##
In certain embodiments, at least one R.sup.X is

(800) ##STR00639##
In certain embodiments, at least one R.sup.X is

(801) ##STR00640##
In certain embodiments, at least one R.sup.X is

(802) ##STR00641##
In certain embodiments, at least one R.sup.X is

(803) ##STR00642##
In certain embodiments, at least one R.sup.X is

(804) ##STR00643##
In certain embodiments, at least one R.sup.X is

(805) ##STR00644##
In certain embodiments, at least one R.sup.X is

(806) ##STR00645##
In certain embodiments, at least one R.sup.X is

(807) ##STR00646##
In certain embodiments, at least one R.sup.X is

(808) ##STR00647##
In certain embodiments, at least one R.sup.X is

(809) ##STR00648##
In certain embodiments, at least one R.sup.X is

(810) ##STR00649##
In certain embodiments, at least one R.sup.X is

(811) ##STR00650##
In certain embodiments, at least one R.sup.X is

(812) ##STR00651##
In certain embodiments, at least one R.sup.X is

(813) ##STR00652##
In certain embodiments, at least one R.sup.X is

(814) ##STR00653##
In certain embodiments, at least one R.sup.X is

(815) ##STR00654##
In certain embodiments, at least one R.sup.X is

(816) ##STR00655##
In certain embodiments, at least one R.sup.X is

(817) ##STR00656##
In certain embodiments, at least one R.sup.X is

(818) ##STR00657##
In certain embodiments, at least one R.sup.X is

(819) ##STR00658##

(820) In certain embodiment, a compound of the invention is a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiment, a compound of the invention is a compound of Formula (A), or a pharmaceutically acceptable salt thereof. In certain embodiment, a compound of the invention is a compound of Formula (I-11), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiment, a compound of the invention is a compound of Formula (I-11), or a pharmaceutically acceptable salt thereof. In certain embodiment, a compound of the invention is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiment, a compound of the invention is a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In certain embodiment, a compound of the invention is a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiment, a compound of the invention is a compound of Formula (V), or a pharmaceutically acceptable salt thereof.

(821) In certain embodiments, compounds of the present invention include those which: exhibit kinase inhibitory activity, exhibit the ability to inhibit transforming growth factor b-activated kinase-1 (TAK1), hemopoietic cell kinase (HCK) or both TAK1 and HCK, exhibit the ability to inhibit hematopoietic progenitor kinase 1 (HPK1, also known as mitogen-activated protein kinase kinase kinase kinase 1 or MAP4K1), exhibit the ability to inhibit Bruton's tyrosine kinase (BTK), v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (SRC) family of kinases or both BTK and SRC, exhibit cytotoxic or growth inhibitory effect on WM cell lines maintained in vitro or in animal studies using a scientifically acceptable cancer cell xenograft model; and/or exhibit a therapeutic profile (e.g., optimum safety and curative effect) that is superior to existing chemotherapeutic agents.

(822) As used herein kinase refers to a large class of enzymes which catalyze the transfer of the -phosphate from ATP to the hydroxyl group on the side chain of Ser/Thr or Tyr in proteins and peptides and are intimately involved in the control of various important cell functions, perhaps most notably: signal transduction, differentiation and proliferation. There are estimated to be about 2,000 distinct protein kinases in the human body and although each of these phosphorylates particular protein/peptide substrates, they all bind the same second substrate ATP in a highly conserved pocket. About 50% of the known oncogene products are protein tyrosine kinases PTKs and their kinase activity has been shown to lead to cell transformation.

(823) In certain embodiments, the kinase to be inhibited is involved in the myeloid differentiation primary response gene (88) (MYD88) signaling pathway. For example, the kinase is Transforming growth factor b-activated kinase-1 (TAK1) or Hemopoietic cell kinase (HCK). In certain embodiments, the compound of the invention inhibits TAK1, HCK, or both TAK1 and HCK.

(824) Myeloid differentiation primary response gene (88) (MYD88) L265P is a widely expressed somatic mutation in WM patients that supports NF-NFB signaling through stimulation of BTK, IRAK1/4, TAK1. MYD88 is an adaptor molecule for Toll-like receptors (TLR) with the exception of TLR-3 and interleukin-1 receptor (IL-1R) signaling. Following TLR or IL-1R stimulation, MYD88 is recruited to the activated receptor complex as a homodimer which then complexes with interleukin-1 receptor-associated kinase 4 (IRAK4) and activates IRAK1 and IRAK2. Tumor necrosis factor receptor associated factor 6 (TRAF6) is then activated by IRAK1 leading to NFB activation via IB phosphorylation and TAK1 activation.

(825) Transforming growth factor b-activated kinase-1 (TAK1; also known as MAP3K7) is a member of the serine/threonine protein kinase family. This kinase mediates the signaling transduction induced by TGF beta and morphogenetic protein (BMP), and controls a variety of cell functions including transcription regulation and apoptosis. TAK1 knockout is embryonic lethal to mice. Conditional knock-down of TAK1 in adult mice results in systemic inflammation, spenomegaly, degeneration in heart, kidneys and liver and increased proliferation and differentiation of myeloid progenitor cells. TAK1 is located downstream of Myd88, Bruton's tyrosine kinase (BTK), and interleukin-1 receptor-associated kinase (IRAK), and is being investigated for its role in innate immunity, inflammatory response, and Ras-dependent cancers.

(826) Hemopoietic cell kinase (HCK) is a non-receptor tyrosine-protein kinase found in hematopoietic cells and is known to interact with Bruton's tyrosine kinase (BTK) upon activation by B cell receptors (Proc. Natl. Acad. Sci. USA. 1994, 91(17), 8152-55). HCK transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. It acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, it mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. It also plays a role in the release of inflammatory molecules, promotes reorganization of the actin cytoskeleton and actin polymerization, and formation of podosomes and cell protrusions.

(827) Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted member of the Ste20 serine/threonine kinase super family. HPK1 is also known as mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1). HPK1 is a tissue-specific upstream activator of the MEKK/JNK/SAPK signaling pathway. HPK1 diminishes T cell receptor (TCR) signaling activity and T cell proliferation by phosphorylating the adaptor protein SLP-76. Cytosolic HPK1 is recruited to the TCR complex, and its kinase activity is induced upon the engagement of the TCR. Overexpression of HPK1 suppresses TCR-induced activation of AP-1-dependent gene transcription in a kinase-dependent manner, suggesting that the kinase activity of HPK1 is required to inhibit the Erk MAPK pathway. This blockage of the Erk MAPK pathway is thought to be the inhibitory mechanism that negatively regulates TCR-induced IL-2 gene transcription (Immunol. Res. 2012, 54(1-3), 262-65). In certain embodiments, the compounds of the invention, such as the compounds of Formula (A), (I-11), (II), or (V) (e.g., compounds of Formula (A-1)-(A-18)), inhibit HPK1.

(828) In certain embodiments, the compounds of the invention are selective inhibitors of TAK1, HCK, or HPK1. The term selective inhibitor as used herein is understood to mean that in contrast to many kinase inhibitors of the prior art, the compounds do not act on a variety of kinases but act specifically on TAK1, HCK, or HPK1. In certain embodiments, the compounds of the invention inhibit one or more kinases in addition to TAK1, HCK, or HPK1 such as BTK or the SRC family of kinases. In certain embodiments of the invention, the specificity of the inhibitors is given by the IC.sub.50 value. In some embodiments, the IC.sub.50 value for a selective inhibitor is <100 M for TAK1, HCK, or HPK1, but >100 M for other kinases.

(829) The IC.sub.50 value is defined as the concentration of inhibitor required to inhibit 50% of the kinase activity. In certain embodiments, the compounds of the invention may exhibit IC.sub.50 values<100 M. In certain other embodiments, the compounds exhibit IC.sub.50 values<50 M. In certain other embodiments, the compounds exhibit IC.sub.50 values<40 M. In certain other embodiments, the compounds exhibit IC.sub.50 values<30 M. In certain other embodiments, the compounds exhibit IC.sub.50 values<20 M. In certain other embodiments, the compounds exhibit IC.sub.50 values<10 M. In certain other embodiments, the compounds exhibit IC.sub.50 values<7.5 M. In certain embodiments, the compounds exhibit IC.sub.50 values<5 M. In certain other embodiments, the compounds exhibit IC.sub.50 values<2.5 M. In certain embodiments, the compounds exhibit IC.sub.50 values<1 M. In certain embodiments, the compounds exhibit IC.sub.50 values<0.75 M. In certain embodiments, the compounds exhibit IC.sub.50 values<0.5 M. In certain embodiments, the compounds exhibit IC.sub.50 values<0.25 M. In certain embodiments, the compounds exhibit IC.sub.50 values<0.1 M. In certain other embodiments, the compounds exhibit IC.sub.50 values<75 nM. In certain other embodiments, the compounds exhibit IC.sub.50 values<50 nM. In certain other embodiments, the compounds exhibit IC.sub.50 values<25 nM. In certain other embodiments, the compounds exhibit IC.sub.50 values<10 nM. In other embodiments, the compounds exhibit IC.sub.50 values<7.5 nM. In other embodiments, the compounds exhibit IC.sub.50 values<5 nM.

(830) In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)) inhibit HCK selectively. In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)) inhibit TAK1 selectively. A non-limiting example of a selective TAK1 inhibitor is:

(831) ##STR00659##

(832) In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)) inhibit both TAK1 and HCK. A non-limiting example of a dual TAK1/HCK inhibitor is:

(833) ##STR00660##

(834) In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)) inhibit HPK1 selectively. A non-limiting example of a selective HPK1 inhibitor is:

(835) ##STR00661##

(836) Also, provided are methods to treat B cell neoplasms using compounds of the invention in combination with inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase. In certain embodiments, one or more compounds of the invention are used in combination with an inhibitor of the phosphoinositide 3-kinase delta isoform (PI3K). In certain embodiments, combinations of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the agents described herein are used for treating WM. In certain embodiments, the agents described herein are used in combination with inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase.

(837) Bruton's tyrosine kinase (BTK) is a key signaling enzyme expressed in all hematopoietic cells types except T lymphocytes and natural killer cells. BTK plays an essential role in the B cell signaling pathway linking cell surface B cell receptor BCR stimulation to downstream intracellular responses. BTK is a key regulator of B cell development activation signaling and survival (Kurosaki, Curr. Op. Imm., 2000, 276-281; Schaeffer and Schwartzberg, Curr. Op. Imm., 2000, 282-288). In addition BTK plays a role in a number of other hematopoietic cell signaling pathways, e.g., Toll like receptor (TLR) and cytokine receptor-mediated TNF- production in macrophages, IgE receptor (FcepsilonRI) signaling in mast cells, inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells, and collagen stimulated platelet aggregation. See e.g., C. A. Jeffries, et al., J. Biol. Chem., 2003, 278, 26258-26264; N. J. Horwood, et al., J. Exp. Med., 2003, 197, 1603-1611; Iwaki et al., J. Biol. Chem., 2005, 280(48), 40261-40270; Vassilev et al., J. Biol. Chem., 1999, 274(3), 1646-1656; and Quek et al., Curr. Biol., 1998, 8(20), 1137-1140. Activated Btk interacts with MyD88 and TRIF, promoting the activation of MyD88-dependent and TRIF-dependent pathways (Nature Immunology, 2011, 12, 416-424).

(838) BTK inhibitors are well-known in the art, and include, for example, ibrutinib and benzonaphthyridinones (see U.S. provisional patent application U.S. Ser. No. 61/716,273, filed Oct. 19, 2012). Additional non-limiting examples of BTK inhibitors are disclosed in WO 1999/054286, WO 2013/010380, WO 2009/137596, WO 2011/029043, WO 2010/056875, WO 2000/056737, and WO 2013/067277.

(839) IRAK1 and 4 are serine/threonine-protein kinases that play a critical role in initiating innate immune response against foreign pathogens. They are involved in Toll-like receptor (TLR) and IL-1R signaling pathways, and are rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation of IRAK1 (Immunity, 1997, 7(6), 837-47). IRAK4/ mice have abolished cellular responses to various IL-1 and TLR ligands and are severely impaired in their response to viral and bacterial challenges. IRAK1/ mice show a similar but partial response.

(840) IRAK1 and IRAK4 inhibitors are well-known in the art, and include, for example, those disclosed in WO 2003/030902, WO 2012/007375, G. M. Buckely et al., Biorg. Med. Chem. Lett., 2008, 18, 3211-3214, and G. M. Buckely et al., Biorg. Med. Chem. Lett., 2008, 18, 3656-3660, WO2013/074986, and U.S. provisional patent application, U.S. Ser. No. 61/727,640, filed Nov. 16, 2012.

(841) In certain embodiments, the IRAK4 inhibitor is of formula:

(842) ##STR00662##
or an analog thereof.

(843) Bone Marrow on X chromosome kinase (BMX, also termed ETK) is a non-receptor tyrosine kinase and is activated downstream of phosphatidylinositol-3 kinase (PI-3K) and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (SRC), but its substrates are unknown. Positional scanning peptide library screening revealed a marked preference for a priming phosphotyrosine (pY) in the 1 position. Potential substrates include multiple tyrosine kinases with kinase domain pYpY sites required for full activity. BMX has been found to phosphorylate residue Y577 of focal adhesion kinase (FAK) subsequent to Y576 phosphorylation by SRC. In addition, BMX loss by RNA interference and mouse embryonic fibroblasts (MEFs) from Bmx negative (Bmx.sup.) mice displayed impaired FAK signaling. Insulin receptor (IR) phosphorylation similarly was decreased by BMX loss, as was hepatic IR phosphorylation in Bmx.sup. mice. However, glucose tolerance was increased, reflecting a marked compensatory decrease in the activity of the AKT phosphatase PHLPP. These findings reveal a mechanism through which BMX functions as a central regulator of multiple kinase pathways.

(844) BMX inhibitors are well-known in the art, and include, for example, those disclosed in U.S. Ser. No. 61/716,273 and 61/717,345, the contents of both of which are incorporated herein by reference. In certain embodiments, the BMX inhibitor is of formula:

(845) ##STR00663##
or an analog thereof.

(846) Phosphatidylinositol 3-kinases (PI3-kinases or PI3Ks) are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. PI3Ks are a family of related intracellular signal transducer enzymes capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol (Ptdlns). Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by PI3KCA gene represents the catalytic subunit, which uses ATP to phosphorylate phosphatidylinositols (Ptdlns), Ptdlns4P and Ptdlns(4,5)P2. Of particular interest is the PI3K delta isoform, which is expressed in white blood cells and is mainly involved in the signaling, development, and survival of B cells.

(847) PI3K inhibitors are well-known in the art, and include, for example, those disclosed in International PCT Publications WO 2013/088404, WO 2012/068096, and WO 2013/052699, which are incorporated herein by reference.

(848) In certain embodiments, the PI3K inhibitor is

(849) ##STR00664##
or its analogs.

(850) Compounds of the invention may be combined with other kinase inhibitors to treat WM or other B cell neoplasms. In certain embodiments, a compound of the invention is administered with an inhibitor of Bruton's tyrosine kinase (BTK) to treat WM or other B cell neoplasm. In certain embodiments, a compound of the invention is administered with an inhibitor of interleukin-1 receptor-associated kinase 1 (IRAK1) to treat WM or otherB cell neoplasm. In certain embodiments, a compound of the invention is administered with an inhibitor of phosphoinositide 3-kinase (PI3K) to treat WM or other B cell neoplasm. In certain embodiments, a compound of of the invention is administered with an inhibitor of the phosphoinositide 3-kinase delta isoform (PI3K) to treat WM or other B cell neoplasm. In certain embodiments, a compound of of the invention is administered with two of any inhibitors of BTK, IRAK1, or PI3K to treat WM or other B cell neoplasm. In certain embodiments, a compound of the invention is administered with more than two of any inhibitors of BTK, IRAK1, or PI3K to treat WM or other B cell neoplasm.

(851) The BTK inhibitors, the IRAK1 inhibitors, the IRAK4 inhibitors, and/or the PI3K inhibitors can be administered to the subject simultaneously or sequentially.

(852) A subject or patient to which administration is contemplated includes, any animal. In some embodiments, a subject includes but is not limited to, humans, commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs), birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys) and experimental animals (e.g., mice, rats, non-human primates). A subject in need of treatment is a subject identified as having a B cell neoplasm, i.e., the subject has been diagnosed by a physician (e.g., using methods well known in the art) as having a B cell neoplasm. In certain embodiments, the subject in need of treatment is a subject suspected of having or developing a B cell neoplasm, such as a subject presenting one or more symptoms indicative of a B cell neoplasm. The term subject in need of treatment further includes people who once had a B cell neoplasm but whose signs and/or symptoms have been ameliorated (i.e., their cancer is in remission). The one or more symptoms or clinical features of B cell neoplasms include, but are not limited to, asymptomatic localized or generalized peripheral lymphadenopathy, plasmacytic difference, bone marrow involvement, autoimmune thrombocytopenia, peripheral blood villous lymphocytes, end organ damage (hypercalcemia, renal insufficiency, bone lesions), recurrent infections, elevated creatine, hyperuricemia, and hypoalbunemia.

(853) In certain embodiments, the subject is diagnosed as having Waldenstrm's macroglobulinemia (WM). The subject may present one or more signs, symptoms, or clinical features of WM including anemia, hyper-viscosity, neuropathy, coagulopathies, splenomegaly, hepatomegaly, adenopathy, and an IgM serum paraprotein. In certain embodiments, the subject is diagnosed as having WM on the basis that the subject has a mutation at position 38182641 of chromosome 3p22.2. In some embodiments, the mutation results in a single nucleotide change from T to C in the MYD88 gene. In some embodiments, the mutation results in an amino acid change from leucine to proline at position 265 in the MYD88 gene. The mutation may be detected in a biological sample obtained from the subject using any suitable method known in the art, including but not limited to, direct sequencing of nucleic acid molecules, HPLC analysis, DNA chip technologies, and mass spectroscopy. Non-limiting examples of the biological sample include bone marrow, lymph node, spleen, or blood.

(854) The terms administer, administering, or administration, as used he rein refers to implanting, absorbing, ingesting, injecting, or inhaling an inventive compound, or a pharmaceutical composition thereof.

(855) As used herein, the terms treatment, treat, and treating refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a B cell neoplasm. In certain embodiments, treatment may be administered after one or more signs or symptoms have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the B cell neoplasm. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

(856) An effective amount of compounds of the invention refers to an amount sufficient to elicit the desired biological response, i.e., treating the B cell neoplasm. As will be appreciated by those of ordinary skill in this art, the effective amount of compounds of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount includes, but is not limited to, that amount necessary to slow, reduce, inhibit, ameliorate or reverse one or more signs and/or symptoms associated with a B cell neoplasm. In the treatment of Waldenstrm's macroglobulinemia, this may refer to a reduction in the levels of IgM serum paraprotein, reduction in anemia, reduction in hyper-viscosity, reduction in neuropathy, reduction in coagulopathies, reduction in splenomegaly, reduction in hepatomegaly, and reduction in adenopathy.

(857) An effective amount of a compound may vary from about 0.001 mg/kg to about 1000 mg/kg in one or more dose administrations, for one or several days (depending on the mode of administration). In certain embodiments, the effective amount varies from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, from about 1.0 mg/kg to about 100 mg/kg, and from about 10.0 mg/kg to about 150 mg/kg.

(858) One or more additional pharmaceutical agents, such as anti-cancer agents (e.g., chemotherapeutics), anti-inflammatory agents, steroids, immunosuppressants, radiation therapy, or other agents, can be used in combination with the compounds of of the invention in the treatment of a B cell neoplasm. The one or more additional pharmaceutical agents can be administered to the subject simultaneously or sequentially.

(859) Exemplary chemotherapeutic agents include alkylating agents such as nitrogen mustards, ethylenimines, methylmelamines, alkyl sulfonates, nitrosuoureas, and triazenes; antimetabolites such as folic acid analogs, pyrimidine analogs, in particular fluorouracil and cytosine arabinoside, and purine analogs; natural products such as vinca alkaloids epi-podophyllotoxins, antibiotics, enzymes, and biological response modifiers; and miscellaneous products such as platinum coordination complexes, anthracenedione, substituted urea such as hydroxyurea, methyl hydrazine derivatives, and adrenocorticoid suppressant.

(860) Exemplary chemotherapeutic agents also include anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, paclitaxel, colchicine, cytochalasin B, emetine, maytansine, amsacrine, cisplatin, carboplatin, mitomycin, altretamine, cyclophosphamide, lomustine, and carmustine.

(861) In yet another aspect, the present invention provides pharmaceutical compositions comprising an effective amount of a compound of of the invention, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs, and optionally a pharmaceutically acceptable excipient, for use in the treatment of a B cell neoplasm. In certain embodiments, provided by the invention are the compounds of of the invention, and pharmaceutically acceptable salts and compositions thereof, for use in the treatment of a B cell neoplasm. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the therapeutically effective amount is an amount useful for the treatment and/or prevention of a B cell neoplasm. In certain embodiments, the B cell neoplasm is, but is not limited to, Hodgkin's lymphomas and most non-Hodgkins lymphomas, such as, diffuse large B cell lymphoma, Follicular lymphoma, Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma (overlaps with Chronic lymphocytic leukemia), Mantle cell lymphoma (MCL), Burkitt lymphoma, Mediastinal large B cell lymphoma, Waldenstrm's macroglobulinemia, Nodal marginal zone B cell lymphoma (NMZL), Splenic marginal zone lymphoma (SMZL), Intravascular large B-cell lymphoma, Primary effusion lymphoma and Lymphomatoid granulomatosis. An effective amount of a compound may vary from about 0.001 mg/kg to about 1000 mg/kg in one or more dose administrations, for one or several days (depending on the mode of administration). In certain embodiments, the effective amount varies from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, and from about 10.0 mg/kg to about 150 mg/kg.

(862) Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing a compound of of the invention (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.

(863) 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. As used herein, 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, for example, one-half or one-third of such a dosage.

(864) The pharmaceutical preparations of the present invention may include or be diluted into a pharmaceutically acceptable carrier. The term pharmaceutically acceptable carrier as used herein means one or more compatible fillers, diluents or other such substances, which are suitable for administration to a human or other mammal, such as a dog, cat, rat, mouse, or horse. The term carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The carriers are capable of being commingled with the preparations of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy or stability. Carriers suitable for oral, subcutaneous, intravenous, intramuscular, etc. formulations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.

(865) 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).

(866) 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. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, thR.sup.ee, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

(867) In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

(868) In certain embodiments, the compound of the invention is administered at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

(869) It will be appreciated that 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.

(870) The present invention is further illustrated by the following Example, which in no way should be construed as further limiting. The entire contents of all of the references (including literature references, issued patents, published patent applications, and co pending patent applications) cited throughout this application are hereby expressly incorporated by reference.

EXAMPLES

(871) In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological 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.

Example 1. Preparation of the Compounds

(872) Preparation of I-11

(873) ##STR00665##

4-methyl-3-((7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzoic acid

(874) 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (284 mg, 1.0 mmol), 3-hydroxy-4-methylbenzoic acid (152 mg, 1.0 mmol) and K.sub.2CO.sub.3 (414 mg, 3.0 mmol) were combined in DMSO (5 mL) and stirred overnight at 100 C. The reaction mixture was then cooled to room temperature. The mixture was acidified with 1N HCl solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by column chromatography to yield 296 mg of product as a colorless oil. MS (ESI) m/z 400 (M+H).sup.+.

(875) ##STR00666##

3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(3-(2-cyanopropan-2-yl)phenyl)-4-methylbenzamide (I-11)

(876) To a solution of 4-methyl-3-((7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzoic acid (200 mg, 0.5 mmol), HATU (230 mg, 0.6 mmol), DMAP (73 mg, 0.6 mmol) and iPr.sub.2NEt (220 uL, 1.25 mmol) in CH.sub.2Cl.sub.2 (3 mL) was added 2-(3-aminophenyl)-2-methylpropanenitrile (80 mg, 0.5 mmol) and the resulting mixture was stirred at room temperature for 24 hours. The solution was filtered to remove solids, concentrated and purified with column chromatography (dichloromethane:methanol=10:1) to afford 455 mg of product as a colorless oil. To the solution of the obtained oil in CH.sub.2Cl.sub.2 (5 mL) was added TFA (0.5 mL) and the resulting mixture was stirred at room temperature for 5 hours. The solution was concentrated and dried with vacuum, then dissolved in THF (4 mL) and 1 N NaOH solution (4 mL). The reaction mixture was stirred for 24 h and extracted with ethyl acetate. The combined organic phase was washed with brine and dried with Na.sub.2SO.sub.4, then filtered and concentrated, and purified by reverse phase HPLC to give 185 mg (90%) of title compound as a white solid.

(877) Preparation of A-17

(878) ##STR00667## ##STR00668##

3-((6-chloropyrimidin-4-yl)oxy)-4-methylbenzoic acid

(879) Sodium hydroxide (2 ml of a 1N solution) was added to a solution of 4,6-dichloropyrimidine (150 mg, 1.0 mmol) and 3-hydroxy-4-methylbenzoic acid (152 mg, 1.0 mmol) in acetone (2 mL) and the reaction mixture as stirred at room temperature for 1 hour at which point LC-MS analysis indicated complete consumption of starting material. The reaction mixture was extracted with ethyl acetate. The combined organic phase was washed with brine and dried with Na.sub.2SO.sub.4, then filtered and concentrated, and purified by column chromatography to yield 250 mg of product as a white solid. MS (ESI) m/z 265 (M+H).sup.+.

(880) ##STR00669##

3-((6-chloropyrimidin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide

(881) To a solution of 3-((6-chloropyrimidin-4-yl)oxy)-4-methylbenzoic acid (210 mg, 0.8 mmol), HATU (365 mg, 0.96 mmol), DMAP (117 mg, 0.96 mmol) and iPr.sub.2NEt (350 uL, 2.0 mmol) in CH.sub.2Cl.sub.2 (4 mL) was added 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (230 mg, 0.8 mmol) and the resulting mixture was stirred at room temperature for 24 hours. The solution was filtered to remove solids, concentrated and purified column chromatography to yield 360 mg (84%) of product as a pale yellow oil. MS (ESI) m/z 534 (M+H).sup.+.

(882) ##STR00670##

3-((6-aminopyrimidin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide

(883) 10 mL of a 2N solution of NH.sub.3 in i-PrOH was added to 3-((6-chloropyrimidin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide (270 mg, 0.5 mmol) and the reaction mixture was stirred for 48 hours at 75 C. then cooled to room temperature and concentrated. The crude product was purified by column chromatography to yield 120 mg of product as a colorless oil. MS (ESI) m/z 515 (M+H).sup.+.

(884) ##STR00671##

3-((6-acrylamidopyrimidin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide (A-17)

(885) To a solution of 3-((6-aminopyrimidin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide (51 mg, 0.1 mmol) in DMF cooled in a dry ice/SOLVENT bath was added acryloyl chloride (8.9 uL, 0.11 mmol). The cooling bath was removed allowing the mixture to warm to room temperature and continue stirring for an half hour. The solution was then diluted in DMSO and purified by reverse phase HPLC to afford 45 mg (80%) of A-17 as a white solid.

(886) Compounds (A-1)-(A-16) and (A-18) were prepared similarly to A-17.

(887) Characterization data for all final compounds is in the table below.

(888) TABLE-US-00001 ID # Structure Name .sup.1H NMR and or MS (m/z) A-1 N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl) phenyl)-4-methyl- 3-((6-(methylamino) pyrimidin-4-yl)oxy) benzamide .sup.1H NMR (400 MHz, DMSO) 10.39 (s, 1H), 8.11 (s, 1H), 9.00 (d, J = 8.4) Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.33 (bs, 1H), 3.60 (s, 2H), 3.38 (m, 2H), 2.97-2.79 (m, 6H), 2.71 (bs, 3H), 2.37-2.22 (m, 2H), 2.09 (s, 3H), 1.12 (t, J = 6.8 Hz, 3H). MS (ESI) m/z 529 (M + H).sup.+. A-2 N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl) phenyl)-4-methyl- 3-((6-(propionamido- pyrimidin)-4-yl)oxy) benzamide .sup.1H NMR (600 MHz, TFA salt, DMSO) 10.89 (s, 1H), 10.42 (s, 1H), 9.36 (br, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.71 (s, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.57 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 3.61 (s, 2H), 3.38 (m, 2H), 3.07 (m, 2H), 2.92 (m, 2H), 2.85 (m, 2H), 2.37 (q, J = 7.2 Hz, 2H), 2.32 (m, 2H), 2.10 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 571 (M + H).sup.+. A-3 3-((6-(cyclopropane- carboxamido) pyrimidin-4-yl)oxy)- N-(4-((4-ethylpiperazin- 1-yl)methyl)-3- (trifluoromethyl) phenyl)-4-methyl- benzamide .sup.1H NMR (600 MHz, DMSO) 11.25 (s, 1H), 10.36 (s, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.70 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 3.49 (s, 2H), 2.32 (m, 8H), 2.24 (m, 2H), 2.09 (s, 3H), 1.97 (m, 1H), 0.91 (t, J = 7.2 Hz, 3H), 0.79 (m, 4H). MS (ESI) m/z 583 (M + H).sup.+. A-4 3-((6-aminopyrimidin- 4-yl)oxy)-N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl) phenyl)-4-methyl- benzamide .sup.1H NMR (600 MHz, TFA salt, DMSO) 8.06 (s, 1H), 8.03 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.43 (d, J = 7.2 Hz, 1H), 5.78 (s, 1H), 3.70 (s, 2H), 3.47 (m, 2H), 3.15 (q, J = 7.2 Hz, 2H), 3.01 (m, 4H), 2.42 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 515 (M + H).sup.+. A-5 N-(4-((4-ethylpiperazin- 1-yl)methyl)-3-(trifluoro- methyl)phenyl)-4- methyl-3-((6-((1- methyl-1H-pyrazol- 4-yl)amino)pyrimidin- 4-yl)oxy)benzamide .sup.1H NMR (600 MHz, DMSO) 10.36 (s, 1H), 9.37 (br, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 5.94 (s, 1H), 3.74 (s, 3H), 3.50 (s, 2H), 2.18-2.42 (m, 10H), 2.12 (s, 3H), 0.92 (m, 3H). MS (ESI) m/z 595 (M + H).sup.+. A-6 3-((6-((1H-pyrazol-5-yl) amino)pyrimidin-4-yl) oxy)-N-(4-((4-ethyl- piperazin-1-yl)methyl)- 3-(trifluoromethyl) phenyl)-4-methyl- benzamide .sup.1H NMR (600 MHz, TFA salt, DMSO) 10.45 (s, 1H), 9.92 (s, 1H), 9.33 (br, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.62 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 3.66 (s, 2H), 3.44 (m, 2H), 3.12 (m, 2H), 2.97 (m, 2H), 2.91 (m, 2H), 2.37 (m, 2H), 2.17 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 581 (M + H).sup.+. A-7 3-((6-((1H-pyrazol-4- yl)amino)pyrimidin-4- yl)oxy)-N-(4-((4- ethylpiperazin-1-yl) methyl)-3-(trifluoro- methyl)phenyl)-4- methylbenzamide .sup.1H NMR (600 MHz, DMSO) 12.63 (br, 1H), 10.44 (s, 1H), 9.42 (br, 1H), 8.26 (br, 1H), 8.19 (s, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.90 (br, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.53 (br, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.00 (s, 1H), 3.60 (s, 2H), 2.25-2.86 (m, 10H), 2.19 (s, 3H), 1.05, (m, 3H). MS (ESI) m/z 581 (M + H).sup.+. A-8 N-(4-((4-ethylpiperazin- 1-yl)methyl)-3-(tri- fluoromethyl)phenyl)- 4-methyl-3-((6- (pyrimidin-5-ylamino) pyrimidin-4-yl)oxy) benzamide .sup.1H NMR (600 MHz, TFA salt, DMSO) 10.49 (s, 1H), 10.02 (s, 1H), 9.44 (br, 1H), 9.08 (s, 2H), 8.82 (s, 1H), 8.42 (s, 1H), 8.19 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.79 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 6.27 (s, 1H), 3.66 (s, 2H), 3.44 (m, 2H), 3.13 (m, 2H), 2.98 (m, 2H), 2.91 (m, 2H), 2.38 (m, 2H), 2.20 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 593 (M + H).sup.+. A-9 0 3-((6-(2-acetylhydra- zinyl)pyrimidin-4- yl)oxy)-N-(4-((4- ethylpiperazin-1-yl) methyl)-3-(trifluoro- methyl)phenyl)-4- methylbenzamide .sup.1H NMR (600 MHz, DMSO) 10.43 (s, 1H), 9.88 (s, 1H), 9.20 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 5.99 (s, 1H), 3.56 (s, 2H), 3.32 (m, 4H), 2.29-2.48 (m, 4H), 2.32 (q, J = 7.2 Hz, 2H), 2.17 (s, 3H), 1.92 (s, 3H), 0.97 (J = 7.2 Hz, 3H). MS (ESI) m/z 572 (M + H).sup.+. A-10 3-((6-(azetidin-3- ylamino)pyrimidin- 4-yl)oxy)-N-(4-((4- ethylpiperazin-1-yl) methyl)-3-(trifluoro- methyl)phenyl)-4- methylbenzamide .sup.1H NMR (600 MHz, TFA salt, DMSO) 10.56 (s, 1H), 10.05 (s, 1H), 9.47 (br, 1H), 8.76 (s, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 7.77 (s, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 6.35 (s, 1H), 4.60 (m, 1H), 4.38 (m, 2H), 3.68 (s, 2H), 3.57 (m, 2H), 3.46 (m, 2H), 3.12 (m, 2H), 2.98 (m, 2H), 2.92 (m, 2H), 2.39 (m, 2H), 2.21 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 570 (M + H).sup.+. A-11 3-((6-(2,2-dimethyl- hydrazinyl)pyrimidin- 4-yl)oxy)-N-(4-((4- ethylpiperazin-1-yl) methyl)-3-(trifluoro- methyl)phenyl)-4- methylbenzamide .sup.1H NMR (600 MHz, TFA salt, DMSO) 10.58 (s, 1H), 9.48 (br, 1H), 8.95 (s, 1H), 8.20 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.79 (s, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.84 (br, 2H), 3.71 (s, 6H), 3.68 (s, 2H), 3.46 (m, 2H), 3.15 (m, 2H), 2.98 (m, 2H), 2.92 (m, 2H), 2.39 (m, 2H), 2.21 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 558 (M + H).sup.+. A-12 N-(4-((4-ethylpiperazin- 1-yl)methyl)-3-(tri- fluoromethyl)phenyl)- 4-methyl-3-((6-((1- methyl-1H-pyrazol- 3-yl)amino)pyrimidin- 4-yl)oxy)benzamide .sup.1H NMR (600 MHz, TFA salt, DMSO) 10.47 (s, 1H), 9.94 (s, 1H), 9.36 (br, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.58 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 6.16 (br, 1H), 3.75 (s, 3H), 3.68 (s, 2H), 3.45 (m, 2H), 3.14 (m, 2H), 2.99 (m, 2H), 2.94 (m, 2H), 2.37 (m, 2H), 2.19 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 595 (M + H).sup.+. A-13 N-(4-((4-ethylpiperazin- 1-yl)methyl)-3-(tri- fluoromethyl)phenyl)- 4-methyl-3-((6- (oxetan-3-ylamino) pyrimidin-4-yl) oxy)benzamide .sup.1H NMR (600 MHz, TFA salt, DMSO) 10.46 (s, 1H), 9.32 (br, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 8.15 (br, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 6.6 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 5.88 (br, 1H), 4.15 (m, 2H), 3.70 (m, 2H), 3.68 (s, 2H), 3.46 (m, 2H), 3.14 (m, 2H), 2.99 (m, 2H), 2.93 (m, 2H), 2.38 (m, 2H), 2.17 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 571 (M + H).sup.+. A-14 N-(4-((4-ethylpiperazin- 1-yl)methyl)-3-(tri- fluoromethyl)phenyl)- 4-methyl-3-((2-((1- methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)oxy)benzamide .sup.1H NMR (600 MHz, DMSO) 10.45 (s, 1H), 9.60 (br, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.98 (m, 1H), 7.88 (m, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.61 (m, 1H), 7.05 (m, 1H), 6.73 (m, 1H), 6.46 (m, 1H), 3.55 (s, 3H), 3.49 (br, 2H), 2.20-2.58 (m, 10H), 2.18 (s, 3H), 0.97 (t, J = 7.2 Hz, 3H), MS (ESI) m/z 595 (M + H).sup.+. A-15 N-(4-((4-ethylpiperazin- 1-yl)methyl)-3- (trifluoromethyl) phenyl)-3-((2-(isoxazol- 4-ylamino)pyrimidin- 4-yl)oxy)-4- methylbenzamide .sup.1H NMR (600 MHz, TFA salt, DMSO) 10.51 (s,1H), 9.90 (m, 1H), 9.31 (br, 1H), 8.44 (d, J = 5.4 Hz, 1H), 8.32 (m, 1H), 8.20 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.97 (m, 1H), 7.87 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 6.62 (s, 1H), 3.69 (s, 2H), 3.46 (m, 2H), 3.15 (m, 2H), 2.99 (m, 2H), 2.94 (m, 2H), 2.39 (m, 2H), 2.19 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 582 (M + H).sup.+. A-16 N-(4-((4-ethylpiperazin- 1-yl)methyl)-3- (trifluoromethyl) phenyl)-3-((6-(isoxazol- 4-ylamino)pyrimidin- 4-yl)oxy)-4- methylbenzamide MS (ESI) m/z 582 (M + H)+. A-17 3-((6-acrylamido- pyrimidin-4-yl)oxy)- N-(4-((4-ethyl-piperazin- 1-yl)methyl)-3-(tri- fluoromethyl)phenyl)- 4-methylbenzamide .sup.1H NMR (600 MHz, DMSO) 11.16 (s, 1H), 10.37 (s, 1H), 8.46 (s, 1H), 8.11 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 6.54 (dd, J = 16.8, 10.8 Hz, 1H), 6.30 (d, J = 16.8 Hz, 1H), 5.81 (d, J = 10.8 Hz, 1H), 3.49 (s, 2H), 2.32 (m, 8H), 2.23 (q, J = 7.2 Hz, 2H), 2.11 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 569 (M + H).sup.+. I-11 3-((7H-pyrrolo[2,3-d] pyrimidin-4-yl)oxy)-N- (3-(2-cyanopropan-2-yl) phenyl)-4-methyl- benzamide .sup.1H NMR (400 MHz, DMSO) 10.23 (s, 1H), 8.22 (s, 1H), 7.86 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0, 1H), 7.43 (d, J = 3.2 Hz, 1H), 7.33 (dd, J = 8.0, 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 3.2 Hz, 1H), 2.10 (s, 3H), 1.61 (s, 6H). MS (ESI) m/z 412 (M + H).sup.+.

Example 2. Biological Assays of the Compounds

(889) In Vitro Activity Assays

(890) The in vitro activity of the compounds described herein in inhibiting TAK1, HCK and other kinases were obtained using an Invitrogen Select Screening assay as known in the art. The IC50 values determined from this assay are shown below.

(891) Cell Proliferation Analysis

(892) CellTiter-Glo Luminescent cell viability assay (Promega) was used to assess cell survival following treatment with the compounds described. Cells were seeded into 384 well plates with the EL406 Combination Washer Dispenser (BioTek Instruments, Inc.) and the compounds were injected into the cells culture media with the JANUS Automated Workstation (PerkinElmer Inc.). Cells were treated with a series diluted inhibitors (200.04 M) for 72 hours at 37 C. Luminescent measurement is performed using the 2104 Envision Multilabel Reader (PerkinElmer Inc.).

(893) Apoptosis Analysis for Primary Patient Bone Marrow Tumor Cells

(894) WM cells were treated with and without the compounds described herein. Cells were incubated at 37 C. with 0.014 uM of the compounds described herein. Apoptosis analysis was performed using Annexin V/Propidium iodide staining with the Apoptosis Detection Kit I (BD Pharmingen). 1106/well cells were treated in 24 well plates for 24 hours with inhibitors or corresponding controls. A minimum of 10,000 events were acquired using a BD FACSCanto II flow cytometer and analyzed with BD FACS DIVA Software.

(895) Results

(896) A number of compounds described herein show inhibitory activity against TAK1, HCK, BTK and other kinases. Shown in Table 1 and 1a are exemplary in vitro IC.sub.50 data of these compounds. Table 2 and 2a shows the in vitro EC.sub.50 values of these compounds.

(897) TABLE-US-00002 TABLE 1 HCK Com- BTK IC.sub.50 TAK1 GCK pound IC.sub.50 (nM) IC.sub.50 IC.sub.50 Structure ID (nM) Inv (nM) (nM) 0 (A-1) 275 364 31 (A-17) 3380 28 45 17 (A-2) 253 100 28 (A-3) 185 92 (A-4) 382 591 (I-11)

(898) TABLE-US-00003 TABLE 1a HCK BTK IC.sub.50 TAK1 Cpd. IC.sub.50 (nM) IC.sub.50 Structure ID (nM) Inv (nM) (A-5) >10000 61.8 100 (A-6) 38.4 63.5 (A-7) 33.8 71.7 (A-8) 889 487 00 (A-9) >10000 7310 01 (A-10) >10000 >10000 02 (A-18) 6980 1750 03 (A-11) >10000 >10000 04 (A-12) 18 76.2 05 (A-13) 392 400 06 (A-14) 27.4 53.8 07 (A-15) 116 136 08 (A-16)

(899) TABLE-US-00004 TABLE 2 BCWM.1 MWCL-1 RPCIWM-1 OCI-Ly3 Ramos OCI-Ly19 Mec1 EC.sub.50 Cpd. ID EC.sub.50 (nM) EC.sub.50 (nM) EC.sub.50 (nM) EC.sub.50 (nM) EC.sub.50 (nM) EC.sub.50 (nM) (nM) (A-1) 1720 3990 11500 9480 4980 (A-2) 42 1350 2960 5340 1750 (A-3) 50 910 480 2680 600 (A-4) 3010 1150 31900 21100 9430 14300 (A-17) 8 202 247 389 188

(900) TABLE-US-00005 TABLE 2a BCWM.1 MWCL-1 TMD8 OCI-Ly7 OCI-Ly3 Ramos OCI-Ly19 Cpd. ID EC.sub.50 (nM) EC.sub.50 (nM) EC.sub.50 (nM) EC.sub.50 (nM) EC.sub.50 (nM) EC.sub.50 (nM) EC.sub.50 (nM) (A-5) 51 73 132 655 4710 3000 173 72 242 6060 417 (A-6) 86 118 4770 3080 302 (A-7) 48 71 4000 3020 192 (A-8) 980 2660 >10000 6180 1700 (A-9) 10800 18700 19600 >20000 >20000 6460 >20000 >20000 (A-10) 8250 24800 8370 >20000 >20000 >20000 >20000 >20000 (A-11) 19700 >20000 >20000 >20000 >20000 (A-12) 38 75 156 2960 209 71 71 472 (A-13) 361 1760 1200 3260 2280 964 2860 1730 (A-14) 33 128 45 173 2090 179 (A-15) 185 718 392 786 4680 307 (A-16) 610 1710 856 1030 1310 777 (A-18) 1980 4090 1860 7240 2780 3750 6740 5030 (I-11) 4950 1440 3460 1120 9690 3890
Kinome Scan

(901) Compounds (A-2) and (A-17) were run in the Kinome Scan (DiscoverRx) assay to determine the inhibition against a broad panel of known kinases.

(902) Results

(903) Table 3 shows the KinomeScan (an active site-directed competition binding assay to measure interactions between test compounds and individual kinases) data of each compound, II-1 and I-13. Lower values indicate a greater inhibition for a given kinase by the test compound. As is shown, II-1 and I-13 inhibited several other kinases include LOK, DDR1, JNK2, ZAK, IKK-alpha, BLK, p38-alpha, ABL1, LYN, and STK36 along with the key target HCK.

(904) TABLE-US-00006 TABLE 3 Kinases A-2 (1 M) A-17 (1 M) TAOK 1 0.45 0.05 LOK 0.05 0.1 TAOK3 0.45 0.1 DDR1 0.35 0.25 HCK 1.5 0.3 JNK2 0.15 0.3 ZAK 1.6 0.4 IKK-alpha 13 0.55 BLK 0.65 0.6 p38-alpha 0 0.75 ABL1-nonphosphorylated 1 0.8 LYN 3.6 0.8 STK36 1 0.9 LCK 1.6 1 FLT3 1.8 1.2 MKK7 11 1.2 MAP4K2 2.8 1.4 p38-beta 1.8 2.1 PDGFRB 5.1 2.5 CSF1R 3.2 2.6 RET(M918T) 7.4 2.8 ABL2 2.9 2.9 ABL1(E255K)-phosphorylated 3.3 3 CDC2L1 0.45 3.2 EPHA8 5.4 3.6 RET 9.9 3.6 CDC2L2 0.4 3.8 KIT(L576P) 2.2 3.9 CDK8 12 4 MAP4K4 6.4 4 KIT(V559D) 3.4 4.2 MINK 18 4.6 MAP3K3 21 4.8 TAOK2 0.15 4.8 JAK3(JH1domain-catalytic) 47 4.9 JNK1 6.8 5 KIT 5.6 5.1 FES 4.1 5.2 CDKL2 1.4 5.5 TIE1 5.5 5.5 ULK3 71 6 HPK1 30 6.2 CDK11 1.6 6.6 CDKL3 1.6 6.8 FGR 13 7.7 TNIK 20 9 CDC2L5 19 10 MST3 36 10 ABL1(M351T)-phosphorylated 6 11 DDR2 3 11 FGFR1 21 12 FLT3(N841I) 14 12 HIPK2 29 12 NLK 29 12 SRC 5.9 12 HIPK3 13 13 MAP4K5 29 14 p38-gamma 6.6 14 RSK2(Kin. Dom. 2-C-terminal) 97 15 KIT(A829P) 32 16 KIT(V559D, T670I) 11 16 OSR1 79 16 TNK1 33 16 EPHB2 69 17 YSK1 21 17 EGFR(L747-E749del, A750P) 21 18 EPHA3 32 18 FRK 19 18 MST4 38 18 PCTK1 45 18 RET(V804M) 26 18 TIE2 13 18 PCTK2 10 20 ULK1 100 20 FGFR4 32 21 BRAF(V600E) 23 22 HIPK1 32 22 EGFR(L747-S752del, P753S) 19 23 FLT3(D835Y) 23 23 JNK3 15 23 p38-delta 15 23 FLT3(D835H) 23 24 CAMK1 38 26 CTK 40 26 FLT1 38 26 MYO3A 59 26 SGK3 97 26 YES 24 27 FGFR2 34 28 NEK4 59 30 SBK1 89 31 ABL1(F317L)-phosphorylated 3.9 33 AURKA 95 33 MEK3 84 33 CAMK1D 73 34 HIPK4 14 34 ZAP70 69 35 MUSK 43 37 ASK2 65 38 EGFR(E746-A750del) 28 38 FLT4 54 38 STK39 23 38 TTK 39 38 FLT3(R834Q) 64 39 PAK3 61 39 SLK 17 39 ABL1(T315I)-phosphorylated 37 40 CDK3 58 40 CSK 69 40 PFTK1 27 40 BRAF 42 41 FER 30 42 IKK-beta 48 42 PIK3CA(Q546K) 85 42 ABL1(T315I)-nonphosphorylated 0 44 MYLK2 63 44 PRKCD 39 44 ROCK1 97 44 CDKL1 45 45 TYK2(JH1domain-catalytic) 90 45 GRK7 68 46 PLK4 78 46 ROCK2 100 46 CDK2 43 47 MAST1 59 47 ABL1(F317I)-nonphosphorylated 0 48 EIF2AK1 62 48 AURKB 77 50 MEK6 77 50 ERBB2 46 51 ERN1 58 51 RET(V804L) 62 51 RPS6KA5(Kin. Dom. 1-N-terminal) 78 51 KIT(V559D, V654A) 50 52 PCTK3 32 52 EGFR(L747-T751del, Sins) 18 53 EPHA2 40 53 EGFR(L861Q) 56 54 MAP3K15 100 54 SGK 100 54 FYN 52 55 PDGFRA 25 55 PIK3CA(C420R) 100 55 SRMS 66 55 CDK5 67 56 IRAK1 97 56 PIK3C2G 81 56 PKNB(M. tuberculosis) 100 56 QSK 69 56 YSK4 89 57 CIT 56 58 EGFR(T790M) 83 58 JAK2(JH1domain-catalytic) 74 58 MAP3K1 60 58 PIK3CA(E545A) 89 58 PIK3CG 94 58 NDR1 87 59 PFPK5(P. falciparum) 100 59 SRPK1 70 59 DYRK2 99 60 EGFR 55 60 GSK3A 40 60 ABL1(F317L)-nonphosphorylated 0 61 CLK1 85 61 PRKCQ 55 61 PAK1 96 62 STK35 80 62 ABL1(F317I)-phosphorylated 7.9 63 CAMK1G 61 64 CAMK4 100 64 CDKL5 93 64 CDK7 33 66 PLK3 100 66 PRKD1 87 66 IRAK4 99 67 PIK3CA(E545K) 88 67 EGFR(S752-I759del) 37 68 INSRR 71 68 PFTAIRE2 100 68 MYLK 100 69 PIK3CA(I800L) 83 70 SYK 21 70 AURKC 100 71 CASK 60 71 CDK9 46 71 CSNK1A1 83 71 EPHB6 92 71 PIK3CA 100 71 BMPR1B 99 72 FLT3-autoinhibited 68 72 PIK3CA(E542K) 87 72 PRKCI 65 73 ANKK1 100 74 EPHA4 64 75 EGFR(G719C) 60 76 EPHA5 86 76 JAK1(JH1domain-catalytic) 86 76 MST2 82 76 PRKCH 94 76 ARK5 96 77 CLK4 66 77 FGFR3 80 77 GAK 77 77 MEK1 100 77 MYO3B 76 77 WNK3 95 77 DCAMKL1 77 78 EPHA6 68 78 FGFR3(G697C) 81 78 KIT(D816H) 82 78 RIPK5 90 78 SNRK 68 78 ERBB4 88 79 EGFR(L858R) 83 80 IKK-epsilon 100 80 TLK1 100 80 TRKC 100 80 ERK2 100 81 PRKD2 73 81 ACVRL1 83 82 BMPR2 86 82 NEK10 100 82 PAK2 78 82 S6K1 54 82 SIK 73 82 GSK3B 83 83 HUNK 100 83 MERTK 100 83 NIK 62 83 PIP5K2B 100 83 RIOK1 100 83 VRK2 96 83 CAMK2D 92 84 PAK6 100 84 TBK1 95 84 GCN2(Kin. Dom. 2, S808G) 84 85 PKN1 100 85 SGK2 100 85 TGFBR2 100 85 WNK1 100 85 ALK 92 86 DCAMKL3 97 86 MEK2 83 86 PIM1 100 86 PRKCE 92 86 TAK1 3.2 86 YANK2 100 86 AXL 68 87 MKNK2 72 87 NEK6 91 87 PIP5K1A 100 87 ADCK3 100 88 CLK2 100 88 ERK8 100 88 PIK3CB 66 88 PIM3 93 88 RAF1 75 88 AKT1 82 89 BUB1 80 89 MAP4K3 100 89 BTK 65 90 ICK 65 90 PAK7 100 90 PIK3CD 100 90 RIOK3 83 90 BMX 79 91 CDK4-cyclinD1 94 91 SNARK 100 91 TRKA 90 91 ALK(L1196M) 90 92 LATS2 100 92 PRKG2 74 92 NEK2 98 93 TRKB 85 93 AAK1 94 94 EGFR(L858R, T790M) 80 94 ERK3 93 94 LRRK2(G2019S) 100 94 PAK4 95 94 PIK3CA(H1047L) 97 94 RIPK4 88 94 RPS6KA4(Kin. Dom. 1-N-terminal) 96 94 TESK1 81 94 CSF1R-autoinhibited 96 95 LIMK2 94 95 LRRK2 95 95 PIK3CA(M1043I) 83 95 RPS6KA4(Kin. Dom. 2-C-terminal) 100 95 TNNI3K 64 95 HASPIN 84 96 MAP3K4 80 96 PRP4 94 96 YANK1 73 96 ABL1(Y253F)-phosphorylated 4.8 97 EGFR(G719S) 65 97 MLK1 91 97 NEK1 93 97 PIK4CB 98 97 BIKE 92 98 RSK2(Kin. Dom. 1-N-terminal) 100 98 SRPK2 100 98 STK16 100 98 AMPK-alpha2 95 99 CAMKK2 79 99 EPHB4 87 99 RSK4(Kin. Dom. 1-N-terminal) 92 99 ABL1(Q252H)-phosphorylated 11 100 ACVR1 100 100 ACVR1B 100 100 ACVR2A 100 100 ACVR2B 95 100 ADCK4 100 100 AKT2 90 100 AKT3 100 100 ALK(C1156Y) 49 100 AMPK-alpha1 85 100 ASK1 96 100 BMPR1A 100 100 BRK 100 100 BRSK1 100 100 BRSK2 100 100 CAMK2A 92 100 CAMK2B 100 100 CAMK2G 86 100 CAMKK1 100 100 CDK4-cyclinD3 100 100 CHEK1 100 100 CHEK2 100 100 CLK3 100 100 CSNK1A1L 99 100 CSNK1D 100 100 CSNK1E 100 100 CSNK1G1 100 100 CSNK1G2 100 100 CSNK1G3 93 100 CSNK2A1 100 100 CSNK2A2 100 100 DAPK1 100 100 DAPK2 93 100 DAPK3 100 100 DCAMKL2 74 100 DLK 100 100 DMPK 100 100 DMPK2 88 100 DRAK1 100 100 DRAK2 85 100 DYRK1A 92 100 DYRK1B 77 100 EPHA1 90 100 EPHA7 75 100 EPHB1 78 100 EPHB3 100 100 ERBB3 100 100 ERK1 100 100 ERK4 96 100 ERK5 98 100 FAK 100 100 GRK1 77 100 GRK4 100 100 IGF1R 100 100 INSR 100 100 IRAK3 100 100 ITK 95 100 JAK1(JH2domain-pseudokinase) 90 100 KIT(D816V) 96 100 KIT-autoinhibited 65 100 LATS1 100 100 LIMK1 100 100 LKB1 100 100 LTK 100 100 LZK 100 100 MAK 93 100 MAP3K2 90 100 MAPKAPK2 100 100 MAPKAPK5 94 100 MARK1 83 100 MARK2 100 100 MARK3 94 100 MARK4 92 100 MEK4 82 100 MEK5 37 100 MELK 89 100 MET 100 100 MET(M1250T) 89 100 MET(Y1235D) 100 100 MKNK1 94 100 MLCK 100 100 MLK2 100 100 MLK3 62 100 MRCKA 100 100 MRCKB 100 100 MST1 80 100 MST1R 100 100 MTOR 86 100 MYLK4 100 100 NDR2 100 100 NEK11 100 100 NEK3 65 100 NEK5 85 100 NEK7 100 100 NEK9 100 100 NIM1 100 100 PDPK1 69 100 PHKG1 100 100 PHKG2 100 100 PIK3C2B 100 100 PIK3CA(H1047Y) 79 100 PIM2 71 100 PIP5K1C 50 100 PIP5K2C 82 100 PKAC-alpha 72 100 PKAC-beta 100 100 PKMYT1 100 100 PKN2 89 100 PLK1 100 100 PLK2 100 100 PRKD3 100 100 PRKG1 100 100 PRKR 100 100 PRKX 100 100 PYK2 97 100 RIOK2 100 100 RIPK1 54 100 RIPK2 86 100 ROS1 75 100 RPS6KA5(Kin. Dom. 2-C-terminal) 100 100 RSK1(Kin. Dom. 1-N-terminal) 100 100 RSK1(Kin. Dom. 2-C-terminal) 100 100 RSK3(Kin. Dom. 1-N-terminal) 100 100 RSK3(Kin. Dom. 2-C-terminal) 100 100 RSK4(Kin. Dom. 2-C-terminal) 100 100 SgK110 100 100 SIK2 100 100 SRPK3 100 100 STK33 97 100 TEC 82 100 TGFBR1 100 100 TLK2 100 100 TNK2 100 100 TRPM6 58 100 TSSK1B 83 100 TXK 89 100 TYK2(JH2domain-pseudokinase) 87 100 TYRO3 92 100 ULK2 81 100 VEGFR2 28 100 WEE1 100 100 WEE2 100 100 YANK3 88 100
Kinative

(905) The kinase selectivity of compounds (A-5) and (A-14) were evaluated using a chemical proteomic approach named KiNativ which detects 260 kinases in A375 cells (ActivX Biosciences). To probe the intracellular targets of the compounds, A375 cells were incubated with the inhibitor at 1 M final concentration and then looked for protection of labeling by an ATP-biotin probe that non-specifically labels conserved lysines on kinases and other nucleotide-dependent enzymes.

(906) Results

(907) Table 4 shows that compound (A-5) inhibits a number of kinases at 1 M, including Ab1 (>90%), FYN (71.2%), LYN (87.8%), and ZAK (75.7%). Table 5 shows that compound (A-14) inhibits a number of kinases at 1 M, including Ab1 (>90%), FYN (88.2%), LYN (85.7%), and ZAK (75.8%).

(908) TABLE-US-00007 TABLE4 SEQ Compound ID Labeling A-4 Kinase Reference Sequence NO: Site (1.0M) ABL,ARG UniRef100_P00519, LMTGDTYTAHAGAKFPIK 1 Activation 95.5 UniRef100_P42684 Loop ACK UniRef100_Q07912 TVSVAVKCLKPDVLSQPEA 2 Lys1 4.9 MDDFIR AGK UniRef100_Q53H12 ATVFLNPAACKGK 3 ATP -31.4 AMPKa1, UniRef100_P54646, DLKPENVLLDAHMNAK 4 Lys2 16.3 AMPKa2 UniRef100_Q13131 ARAF UniRef100_P10398 DLKSNNIFLHEGLTVK 5 Lys2 12.2 ATR UniRef100_Q13535 FYIMMCKPK 6 ATP 23.0 AurA UniRef100_O14965 FILALKVLFK 7 Lys1 -16.0 AurB UniRef100_Q96GD4 SHFIVALKVLFK 8 Lys1 -51.1 BARK1 UniRef100_P25098 DLKPANILLDEHGHVR 9 Lys2 -13.4 BRAF UniRef100_P15056 DLKSNNIFLHEDLTVK 10 Lys2 18.9 BTK UniRef100_Q06187 YVLDDEYTSSVGSKFPVR 11 Activation -18.8 Loop CaMK1a UniRef100_Q14012 LVAIKCIAK 12 Lys1 12.4 CaMK1d UniRef100_Q8IU85 LFAVKCIPK 13 Lys1 -6.0 CaMK2d UniRef100_Q13557 IPTGQEYAAKIINTKK 14 Lys1 -8.1 CaMK2g UniRef100_Q13555 TSTQEYAAKIINTK 15 Lys1 -23.1 CaMK4 UniRef100_Q16566 DLKPENLLYATPAPDAPLK 16 Lys2 5.9 CaMKK2 UniRef100_Q96RR4 DIKPSNLLVGEDGHIK 17 Lys2 6.2 CASK UniRef100_O14936, ETGQQFAVKIVDVAK 18 Lys1 -28.1 UniRef100_C9JGY0 CDC2 UniRef100_P06493 DLKPQNLLIDDKGTIK 19 Lys2 -2.3 CDK11, UniRef100_P49336, DLKPANILVMGEGPER 20 Lys2 50.0 CDK8 UniRef100_Q9BWU1 CDK2 UniRef100_P24941 DLKPQNLLINTEGAIK 21 Lys2 -3.5 CDK4 UniRef100_P11802 DLKPENILVTSGGTVK 22 Lys2 17.4 CDK5 UniRef100_Q00535 DLKPQNLLINR 23 Lys2 -27.3 CDK6 UniRef100_Q00534 DLKPQNILVTSSGQIK 24 Lys2 13.1 CDK7 UniRef100_P50613 DLKPNNLLLDENGVLK 25 Lys2 3.9 CDK9 UniRef100_P50750 DMKAANVLITR 26 Lys2 -16.2 CHK1 UniRef100_B5BTY6, DIKPENLLLDER 27 Lys2 -5.0 UniRef100_O14757 CHK2 UniRef100_O96017 DLKPENVLLSSQEEDCLIK 28 Lys2 -7.8 CK1a UniRef100_P48729, DIKPDNFLMGIGR 29 Lys2 -0.6 UniRef100_B4E1D9 CK1g2 UniRef100_P78368 DVKPENFLVGRPGTK 30 Lys2 -9.1 CK2a2 UniRef100_P19784 DVKPHNVMIDHQQK 31 Lys2 -18.2 CLK3 UniRef100_P49761 YEIVGNLGEGTFGKVVECL 32 ATPLoop -52.8 DHAR CSK UniRef100_P41240 VSDFGLTKEASSTQDTGKL 33 Activation 15.3 PVK Loop DGKA UniRef100_P23743 IDPVPNTHPLLVFVNPKSG 34 ATP -4.8 GK DGKH UniRef100_Q86XP1 ATFSFCVSPLLVFVNSKSG 35 ATP -6.3 DNQGVK DGKQ UniRef100_P52824 GRLLTALVLPDLLHAKLPP 36 ATP 11.0 DSCPLLVFVNPKSGGLK DNAPK UniRef100_P78527 KGGSWIQEINVAEK 37 ATP -61.5 DNAPK UniRef100_P78527 EHPFLVKGGEDLR 38 ATP -64.6 eEF2K UniRef100_O00418 YIKYNSNSGFVR 39 ATP -30.5 EphB1 UniRef100_P54762 YLQDDTSDPTYTSSLGGKI 40 Activation -1.7 PVR Loop EphB2 UniRef100_P29323 FLEDDTSDPTYTSALGGKI 41 Activation -12.8 PIR Loop Erk1 UniRef100_P27361 DLKPSNLLINTTCDLK 42 Lys2 -9.0 Erk2 UniRef100_P28482 DLKPSNLLLNTTCDLK 43 Lys2 -3.8 Erk5 UniRef100_Q13164 DLKPSNLLVNENCELK 44 Lys2 25.9 FER UniRef100_P16591 TSVAVKTCKEDLPQELK 45 Lys1 91.4 FES UniRef100_P07332 LRADNTLVAVKSCR 46 Lys1 89.1 FGR UniRef100_P09769 LIKDDEYNPCQGSKFPIK 47 Activation 31.9 Loop FRAP UniRef100_P42345 IQSIAPSLQVITSKQRPR 48 ATP -7.5 FRK UniRef100_P42685 HEIKLPVK 49 Activation 91.1 Loop FYN,SRC, UniRef100_P12931, QGAKFPIKWTAPEAALYG 50 Activation 71.2 YES UniRef100_P07947, R Loop UniRef100_P06241 GCK UniRef100_Q12851 DIKGANLLLTLQGDVK 51 Lys2 94.9 GCN2 UniRef100_Q9P2K8 DLKPVNIFLDSDDHVK 52 Lys2 20.8 GSK3A UniRef100_P49840 DIKPQNLLVDPDTAVLK 53 Lys2 36.0 GSK3B UniRef100_P49841 DIKPQNLLLDPDTAVLK 54 Lys2 0.5 HPK1 UniRef100_Q92918 DIKGANILINDAGEVR 55 Lys2 68.1 IKKa UniRef100_O15111 DLKPENIVLQDVGGK 56 Lys2 -17.0 IKKb UniRef100_O14920 DLKPENIVLQQGEQR 57 Lys2 -12.6 IKKe UniRef100_Q14164 SGELVAVKVFNTTSYLRPR 58 Lys1 -9.9 ILK UniRef100_Q13418 WQGNDIVVKVLK 59 Lys1 5.2 IRAK1 UniRef100_P51617 AIQFLHQDSPSLIHGDIKSS 60 Lys2 -3.5 NVLLDER IRAK4 UniRef100_Q9NWZ3 DIKSANILLDEAFTAK 61 Lys2 1.9 IRE1 UniRef100_O75460 DLKPHNILISMPNAHGK 62 Lys2 -2.2 ITPK1 UniRef100_Q13572 ESIFFNSHNVSKPESSSVLT 63 ATP 1.2 ELDKIEGVFERPSDEVIR JAK1 UniRef100_P23458 QLASALSYLEDKDLVHGN 64 Protein 4.3 VCTKNLLLAR Kinase Domain JAK1 UniRef100_P23458 IGDFGLTKAIETDKEYYTVK 65 Activation -6.2 domain2 Loop JAK3 UniRef100_P52333 IADFGLAKLLPLDKDYYVV 66 Activation 7.7 domain2 R Loop JNK1, UniRef100_P45983, DLKPSNIVVK 67 Lys2 77.2 JNK2, UniRef100_P53779, JNK3 UniRef100_P45984 KHS1 UniRef100_Q9Y4K4 NVHTGELAAVKIIK 68 Lys1 15.8 KSR1 UniRef100_Q8IVT5 SKNVFYDNGKVVITDFGLF 69 Activation -22.0 GISGVVR Loop KSR1, UniRef100_Q6VAB6, SKNVFYDNGK 70 Activation -10.0 KSR2 UniRef100_Q8IVT5 Loop LATS1 UniRef100_095835 ALYATKTLR 71 Lys1 5.4 LATS2 UniRef100_Q9NRM7 DIKPDNILIDLDGHIK 72 Lys2 -1.9 LCK UniRef100_P06239 EGAKFPIKWTAPEAINYGT 73 Activation 92.3 FTIK Loop LKB1 UniRef100_Q15831 DIKPGNLLLTTGGTLK 74 Lys2 -6.0 LOK UniRef100_O94804 DLKAGNVLMTLEGDIR 75 Lys2 19.9 LRRK2 UniRef100_Q5S007 DLKPHNVLLLYPNAAIIA 76 Lys2 -15.9 K LYN UniRef100_P07948 VAVKTLKPGTMSVQAFLE 77 Lys1 87.8 EANLMK MAP2K1 UniRef100_Q02750 IMHRDVKPSNILVNSR 78 Lys2 11.4 MAP2K1, UniRef100_P36507, DVKPSNILVNSR 79 Lys2 -16.3 MAP2K2 UniRef100_Q02750 MAP2K3 UniRef100_P46734 DVKPSNVLINK 80 Lys2 -1.0 MAP2K4 UniRef100_P45985 DIKPSNILLDR 81 Lys2 -14.1 MAP2K5 UniRef100_Q13163 DVKPSNMLVNTR 82 Lys2 20.5 MAP2K6 UniRef100_P52564 DVKPSNVLINALGQVK 83 Lys2 0.5 MAP2K7 UniRef100_O14733 DVKPSNILLDER 84 Lys2 -38.2 MAP3K1 UniRef100_Q13233 DVKGANLLIDSTGQR 85 Lys2 26.9 MAP3K2 UniRef100_Q9Y2U5 ELAVKQVQFDPDSPETSK 86 Lys1 4.2 EVNALECEIQLLK MAP3K2, UniRef100_Q9Y2U5, DIKGANILR 87 Lys2 3.2 MAP3K3 UniRef100_Q99759 MAP3K3 UniRef100_Q99759 ELASKQVQFDPDSPETSKE 88 Lys1 3.7 VSALECEIQLLK MAP3K4 UniRef100_Q9Y6R4 DIKGANIFLTSSGLIK 89 Lys2 19.2 MAP3K5 UniRef100_Q99683 DIKGDNVLINTYSGVLK 90 Lys2 -30.4 MAP3K6 UniRef100_O95382 DIKGDNVLINTFSGLLK 91 Lys2 -25.0 MARK2, UniRef100_P27448, DLKAENLLLDADMNIK 92 Lys2 4.6 MARK3 UniRef100_Q7KZI7 MARK3 UniRef100_P27448 EVAIKIIDKTQLNPTSLQK 93 Lys1 -26.1 MARK3, UniRef100_Q96L34, EVAIKIIDK 94 Lys1 -16.2 MARK4 UniRef100_P27448 MARK4 UniRef100_Q96L34 DLKAENLLLDAEANIK 95 Lys2 2.9 MAST1, UniRef100_Q6P0Q8, DLKPDNLLITSMGHIK 96 Lys2 35.6 MAST2 UniRef100_Q9Y2H9 MAST3 UniRef100_O60307 DLKPDNLLITSLGHIK 97 Lys2 -8.1 MASTL UniRef100_Q96GX5 GAFGKVYLGQK 98 ATPLoop 12.8 MASTL UniRef100_Q96GX5 LYAVKVVK 99 Lys1 3.3 MELK UniRef100_Q14680 DLKPENLLFDEYHK 100 Lys2 -19.6 MER UniRef100_Q12866 NCMLRDDMTVCVADFGL 101 Activation 49.8 SKK Loop MER, UniRef100_Q06418, KIYSGDYYR 102 Activation 1.6 TYRO3 UniRef100_Q12866 Loop MET UniRef100_P08581 DMYDKEYYSVHNK 103 Activation -21.0 Loop MLK3 UniRef100_Q16584 DLKSNNILLLQPIESDDME 104 Lys2 20.7 HK MLK4 UniRef100_Q5TCX8 DLKSSNILLLEK 105 Lys2 -1.7 MLKL UniRef100_Q8NB16 APVAIKVFK 106 Lys1 -14.9 MPSK1 UniRef100_O75716 DLKPTNILLGDEGQPVLM 107 Lys2 16.1 DLGSMNQACIHVEGSR MSK1 UniRef100_O75582 DIKLENILLDSNGHVVLTD 108 Lys2 5.7 domain1 FGLSK MSK2 UniRef100_O75676 DLKLENVLLDSEGHIVLTD 109 Lys2 -64.9 domain1 FGLSK MST1 UniRef100_Q13043 ETGQIVAIKQVPVESDLQE 110 Lys1 -4.7 IIK MST2 UniRef100_Q13188 ESGQVVAIKQVPVESDLQ 111 Lys1 -6.2 EIIK MST3 UniRef100_Q9Y6E0 DIKAANVLLSEHGEVK 112 Lys2 -3.7 MST4 UniRef100_Q9P289 TQQVVAIKIIDLEEAEDEIE 113 Lys1 6.2 DIQQEITVLSQCDSSYVTK MST4, UniRef100_000506, DIKAANVLLSEQGDVK 114 Lys2 4.6 YSK1 UniRef100_Q9P289 MYO3A, UniRef100_Q8NEV4, DVKGNNILLTTEGGVK 115 Lys2 -15.3 MYO3B UniRef100_Q8WXR4 NDR1 UniRef100_Q15208 DIKPDNLLLDSK 116 Lys2 9.3 NDR2 UniRef100_Q9Y2H1 DIKPDNLLLDAK 117 Lys2 -10.9 NEK1 UniRef100_Q96PY6 DIKSQNIFLTK 118 Lys2 -3.0 NEK2 UniRef100_P51955 DLKPANVFLDGK 119 Lys2 -22.7 NEK3 UniRef100_P51956 SKNIFLTQNGK 120 Activation 13.1 Loop NEK4 UniRef100_P51957 DLKTQNVFLTR 121 Lys2 1.5 NEK6, UniRef100_Q8TDX7, DIKPANVFITATGVVK 122 Lys2 -12.5 NEK7 UniRef100_Q9HC98 NEK7 UniRef100_Q8TDX7 AACLLDGVPVALKK 123 Lys1 -7.2 NEK8 UniRef100_Q86SG6 DLKTQNILLDK 124 Lys2 -11.4 NEK9 UniRef100_Q8TD19 DIKTLNIFLTK 125 Lys2 -1.2 OSR1 UniRef100_C9JIG9, DVKAGNILLGEDGSVQIA 126 Lys2 -11.1 UniRef100_O95747 DFGVSAFLATGGDITR p38a UniRef100_Q16539 DLKPSNLAVNEDCELK 127 Lys2 61.4 p38a UniRef100_Q16539 QELNKTIWEVPER 128 Protein 92.2 Kinase Domain p38b UniRef100_015759 QELNKTVWEVPQR 129 Protein 51.4 Kinase Domain p38d, UniRef100_O15264, DLKPGNLAVNEDCELK 130 Lys2 62.5 p38g UniRef100_P53778 p70SEK UniRef100_P23443 DLKPENIMLNHQGHVK 131 Lys2 -2.3 p70S6Kb UniRef100_Q9UBS0 DLKPENIMLSSQGHIK 132 Lys2 8.2 PAN3 UniRef100_Q58A45 VMDPTKILITGK 133 ATP 12.1 PCTAIRE1 UniRef100_Q00536 SKLTDNLVALKEIR 134 Lys1 -3.5 PCTAIRE2, UniRef100_Q00537, SKLTENLVALKEIR 135 Lys1 11.7 PCTAIRE3 UniRef100_Q07002 PDK1 UniRef100_O15530 EYAIKILEK 136 Lys1 18.8 PEK UniRef100_Q9N2J5 DLKPSNIFFTMDDVVK 137 Lys2 9.4 PFTAIRE1 UniRef100_O94921 LVALKVIR 138 Lys1 4.3 PHKg1 UniRef100_Q16816 DLKPENILLDDNMNIK 139 Protein -49.0 Kinase Domain PHKg2 UniRef100_P15735 ATGHEFAVKIMEVTAER 140 Lys1 15.2 PI4KA, UniRef100_A4QPH2, SGTPMQSAAKAPYLAK 141 ATP 19.3 PI4KAP2 UniRef100_P42356 PI4KB UniRef100_Q9UBF8 VPHTQAVVLNSKDK 142 ATP -0.2 PIK3C2B UniRef100_O00750 VIFKCGDDLRQDMLTLQ 143 ATP 24.0 MIR PIK3C3 UniRef100_Q8NEB9 TEDGGKYPVIFKHGDDLR 144 ATP -5.1 PIK3CB UniRef100_Q9BTS4, VFGEDSVGVIFKNGDDLR 145 ATP 27.8 UniRef100_P42338 QDMLTLQMLR PIK3CD UniRef100_O00329 VNWLAHNVSKDNRQ 146 ATP 2.2 PIK3CG UniRef100_P48736 KKPLWLEFK 147 ATP -21.1 PIP4K2A UniRef100_P48426 AKELPTLKDNDFINEGQK 148 ATP -26.7 PIP4K2B UniRef100_P78356 AKDLPTFKDNDFLNEGQK 149 ATP -44.7 PIP4K2C UniRef100_Q8TBX8 TLVIKEVSSEDIADMHSNL 150 ATP 5.2 SNYHQYIVK PIP5K3 UniRef100_Q9Y217 GGKSGAAFYATEDDRFILK 151 ATP 0.9 PITSLRE UniRef100_P21127 DLKTSNLLLSHAGILK 152 Lys2 -10.4 PKCa, UniRef100_P17252, DLKLDNVMLDSEGHIK 153 Lys2 2.3 PKCb UniRef100_P05771, UniRef100_B5BU22 PKD2 UniRef100_Q9BZL6 DVAVKVIDK 154 Lys1 -6.9 PKN1 UniRef100_Q16512 VLLSEFRPSGELFAIKALK 155 Lys1 -32.1 PKR UniRef100_P19525 DLKPSNIFLVDTK 156 Lys2 -28.4 PLK1 UniRef100_P53350 CFEISDADTEVFAGKIVP 157 Lys1 -9.1 K PRP4 UniRef100_Q13523 CNILHADIKPDNILVNESK 158 Lys2 -20.1 PRPK UniRef100_Q96S44 FLSGLELVKQGAEAR 159 ATPLoop -13.7 PYK2 UniRef100_Q14289 YIEDEDYYKASVTR 160 Activation 10.9 Loop RAF1 UniRef100_P04049 DMKSNNIFLHEGLTVK 161 Lys2 36.6 RIPK3 UniRef100_Q9Y572 DLKPSNVLLDPELHVK 162 Lys2 32.6 ROCK1, UniRef100_O75116, DVKPDNMLLDK 163 Lys2 22.0 ROCK2 UniRef100_Q13464 RSK1 UniRef100_Q15418 DLKPENILLDEEGHIKLTDF 164 Lys2 -20.9 domain1 GLSKEAIDHEK RSK1 UniRef100_Q15418, DLKPENILLDEEGHIK 165 Lys2 -17.7 domain1, UniRef100_P51812, RSK2 UniRef100_Q15349 domain1, RSK3 domain1 RSK1 UniRef100_Q15418 DLKPSNILYVDESGNPECL 166 Lys2 -16.3 domain1 R RSK2 UniRef100_P51812 DLKPENILLDEEGHIKLTDF 167 Lys2 -3.3 domain1 GLSKESIDHEK RSK2 UniRef100_P51812 DLKPSNILYVDESGNPESIR 168 Lys2 -24.1 domain2 RSK3 UniRef100_015349 DLKPENILLDEEGHIKITDF 169 Lys2 -32.6 domain1 GLSK RSK4 UniRef100_Q9UK32 DLKPENILLDEIGHIK 170 Lys2 27.6 domain1 RSKL1 UniRef100_Q96S38 VLGVIDKVLLVMDTR 171 ATP 31.5 SGK3 UniRef100_Q96BR1 FYAVKVLQK 172 Lys1 -10.2 SLK UniRef100_Q9H2G2 DLKAGNILFTLDGDIK 173 Lys2 -14.3 SMG1 UniRef100_Q96Q15 DTVTIHSVTITILPTKTK 174 ATP -4.0 PK SNRK UniRef100_Q9NRH2 DLKPENVVFFEK 175 Lys2 18.0 SRC UniRef100_P12931 VAIKTLKPGTMSPEAFLQE 176 Lys1 76.1 AQVMKK SRPK1 UniRef100_Q96SB4 IIHTDIKPENILLSVNEQYIR 177 Lys2 -34.1 STK33 UniRef100_Q9BYT3 DLKLENIMVK 178 Lys2 12.9 STLK5 UniRef100_Q7RTN6 YSVKVLPWLSPEVLQQNL 179 Activation 5.0 QGYDAK Loop SYK UniRef100_P43405 ISDFGLSKALR 180 Activation 17.4 Loop TAK1 UniRef100_043318 DLKPPNLLLVAGGTVLK 181 Lys2 32.0 TAO1, UniRef100_Q9H2K8, DIKAGNILLTEPGQVK 182 Lys2 76.5 TAO3 UniRef100_Q7L7X3 TAO2 UniRef100_Q9UL54 DVKAGNILLSEPGLVK 183 Lys2 86.0 TBK1 UniRef100_Q9UHD2 TGDLFAIKVFNNISFLRPV 184 Lys1 18.2 DVQMR TEC UniRef100_P42680 YVLDDQYTSSSGAKFPVK 185 Activation -12.8 Loop TLK1 UniRef100_Q9UKI8 YLNEIKPPIIHYDLKPGNILL 186 Lys2 4.9 VDGTACG TLK2 UniRef100_Q86UE8 YLNEIKPPIIHYDLKPGNILL 187 Lys2 7.1 VNGTACGEIK TYK2 UniRef100_P29597 IGDFGLAKAVPEGHEYYR 188 Activation -18.1 domain2 Loop ULK1 UniRef100_075385 DLKPQNILLSNPAGR 189 Lys2 -6.0 ULK3 UniRef100_D3DW67, NISHLDLKPQNILLSSLEKP 190 Lys2 -4.4 UniRef100_Q6PHR2 HLK VRK2 UniRef100_Q86Y07 MLDVLEYIHENEYVHGDIK 191 Lys2 27.9 AANLLLGYK Wee1 UniRef100_P30291 YIHSMSLVHDIKPSNIFIS 192 Lys2 23.2 R Wnk1, UniRef100_Q9Y3S1, GSFKTVYK 193 ATPLoop 24.2 Wnk2 UniRef100_D3DUP1, UniRef100_Q9H4A3 Wnk1, UniRef100_Q9Y3S1, DLKCDNIFITGPTGSVK 194 Lys2 0.2 Wnk2, UniRef100_D3DUP1, Wnk3 UniRef100_Q9BYP7, UniRef100_Q9H4A3 YANK3 UniRef100_Q86UX6 DVKPDNILLDER 195 Lys2 27.7 ZAK UniRef100_Q9NYL2 WISQDKEVAVKK 196 Lys1 75.7 ZAP70 UniRef100_P43403 ISDFGLSKALGADDSYYTA 197 Activation 49.2 R Loop ZC1/HGK, UniRef100_O95819, DIKGQNVLLTENAEVK 198 Lys2 19.2 ZC2/TNIK, UniRef100_Q9UKE5, ZC3/MINK UniRef100_Q8N4C8 ZC2/TNIK UniRef100_Q9UKE5 TGQLAAIKVMDVTGDEEE 199 Lys1 23.9 EIKQEINMLKK

(909) TABLE-US-00008 TABLE5 SEQ Cmpd. ID Labeling A-14 Kinase Reference Sequence NO: Site (1.0M) ABL,ARG UniRef100_P00519, LMTGDTYTAHAGAKFPIK 200 Activation 98.4 UniRef100_P42684 Loop ACK UniRef100_Q07912 TVSVAVKCLKPDVLSQPEA 201 Lys1 8.5 MDDFIR AGK UniRef100_Q53H12 ATVFLNPAACKGK 202 ATP 5.9 AKT1 UniRef100_P31749 GTFGKVILVK 203 ATPLoop -23.9 AKT2, UniRef100_Q9Y243, GTFGKVILVR 204 ATPLoop -19.7 AKT3 UniRef100_P31751 AMPKa1, UniRef100_P54646, DLKPENVLLDAHMNAK 205 Lys2 -17.5 AMPKa2 UniRef100_Q96E92 ANPa UniRef100_P16066 GMLFLHNGAICSHGNLKS 206 Lys2 -5.3 SNCVVDGR ARAF UniRef100_P10398 DLKSNNIFLHEGLTVK 207 Lys2 2.0 ATR UniRef100_Q13535 FYIMMCKPK 208 ATP -20.3 AurA UniRef100_O14965 FILALKVLFK 209 Lys1 14.6 AurA UniRef100_O14965 DIKPENLLLGSAGELK 210 Lys2 6.1 AurA, UniRef100_O14965, GKFGNVYLAR 211 ATPLoop -2.4 AurB, UniRef100_Q9UQB9, AurC UniRef100_Q96GD4 AurB UniRef100_Q96GD4 SHFIVALKVLFK 212 Lys1 3.3 BARK1 UniRef100_P25098 DLKPANILLDEHGHVR 213 Lys2 -13.6 BRAF UniRef100_P15056 DLKSNNIFLHEDLTVK 214 Lys2 18.9 BTK UniRef100_006187 YVLDDEYTSSVGSKFPVR 215 Activation -10.2 Loop CaMK1a UniRef100_Q14012 LVAIKCIAK 216 Lys1 -5.4 CaMK1d UniRef100_Q8IU85 LFAVKCIPK 217 Lys1 -1.8 CaMK2d UniRef100_Q13557 IPTGQEYAAKIINTKK 218 Lys1 -7.3 CaMK2g UniRef100_Q13555 TSTQEYAAKIINTK 219 Lys1 2.0 CaMK4 UniRef100_Q16566 DLKPENLLYATPAPDAPLK 220 Lys2 -2.0 CaMKK2 UniRef100_Q96RR4 DIKPSNLLVGEDGHIK 221 Lys2 16.2 CASK UniRef100_014936 ETGQQFAVKIVDVAK 222 Lys1 7.1 CDC2 UniRef100_Q5H9N4 DLKPQNLLIDDKGTIK 223 Lys2 9.0 CDK11, UniRef100_P49336, DLKPANILVMGEGPER 224 Lys2 49.2 CDK8 UniRef100_Q9BWU1 CDK2 UniRef100_P24941 DLKPQNLLINTEGAIK 225 Lys2 34.5 CDK4 UniRef100_P11802 DLKPENILVTSGGTVK 226 Lys2 11.4 CDKS UniRef100_Q00535 DLKPQNLLINR 227 Lys2 11.3 CDK6 UniRef100_Q00534 DLKPQNILVTSSGQIK 228 Lys2 13.6 CDK7 UniRef100_P50613 DLKPNNLLLDENGVLK 229 Lys2 -7.3 CDK9 UniRef100_P50750 DMKAANVLITR 230 Lys2 -13.1 CHK1 UniRef100_B4DT73 DIKPENLLLDER 231 Lys2 12.2 CHK2 UniRef100_O96017 DLKPENVLLSSQEEDCLIK 232 Lys2 -1.6 CK1a UniRef100_P48729 DIKPDNFLMGIGR 233 Lys2 -19.6 CK1d, UniRef100_P49674, DVKPDNFLMGLGKK 234 Lys2 -9.3 CK1e UniRef100_P48730 CK1g1, UniRef100_Q9Y6M4, KIGCGNFGELR 235 ATPLoop 1.3 CK1g2, UniRef100_P78368, CK1g3 UniRef100_Q9HCP0 CK1g2 UniRef100_P78368 DVKPENFLVGRPGTK 236 Lys2 -23.3 CLK2 UniRef100_P49760 LTHTDLKPENILFVNSDYEL 237 Lys2 -30.3 TYNLEK CLK3 UniRef100_P49761 YEIVGNLGEGTFGKVVECL 238 ATPLoop -4.0 DHAR CSK UniRef100_P41240 VSDFGLTKEASSTQDTGKL 239 Activation 20.0 PVK Loop DGKA UniRef100_P23743 IDPVPNTHPLLVFVNPKSG 240 ATP -16.3 GK DGKH UniRef100_Q86XP1 ATFSFCVSPLLVFVNSKSG 241 ATP 32.6 DNQGVK DGKQ UniRef100_P52824 GRLLTALVLPDLLHAKLPP 242 ATP -23.2 DSCPLLVFVNPKSGGLK DNAPK UniRef100_P78527 KGGSWIQEINVAEK 243 ATP -35.9 DNAPK UniRef100_P78527 EHPFLVKGGEDLR 244 ATP -63.7 eEF2K UniRef100_O00418 YIKYNSNSGFVR 245 ATP -22.0 Erk1 UniRef100_P27361 DLKPSNLLINTTCDLK 246 Lys2 -16.3 Erk2 UniRef100_P28482 DLKPSNLLLNTTCDLK 247 Lys2 -2.7 Erk3 UniRef100_Q16659 DLKPANLFINTEDLVLK 248 Lys2 31.8 ErkS UniRef100_Q13164 DLKPSNLLVNENCELK 249 Lys2 -42.7 FER UniRef100_P16591 TSVAVKTCKEDLPQELK 250 Lys1 74.0 FES UniRef100_P07332 LRADNTLVAVKSCR 251 Lys1 36.1 FGR UniRef100_P09769 LIKDDEYNPCQGSKFPIK 252 Activation 70.3 Loop FRAP UniRef100_P42345 IQSIAPSLQVITSKQRPR 253 ATP -3.3 FRK UniRef100_P42685 HEIKLPVK 254 Activation 98.0 Loop FYN,SRC, UniRef100_P12931, QGAKFPIKWTAPEAALYG 255 Activation 88.2 YES UniRef100_P07947, R Loop UniRef100_P06241 GCK UniRef100_Q12851 DIKGANLLLTLQGDVK 256 Lys2 96.3 GCN2 UniRef100_Q9P2K8 DLKPVNIFLDSDDHVK 257 Lys2 5.4 GPRK6 UniRef100_P43250 DLKPENILLDDHGHIR 258 Lys2 -1.9 GSK3A UniRef100_P49840 DIKPQNLLVDPDTAVLK 259 Lys2 25.5 GSK3B UniRef100_P49841 DIKPQNLLLDPDTAVLK 260 Lys2 -3.5 HPK1 UniRef100_Q92918 DIKGANILINDAGEVR 261 Lys2 88.2 IKKa UniRef100_O15111 DLKPENIVLQDVGGK 262 Lys2 -3.1 IKKb UniRef100_O14920 DLKPENIVLQQGEQR 263 Lys2 -12.2 IKKe UniRef100_Q14164 SGELVAVKVFNTTSYLRPR 264 Lys1 -3.9 ILK UniRef100_Q13418 WQGNDIVVKVLK 265 Lys1 -0.4 ILK UniRef100_Q13418 ISMADVKFSFQCPGR 266 Protein 6.8 Kinase Domain IRAK1 UniRef100_P51617 AIQFLHQDSPSLIHGDIKSS 267 Lys2 7.6 NVLLDER IRAK3 UniRef100_Q9Y616 VEIQNLTYAVKLFK 268 Lys1 -7.1 IRAK4 UniRef100_Q9NWZ3 DIKSANILLDEAFTAK 269 Lys2 6.3 IRE1 UniRef100_O75460 DLKPHNILISMPNAHGK 270 Lys2 -0.6 ITPK1 UniRef100_Q13572 ESIFFNSHNVSKPESSSVLT 271 ATP -16.2 ELDKIEGVFERPSDEVIR JAK1 UniRef100_P23458 QLASALSYLEDKDLVHGN 272 Protein 9.0 domain1 VCTKNLLLAR Kinase Domain JAK1 UniRef100_P23458 IGDFGLTKAIETDKEYYTVK 273 Activation 29.3 domain2 Loop JAK1 UniRef100_P23458 YDPEGDNTGEQVAVKSLK 274 Lys1 24.0 domain2 PESGGNHIADLKK JAK3 UniRef100_P52333 IADFGLAKLLPLDKDYYVV 275 Activation -4.3 domain2 R Loop JNK1, UniRef100_P45983, DLKPSNIVVK 276 Lys2 31.5 JNK2, UniRef100_P53779, JNK3 UniRef100_P45984 KHS1 UniRef100_Q9Y4K4 NVHTGELAAVKIIK 277 Lys1 33.9 KHS2 UniRef100_Q8IVH8 NVNTGELAAIKVIK 278 Lys1 3.8 KSR1 UniRef100_Q8IVT5 SKNVFYDNGKVVITDFGLF 279 Activation -0.2 GISGVVR Loop KSR1, UniRef100_Q6VAB6, SKNVFYDNGK 280 Activation 1.4 KSR2 UniRef100_Q8IVT5 Loop LATS1 UniRef100_O95835 ALYATKTLR 281 Lys1 15.8 LATS2 UniRef100_Q9NRM7 DIKPDNILIDLDGHIK 282 Lys2 0.8 LCK UniRef100_P06239 EGAKFPIKWTAPEAINYGT 283 Activation 83.8 FTIK Loop LKB1 UniRef100_Q15831 DIKPGNLLLTTGGTLK 284 Lys2 3.6 LOK UniRef100_O94804 DLKAGNVLMTLEGDIR 285 Lys2 28.8 LRRK2 UniRef100_Q5S007 DLKPHNVLLLYPNAAIIA 286 Lys2 -11.8 K LYN UniRef100_P07948 VAVKTLKPGTMSVQAFLE 287 Lys1 85.7 EANLMK MAP2K1 UniRef100_Q02750 IMHRDVKPSNILVNSR 288 Lys2 6.6 MAP2K1, UniRef100_P36507, KLIHLEIKPAIR 289 Lys1 9.4 MAP2K2 UniRef100_Q02750 MAP2K1, UniRef100_P36507, DVKPSNILVNSR 290 Lys2 2.2 MAP2K2 UniRef100_Q02750 MAP2K2 UniRef100_P36507 HQIMHRDVKPSNILVNSR 291 Lys2 3.9 MAP2K3 UniRef100_P46734 DVKPSNVLINK 292 Lys2 -1.0 MAP2K4 UniRef100_P45985 DIKPSNILLDR 293 Lys2 0.4 MAP2K5 UniRef100_Q13163 DVKPSNMLVNTR 294 Lys2 -46.0 MAP2K6 UniRef100_P52564 DVKPSNVLINALGQVK 295 Lys2 2.0 MAP2K7 UniRef100_O14733 DVKPSNILLDER 296 Lys2 19.3 MAP3K1 UniRef100_Q13233 DVKGANLLIDSTGQR 297 Lys2 27.5 MAP3K2 UniRef100_Q9Y2U5 ELAVKQVQFDPDSPETSK 298 Lys1 -1.1 EVNALECEIQLLK MAP3K2, UniRef100_Q9Y2U5, DIKGANILR 299 Lys2 8.4 MAP3K3 UniRef100_Q99759 MAP3K3 UniRef100_Q99759 ELASKQVQFDPDSPETSKE 300 Lys1 10.0 VSALECEIQLLK MAP3K4 UniRef100_Q9Y6R4 DIKGANIFLTSSGLIK 301 Lys2 17.3 MAP3K5 UniRef100_Q99683 DIKGDNVLINTYSGVLK 302 Lys2 -10.2 MAP3K6 UniRef100_095382 DIKGDNVLINTFSGLLK 303 Lys2 2.1 MARK2, UniRef100_P27448, DLKAENLLLDADMNIK 304 Lys2 -15.6 MARK3 UniRef100_Q7KZI7 MARK3 UniRef100_P27448 EVAIKIIDKTQLNPTSLQK 305 Lys1 2.6 MARK3, UniRef100_Q96L34, EVAIKIIDK 306 Lys1 -7.5 MARK4 UniRef100_P27448 MARK4 UniRef100_Q96L34 DLKAENLLLDAEANIK 307 Lys2 -28.5 MAST1, UniRef100_Q6P0Q8, DLKPDNLLITSMGHIK 308 Lys2 -24.8 MAST2 UniRef100_Q9Y2H9 MAST3 UniRef100_O60307 DLKPDNLLITSLGHIK 309 Lys2 -4.7 MASTL UniRef100_Q96GX5 GAFGKVYLGQK 310 ATPLoop 1.1 MASTL UniRef100_Q96GX5 LYAVKVVK 311 Lys1 -7.6 MELK UniRef100_Q14680 DLKPENLLFDEYHK 312 Lys2 -3.0 MER, UniRef100_Q06418, KIYSGDYYR 313 Activation 21.2 TYRO3 UniRef100_Q12866 Loop MET UniRef100_P08581 DMYDKEYYSVHNK 314 Activation 5.7 Loop MLK3 UniRef100_Q16584 DLKSNNILLLQPIESDDME 315 Lys2 -0.2 IIK MLK4 UniRef100_Q5TCX8 DLKSSNILLLEK 316 Lys2 1.5 MLKL UniRef100_Q8NB16 APVAIKVFK 317 Lys1 -5.5 MPSK1 UniRef100_O75716 DLKPTNILLGDEGQPVLM 318 Lys2 -2.3 DLGSMNQACIHVEGSR MSK1 UniRef100_O75582 DIKLENILLDSNGHVVLTD 319 Lys2 -21.5 domain1 FGLSK MSK2 UniRef100_O75676 DLKLENVLLDSEGHIVLTD 320 Lys2 -8.1 domain1 FGLSK MST1 UniRef100_Q13043 ETGQIVAIKQPVESDLQE 321 Lys1 7.5 IIK MST2 UniRef100_Q13188 ESGQVVAIKQVPVESDLQ 322 Lys1 8.6 EIIK MST3 UniRef100_Q9Y6E0 DIKAANVLLSEHGEVK 323 Lys2 -8.9 MST4 UniRef100_Q9P289 TQQVVAIKIIDLEEAEDEIE 324 Lys1 -37.3 DIQQEITVLSQCDSSYVTK MST4, UniRef100_O00506, DIKAANVLLSEQGDVK 325 Lys2 -2.4 YSK1 UniRef100_Q9P289 MYO3A, UniRef100_Q8NEV4, DVKGNNILLTTEGGVK 326 Lys2 22.9 MYO3B UniRef100_Q8WXR4 NDR1 UniRef100_Q15208 DIKPDNLLLDSK 327 Lys2 2.3 NDR2 UniRef100_Q9Y2H1 DIKPDNLLLDAK 328 Lys2 9.8 NEK1 UniRef100_Q96PY6 DIKSQNIFLTK 329 Lys2 -7.1 NEK2 UniRef100_P51955 DLKPANVFLDGK 330 Lys2 12.5 NEK3 UniRef100_P51956 SKNIFLTQNGK 331 Activation -8.6 Loop NEK4 UniRef100_P51957 DLKTQNVFLTR 332 Lys2 2.8 NEK6, UniRef100_Q8TDX7, DIKPANVFITATGVVK 333 Lys2 -1.8 NEK7 UniRef100_Q9HC98 NEK7 UniRef100_Q8TDX7 AACLLDGVPVALKK 334 Lys1 2.7 NEK8 UniRef100_Q86SG6 DLKTQNILLDK 335 Lys2 -7.8 NEK9 UniRef100_Q8TD19 DIKTLNIFLTK 336 Lys2 -10.7 NLK UniRef100_Q9UBE8 DIKPGNLLVNSNCVLK 337 Lys2 22.3 OSR1 UniRef100_C9JIG9, DVKAGNILLGEDGSVQIA 338 Lys2 32.2 UniRef100_095747 DFGVSAFLATGGDITR p38a UniRef100_Q16539 DLKPSNLAVNEDCELK 339 Lys2 76.1 p38a UniRef100_Q16539 QELNKTIWEVPER 340 Protein 88.4 Kinase Domain p38d, UniRef100_O15264, DLKPGNLAVNEDCELK 341 Lys2 51.5 p38g UniRef100_P53778 p70S6K UniRef100_P23443 DLKPENIMLNHQGHVK 342 Lys2 -74.1 p70S6Kb UniRef100_Q9UBS0 DLKPENIMLSSQGHIK 343 Lys2 3.5 PAN3 UniRef100_Q58A45 VMDPTKILITGK 344 ATP 7.3 PCTAIRE1 UniRef100_Q00536 SKLTDNLVALKEIR 345 Lys1 53.3 PCTAIRE2, UniRef100_Q00537, SKLTENLVALKEIR 346 Lys1 72.9 PCTAIRE3 UniRef100_Q07002 PDHK1 UniRef100_Q15118 SPGQPIQVVYVPSHLYHM 347 ATP -23.7 VFELFKNAMR PEK UniRef100_Q9NZJ5 DLKPSNIFFTMDDVVK 348 Lys2 -21.9 PFTAIRE1 UniRef100_O94921 LVALKVIR 349 Lys1 64.0 PHKg1 UniRef100_Q16816 DLKPENILLDDNMNIK 350 Protein -0.9 Kinase Domain PHKg2 UniRef100_P15735 ATGHEFAVKIMEVTAER 351 Lys1 7.1 PI4K2B UniRef100_Q8TCG2 SEEPYGQLNPKWTK 352 ATP 33.4 PI4KA, UniRef100_A4QPH2, SGTPMQSAAKAPYLAK 353 ATP 2.1 PI4KAP2 UniRef100_P42356 P14KB UniRef100_Q9UBF8 VPHTQAVVLNSKDK 354 ATP 23.7 PIK3C2B UniRef100_O00750 VIFKCGDDLRQDMLTLQ 355 ATP -15.7 MIR PIK3C3 UniRef100_Q8NEB9 TEDGGKYPVIFKHGDDLR 356 ATP -29.7 PIK3CB UniRef100_P42338 VFGEDSVGVIFKNGDDLR 357 ATP -3.9 QDMLTLQMLR PIK3CD UniRef100_O00329 VNWLAHNVSKDNRQ 358 ATP -22.8 PIK3CG UniRef100_P48736 KKPLWLEFK 359 ATP -20.1 PIP4K2A UniRef100_P48426 AKELPTLKDNDFINEGQK 360 ATP -19.5 PIP4K2C UniRef100_Q8TBX8 TLVIKEVSSEDIADMHSNL 361 ATP -7.3 SNYHQYIVK PIP5K3 UniRef100_Q9Y217 GGKSGAAFYATEDDRFILK 362 ATP 21.7 PITSLRE UniRef100_P21127 DLKTSNLLLSHAGILK 363 Lys2 10.2 PKCa, UniRef100_P05771, DLKLDNVMLDSEGHIK 364 Lys2 -86.4 PKCb UniRef100_P17252 PKCe UniRef100_Q02156 DLKLDNILLDAEGHCK 365 Lys2 27.7 PKCi UniRef100_P41743 IYAMKVVK 366 Lys1 -54.3 PKD2 UniRef100_Q9BZL6 DVAVKVIDK 367 Lys1 -5.4 PKN1 UniRef100_Q16512 VLLSEFRPSGELFAIKALK 368 Lys1 1.8 PKR UniRef100_P19525 DLKPSNIFLVDTK 369 Lys2 -1.7 K PLK1 UniRef100_P53350 CFEISDADTKEVFAGKIVP 370 Lys1 18.8 K PLK4 UniRef100_O00444 AESIHTGLEVAIKMIDKK 371 Lys1 -17.3 PRP4 UniRef100_Q13523 CNILHADIKPDNILVNESK 372 Lys2 -5.5 PRPK UniRef100_Q96544 FLSGLELVKQGAEAR 373 ATPLoop -16.0 PYK2 UniRef100_Q14289 YIEDEDYYKASVTR 374 Activation 30.5 Loop RIPK1 UniRef100_Q13546 DLKPENILVDNDFHIK 375 Lys2 23.1 RIPK3 UniRef100_Q9Y572 DLKPSNVLLDPELHVK 376 Lys2 70.2 ROCK1, UniRef100_O75116, DVKPDNMLLDK 377 Lys2 -0.2 ROCK2 UniRef100_Q13464 RSK1 UniRef100_Q15418 DLKPENILLDEEGHIKLTDF 378 Lys2 -29.6 domain1 GLSKEAIDHEK RSK1 UniRef100_P51812, DLKPENILLDEEGHIK 379 Lys2 -25.1 domain1, UniRef100_Q15418, RSK2 UniRef100_Q15349 domain1, RSK3 domain1 RSK1 UniRef100_Q15418 DLKPSNILYVDESGNPECL 380 Lys2 1.0 domain2 R RSK2 UniRef100_P51812 DLKPENILLDEEGHIKLTDF 381 Lys2 -36.7 domain1 GLSKESIDHEK RSK2 UniRef100_P51812 DLKPSNILYVDESGNPESIR 382 Lys2 2.8 domain2 RSK3 UniRef100_015349 DLKPENILLDEEGHIKITDF 383 Lys2 -37.8 domain1 GLSK RSKL1 UniRef100_Q96S38 VLGVIDKVLLVMDTR 384 ATP 21.8 SGK3 UniRef100_Q96BR1 FYAVKVLQK 385 Lys1 16.6 SLK UniRef100_Q9H2G2 DLKAGNILFTLDGDIK 386 Lys2 13.8 SMG1 UniRef100_Q96Q15 DTVTIHSVTITILPTKTK 387 ATP -3.6 PK SNRK UniRef100_Q9NRH2 DLKPENVVFFEK 388 Lys2 24.5 SRC UniRef100_P12931 VAIKTLKPGTMSPEAFLQE 389 Lys1 82.7 AQVMKK SRPK1 UniRef100_Q96SB4 IIHTDIKPENILLSVNEQYIR 390 Lys2 -9.1 SRPK1, UniRef100_P78362, FVAMKVVK 391 Lys1 -38.7 SRPK2 UniRef100_Q96SB4 STK33 UniRef100_Q9BYT3 DLKLENIMVK 392 Lys2 -8.0 STLK5 UniRef100_Q7RTN6 YSVKVLPWLSPEVLQQNL 393 Activation 12.0 QGYDAK Loop SYK UniRef100_P43405 ISDFGLSKALR 394 Activation 6.6 Loop TAK1 UniRef100_043318 DLKPPNLLLVAGGTVLK 395 Lys2 0.4 TAO1, UniRef100_Q7L7X3, DIKAGNILLTEPGQVK 396 Lys2 87.1 TAO3 UniRef100_Q9H2K8 TAO2 UniRef100_Q9UL54 DVKAGNILLSEPGLVK 397 Lys2 92.0 TBK1 UniRef100_Q9UHD2 TGDLFAIKVFNNISFLRPV 398 Lys1 -18.0 DVQMR TEC UniRef100_P42680 YVLDDQYTSSSGAKFPVK 399 Activation 20.6 Loop TLK1 UniRef100_Q9UKI8 YLNEIKPPIIHYDLKPGNILL 400 Lys2 11.5 VDGTACGEIK TLK2 UniRef100_Q86UE8 YLNEIKPPIIHYDLKPGNILL 401 Lys2 10.2 VNGTACGEIK ULK1 UniRef100_O75385 DLKPQNILLSNPAGR 402 Lys2 8.8 ULK3 UniRef100_D3DW67 NISHLDLKPQNILLSSLEKP 403 Lys2 27.1 HLK VRK2 UniRef100_Q86Y07 MLDVLEYIHENEYVHGDIK 404 Lys2 -1.2 AANLLLGYK Wnk1, UniRef100_Q9Y3S1, GSFKTVYK 405 ATPLoop 11.2 Wnk2 UniRef100_D3DUP1 Wnk1, UniRef100_Q9Y3S1, DLKCDNIFITGPTGSVK 406 Lys2 -1.1 Wnk2, UniRef100_D3DUP1, Wnk3 UniRef100_Q9BYP7 YANK3 UniRef100_Q86UX6 DVKPDNILLDER 407 Lys2 -43.1 ZAK UniRef100_Q9NYL2 WISQDKEVAVKK 408 Lys1 75.8 ZAP70 UniRef100_P43403 ISDFGLSKALGADDSYYTA 409 Activation 10.7 R Loop ZC1/HGK, UniRef100_095819, DIKGQNVLLTENAEVK 410 Lys2 57.5 ZC2/TNIK, UniRef100_Q9UKE5, ZC3/MINK UniRef100_Q8N4C8 ZC2/TNIK UniRef100_Q9UKE5 TGQLAAIKVMDVTGDEEE 411 Lys1 46.0 EIKQEINMLKK

Example 3. p-BTK and p-Hck Inhibition

(910) Protocol for PhosFlow Studies

(911) PhosFlow was performed to detect levels of phosphorylation for BTK-pY223 (BD Biosciences) and Hck-pY410 (Abcam) in BCWM.1 cells, in BCWM cells that stably overexpress HCK (BCWM.1_HCK-wt) and in BCWM.1 cells that stably overexpress the T338M mutant of HCK (BCWM.1_HCK-mu). Cells were fixed with BD Phosflow Fix Buffer I (BD Biosciences) at 37 C. for 10 min, then washed twice with BD Phosflow Perm/Wash Buffer I (BD Biosciences). Cells were suspended in BD Phosflow Perm/Wash Buffer I at 10 million/ml and antibodies aliquoted to flow tubes with 100 l cells. Cells were incubated at room temperature for 30 min in the dark. Cells were washed twice with BD Phosflow Perm/Wash Buffer I before performing flow analysis using a BD FACSCanto II flow cytometer.

(912) Protocol for Apoptosis Analysis

(913) Apoptosis analysis of WM patient primary lymphoplasmacytic cells (LPCs) was preformed following A-5 and A-14 treatment of Bone marrow mononuclear cells (BMMC) from WM patients for 24 hours. Apoptosis analysis was performed using Annexin V/Propidium iodide staining with the Apoptosis Detection Kit I (BD Pharmingen) in CD19-APC-cy7 antibody (BD Pharmingen) gated LPCs population.

(914) Results

(915) PhosFlow studies indicate both A-5 and A-14 inhibit Hck and BTK phosphorylation in BCWM.1 cells and BCWM.1 cells with genetic engineered expression of Hck wild type (-wt) and T338M gatekeeper mutant (-mu) with both 0.5 M and 0.1 M doses (shown by Table 6 and Table 7, respectively). In addition, the expression of Hck-wt or Hck-mu increased the resistance to the inhibition of both Hck and BTK phosphorylations by A-5 and A-14, with more resistance presented in Hck-mu expressing BCWM.1 cells. Both A-5 and A-14 induced significant apoptosis in WM patient primary LPCs compared with DMSO control, as shown in Table 8.

(916) TABLE-US-00009 TABLE 6 Relative p-BTK p-Hck MFI % _Hck- _Hck- _Hck- _Hck- (0.5 M BCW M.1 BCWM.1 wt BCWM.1 mu BCW M.1 BCWM.1 wt BCWM.1 mu drugs) 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min DMSO 100 100 100 100 100 100 100 100 100 100 100 100 A-5 56.3 42.3 73.6 69.9 100.7 90.4 68.2 49 80.4 77.7 102.2 81.1 A-14 51.5 27.4 65.6 29.7 112.1 83.9 59.3 35.6 68.6 41.5 89.7 52.3

(917) TABLE-US-00010 TABLE 7 Relative p-BTK p-Hck MFI % _Hck- _Hck- _Hck- _Hck- (0.1 M BCW M.1 BCWM.1 wt BCWM.1 mu BCW M.1 BCWM.1 wt BCWM.1 mu drugs) 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min DMSO 100 100 100 100 100 100 100 100 100 100 100 100 A-5 68.1 52.7 82.1 78.3 70.9 70.4 76.3 50.5 76 80.6 95.3 69.6 A-14 81.8 50.1 76.3 72 75.3 61.2 73.6 57.8 75.8 78.9 83.1 63.7

(918) TABLE-US-00011 TABLE 8 Dose (1.0 M) Dose (0.5 M) Dose (0.2 M) Apoptosis Apoptosis Relative Apoptosis Apoptosis Relative Apoptosis Apoptosis Relative Treatments (%) to DMSO (%) to DMSO (%) to DMSO Patient 1 Untreated 40.9 114.30% DMSO 39.2 100% A-5 57.7 147.20% Patient 2 N 14.2 97.30% DMSO 14.6 100% A-5 28.9 197.90% Patient 3 N 14.529 95.49% DMSO 15.216 100.00% A-5 29.48 193.70% Patient 4 N 29.83 103.00% DMSO 29.75 100.00% A-5 48.56 163.20% Patient 5 N 18.69 110.70% DMSO 16.89 100% A-5 30.5 180.60% 23.25 137.70% A-14 46.86 277.40% 39.24 232.30% Patient 6 N 8.66 117.50% DMSO 7.37 100% A-5 17.82 241.80% A-14 20.88 283.30% Patient 7 DMSO 6.46 100.00% A-5 18.2 281.70% 17.23 266.70% A-14 31.51 487.80% 22.62 350.20% Patient 8 DMSO 5.38 100.00% A-5 17.31 321.75% 11.04 205.20% A-14 31.58 586.99% 12.9 239.78% Patient 9 DMSO 7.6 100.00% A-14 43.7 575.00% 24.8 326.32% Patient N 17.6 113.50% 10 DMSO 15.5 100% A-5 28.7 185.20% 21.5 138.70% A-14 52 335.50% 27.9 180.00% Patient N 26.2 112.70% 11 DMSO 25.5 100% A-5 47 184.30% 30.2 118.40% A-14 71.8 281.60% 53.1 208.20%

EQUIVALENTS AND SCOPE

(919) 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.

(920) 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.

(921) 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.

(922) 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.