BENZOTHIAZOLE DERIVATIVES AND 7-AZA-BENZOTHIAZOLE DERIVATIVES AS JANUS KINASE 2 INHIBITORS AND USES THEREOF
20230148448 · 2023-05-11
Assignee
Inventors
- Nathanael S. Gray (Boston, MA)
- Tinghu Zhang (Brookline, MA)
- Yao Liu (Brookline, MA, US)
- Mingfeng Hao (Hefei, CN)
- David Weinstock (Jamaica Plain, MA, US)
- Loretta Sze-Mun Lin (Chicago, IL, US)
Cpc classification
A61K45/06
HUMAN NECESSITIES
A61K31/496
HUMAN NECESSITIES
A61K31/4353
HUMAN NECESSITIES
International classification
A61K31/4353
HUMAN NECESSITIES
A61K31/496
HUMAN NECESSITIES
Abstract
The present disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The provided compounds may be kinase (e.g., Janus kinase (JAK), e.g., Janus kinase 2 (JAK2)) inhibitors. Also provided are pharmaceutical compositions and kits including the provided compounds. Further provided are methods of using the provided compounds, pharmaceutical compositions, and kits (e.g., for treating a disease (e.g., proliferative disease) in a subject in need thereof).
##STR00001##
Claims
1. A compound of Formula (I): ##STR00194## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R.sup.A is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.1, —N(R.sup.1).sub.2, —SR.sup.1, —CN, —SCN, —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, —C(═NR.sup.1)N(R.sup.1).sub.2, —C(═O)R.sup.1, —C(═O)OR.sup.1, —C(═O)N(R.sup.1).sub.2, —NO.sub.2, —NR.sup.1C(═O)R.sup.1, —NR.sup.1C(═O)OR.sup.1, —NR.sup.1C(═O)N(R.sup.1).sub.2, —OC(═O)R.sup.1, —OC(═O)OR.sup.1, or —OC(═O)N(R.sup.1).sub.2; each instance of R.sup.1 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 instances of R.sup.1 are joined to form a substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring; R.sup.B is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.1, —N(R.sup.1).sub.2, —SR.sup.1, —CN, —SCN, —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, —C(═NR.sup.1)N(R.sup.1).sub.2, —C(═O)R.sup.1, —C(═O)OR.sup.1, —C(═O)N(R.sup.1).sub.2, —NO.sub.2, —NR.sup.1C(═O)R.sup.1, —NR.sup.1C(═O)OR.sup.1, —NR.sup.1C(═O)N(R.sup.1).sub.2, —OC(═O)R.sup.1, —OC(═O)OR.sup.1, or —OC(═O)N(R.sup.1).sub.2; R.sup.K is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.1, —N(R.sup.1).sub.2, —SR.sup.1, —CN, —SCN, —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, —C(═NR.sup.1)N(R.sup.1).sub.2, —C(═O)R.sup.1, —C(═O)OR.sup.1, —C(═O)N(R.sup.1).sub.2, —NO.sub.2, —NR.sup.1C(═O)R.sup.1, —NR.sup.1C(═O)OR.sup.1, —NR.sup.1C(═O)N(R.sup.1).sub.2, —OC(═O)R.sup.1, —OC(═O)OR.sup.1, or —OC(═O)N(R.sup.1).sub.2; provided that: at least one of R.sup.A and R.sup.B is -(substituted or unsubstituted alkylene)-(substituted or unsubstituted heterocyclyl); or each of R.sup.B and R.sup.K is not hydrogen; each instance of R.sup.C is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.1, —N(R.sup.1).sub.2, —SR.sup.1, —CN, —SCN, —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, —C(═NR.sup.1)N(R.sup.1).sub.2, —C(═O)R.sup.1, —C(═O)OR.sup.1, —C(═O)N(R.sup.1).sub.2, —NO.sub.2, —NR.sup.1C(═O)R.sup.1, —NR.sup.1C(═O)OR.sup.1, —NR.sup.1C(═O)N(R.sup.1).sub.2, —OC(═O)R.sup.1, —OC(═O)OR.sup.1, or —OC(═O)N(R.sup.1).sub.2; k is 0, 1, or 2; .sup.aL.sup.Ab is —C(═O)—, —N(R.sup.G)—, —NR.sup.GC(═O)—, —C(═O)NR.sup.G—, or —NR.sup.GC(═O)NR.sup.G—; each instance of R.sup.G is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group; ##STR00195## ##STR00196## is a monocyclic heterocyclyl ring or monocyclic heteroaryl ring; each instance of R.sup.D is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.1, —N(R.sup.1).sub.2, —SR.sup.1, —CN, —SCN, —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, —C(═NR.sup.1)N(R.sup.1).sub.2, —C(═O)R.sup.1, —C(═O)OR.sup.1, —C(═O)N(R.sup.1).sub.2, —NO.sub.2, —NR.sup.1C(═O)R.sup.1, —NR.sup.1C(═O)OR.sup.1, —NR.sup.1C(═O)N(R.sup.1).sub.2, —OC(═O)R.sup.1, —OC(═O)OR.sup.1, or —OC(═O)N(R.sup.1).sub.2; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, as valency permits; L.sup.B is a single bond or 0; X is CR.sup.E or N; each instance of R.sup.E is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.1, —N(R.sup.1).sub.2, —SR.sup.1, —CN, —SCN, —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, —C(═NR.sup.1)N(R.sup.1).sub.2, —C(═O)R.sup.1, —C(═O)OR.sup.1, —C(═O)N(R.sup.1).sub.2, —NO.sub.2, —NR.sup.1C(═O)R.sup.1, —NR.sup.1C(═O)OR.sup.1, —NR.sup.1C(═O)N(R.sup.1).sub.2, —OC(═O)R.sup.1, —OC(═O)OR.sup.1, or —OC(═O)N(R.sup.1).sub.2; R.sup.F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group; each instance of R.sup.H is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.1, —N(R.sup.1).sub.2, —SR.sup.1, —CN, —SCN, —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, —C(═NR.sup.1)N(R.sup.1).sub.2, —C(═O)R.sup.1, —C(═O)OR.sup.1, —C(═O)N(R.sup.1).sub.2, —NO.sub.2, —NR.sup.1C(═O)R.sup.1, —NR.sup.1C(═O)OR.sup.1, —NR.sup.1C(═O)N(R.sup.1).sub.2, —OC(═O)R.sup.1, —OC(═O)OR.sup.1, or —OC(═O)N(R.sup.1).sub.2; and n is 0, 1, 2, 3, 4, or 5.
2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is not of the formula: ##STR00197##
3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00198##
4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00199##
5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00200##
6. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00201##
7. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00202##
8. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00203##
9. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00204##
10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00205##
11. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00206##
12. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00207## wherein R.sup.J is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group.
13. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00208##
14. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00209##
15. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00210##
16. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00211##
17. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00212##
18. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00213##
19. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00214##
20. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00215##
21. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00216##
22. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00217## wherein R.sup.J is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group.
23. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00218## wherein R.sup.J is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group.
24. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the compound is of the formula: ##STR00219## wherein R.sup.J is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group.
25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein ##STR00220##
26. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein ##STR00221##
27. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein ##STR00222##
28. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, provided that ##STR00223## wherein: R.sup.B is -(substituted or unsubstituted alkylene)-(substituted or unsubstituted heterocyclyl); and R.sup.C is substituted or unsubstituted, C.sub.1-6 alkyl.
29. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R.sup.A is -(substituted or unsubstituted alkylene)-(substituted or unsubstituted heterocyclyl).
30. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R.sup.A is -(substituted or unsubstituted, C.sub.1-3 alkylene)-(substituted or unsubstituted, monocyclic, 5- or 6-membered heterocyclyl comprising in the heterocyclic system 1 or 2 heteroatoms independently selected from the group consisting of oxygen and nitrogen).
31. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R.sup.A is -(substituted or unsubstituted, C.sub.1-3 alkylene)-(substituted or unsubstituted piperazinyl).
32. The compound of any of claims 1-25, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R.sup.A is hydrogen.
33. The compound of any one of claims 1-24 and 26-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R.sup.B is -(substituted or unsubstituted alkylene)-(substituted or unsubstituted heterocyclyl).
34. The compound of any one of claims 1-24 and 26-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R.sup.B is -(substituted or unsubstituted, C.sub.1-3 alkylene)-(substituted or unsubstituted, monocyclic, 5- or 6-membered heterocyclyl comprising in the heterocyclic system 1 or 2 heteroatoms independently selected from the group consisting of oxygen and nitrogen).
35. The compound of any one of claims 1-24 and 26-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R.sup.B is -(substituted or unsubstituted, C.sub.1-3 alkylene)-(substituted or unsubstituted piperazinyl).
36. The compound of any one of claims 1-24 and 26-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R.sup.B is hydrogen.
37. The compound of any one of claims 1-24 and 26-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R.sup.B is halogen.
38. The compound of any one of claims 1-24, 27, and 29-37, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R.sup.K is hydrogen.
39. The compound of any one of claims 1-24, 27, and 29-37, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R.sup.K is halogen.
40. The compound of any one of claims 1-26 and 28-39, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein at least one instance of R.sup.C is substituted or unsubstituted alkyl.
41. The compound of any one of claims 1-4, 10-13, 20-22, and 25-40, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein .sup.aL.sup.Ab is C(═O)—.
42. The compound of any one of claims 1-4, 10-13, 20-24, and 25-40, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein .sup.aL.sup.Ab is —N(R.sup.G)—.
43. The compound of any one of claims 1-4, 6-7, 10-13, 18-22, and 25-40, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein .sup.aL.sup.Ab is —NR.sup.GC(═O)—.
44. The compound of any one of claims 1-5, 8-13, 16-17, 20-22, and 25-40, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein .sup.aL.sup.Ab is —C(═O)NR.sup.G—.
45. The compound of any one of claims 1-4, 10-15, 20-22, and 25-40, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein .sup.aL.sup.Ab is —NR.sup.GC(═O)NR.sup.G—.
46. The compound of any one of claims 42-45, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein each instance of R.sup.G is hydrogen.
47. The compound of any one of claims 1-9, 13-19, and 25-46, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein ##STR00224##
48. The compound of any one of claims 1-9, 13-19, and 25-46, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein ##STR00225##
49. The compound of any one of claims 1-2, 10-12, and 20-46, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein ##STR00226##
50. The compound of any one of claims 1-2, 10-11, 20-21, and 25-46, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein ##STR00227##
51. The compound of any one of claims 1-2, 10, 12, and 22-46, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein ##STR00228## wherein R.sup.J is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group.
52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein at least one instance of R.sup.D is substituted or unsubstituted alkyl.
53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein at least one instance of R.sup.D is —CH.sub.3.
54. The compound of any one of claims 1-47 and 49-53, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein m is 0 or 1.
55. The compound of any one of claims 1-12 and 25-54, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein L.sup.B is a single bond.
56. The compound of any one claims 1-2 and 13-54, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein L.sup.B is O.
57. The compound of any one of claims 1-6, 8, 10-14, 16, 18, 20-23, and 25-56, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein X is CR.sup.E.
58. The compound of any one of claims 1-3 and 6-56, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein X is N.
59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein each instance of R.sup.E is hydrogen.
60. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R.sup.F is hydrogen.
61. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein n is 0.
62. The compound of claim 1, wherein the compound is of the formula: ##STR00229## ##STR00230## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
63. The compound of claim 1, wherein the compound is of the formula: ##STR00231## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
64. A compound of the formula: ##STR00232## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
65. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
66. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt thereof.
67. A pharmaceutical composition comprising: a compound of any one of claims 1-66, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; and optionally a pharmaceutically acceptable excipient.
68. The pharmaceutical composition of claim 67 further comprising an additional pharmaceutical agent.
69. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-66, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition of claim 67 or 68.
70. The method of claim 69, wherein the disease is a disease associated with overexpression and/or aberrant activity of a kinase.
71. The method of claim 68 or 69 further comprising administering to the subject in need thereof an additional therapy.
72. The method of claim 71, wherein the additional therapy is a cytotoxic chemotherapy, epigenetic modifier, glucocorticoid, or immunotherapy.
73. The method of any one of claims 69-72, wherein the disease is a proliferative disease.
74. The method of claim 73, wherein the proliferative disease is cancer.
75. The method of claim 74, wherein the cancer is an adenocarcinoma, blastoma, carcinoma, leukemia, lymphoma, myeloma, or sarcoma.
76. The method of claim 74, wherein the cancer is brain cancer.
77. The method of claim 74, wherein the cancer is pancreatic cancer.
78. The method of claim 74, wherein the cancer is leukemia or lymphoma.
79. The method of claim 74, wherein the cancer is essential thrombocythemia.
80. The method of claim 74, wherein the cancer is myelofibrosis, myeloproliferative neoplasm, myeloid malignancy, or polycythemia vera.
81. The method of claim 73, wherein the proliferative disease is a benign neoplasm, inflammatory disease, autoimmune disease, or pathological angiogenesis.
82. The method of claim 81, wherein the proliferative disease is an autoimmune disease, wherein the autoimmune disease is psoriasis, rheumatoid arthritis, graft-versus-host disease, alopecia, alopecia universalis, or vitiligo.
83. The method of any one of claims 69-72, wherein the disease is myelodysplastic syndrome.
84. The method of any one of claims 69-72, wherein the disease is a premalignant condition.
85. The method of claim 84, wherein the premalignant condition is clonal hematopoiesis.
86. The method of any one of claims 69-85, wherein the disease is causing a syndrome of wasting that comprises weight loss as a symptom.
87. A method of inhibiting the activity of a kinase in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1-66, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition of claim 67 or 68.
88. The method of any one of claims 69-87, wherein the subject is a human.
89. The method of any one of claims 69-87, wherein the subject is a non-human mammal.
90. The method of claim 89, wherein the non-human mammal is a dog.
91. A method of inhibiting the activity of a kinase in a biological sample or cell, the method comprising contacting the biological sample or cell with an effective amount of a compound of any one of claims 1-66, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition of claim 67 or 68.
92. The method of claim 91, wherein the biological sample or cell is in vitro.
93. The method of claim 91 or 92, wherein the cell is a malignant cell or premalignant cell.
94. The method of any one of claims 70-93, wherein the kinase is a Janus kinase (JAK), ABL1, ABL2, BRAF, CDC2L2, CDKL3, CIT, CSF1R, EPHA4, EPHA6, EPHA8, EPHB1, EPHB2, EPHB4, FES, FGR, FLT4, HPK1, INSRR, ITK, KIT, LYN, MAP4K2, MERTK, p38-delta, PDGFRA, PDGFRB, PFTAIRE2, PFTK1, RAF1, RET, RIPK1, SRC, TAK1, TAOK3, TIE1, TIE2, TRKB, TRKC, or a combination thereof.
95. The method of claim 94, wherein the kinase is a Janus kinase (JAK).
96. The method of claim 95, wherein the JAK is Janus kinase 2 (JAK2).
97. The method of claim 95, wherein the JAK is Janus kinase 1 (JAK1).
98. The method of claim 95, wherein the JAK is Janus kinase 3 (JAK3).
99. The method of claim 95, wherein the JAK is tyrosine kinase 2 (TYK2).
100. The method of any one of claims 70-99, wherein the kinase is a wild type kinase or mutant kinase.
101. A kit comprising: a compound of any one of claims 1-66, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition of claim 67 or 68; and instructions for using the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or the pharmaceutical composition.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0096] The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.
[0097]
[0098]
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
[0099] Kinases are implicated in a range of diseases, such as proliferative diseases. Provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The provided compounds may be kinase inhibitors. In certain embodiments, the kinase being targeted is a Janus kinase (JAK (e.g., JAK2)). Also provided are pharmaceutical compositions and kits comprising the provided compounds. Further provided are methods of using the provided compounds, pharmaceutical compositions, and kits for treating a disease in a subject in need thereof. In certain embodiments, the disease is a proliferative disease. Further provided are methods of using the provided compounds, pharmaceutical compositions, and kits for inhibiting the activity of a kinase in a subject in need thereof or in a biological sample or cell.
Compounds
[0100] In one aspect of the present invention, provided are compounds of Formula (I):
##STR00007##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein:
[0101] R.sup.A is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.1, —N(R.sup.1).sub.2, —SR.sup.1, —CN, —SCN, —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, —C(═NR.sup.1)N(R.sup.1).sub.2, —C(═O)R.sup.1, —C(═O)OR.sup.1, —C(═O)N(R.sup.1).sub.2, —NO.sub.2, —NR.sup.1C(═O)R.sup.1, —NR.sup.1C(═O)OR.sup.1, —NR.sup.1C(═O)N(R.sup.1).sub.2, —OC(═O)R.sup.1, —OC(═O)OR.sup.1, or —OC(═O)N(R.sup.1).sub.2;
[0102] each instance of R.sup.1 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 instances of R.sup.1 are joined to form a substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring;
[0103] R.sup.B is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.1, —N(R.sup.1).sub.2, —SR.sup.1, —CN, —SCN, —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, —C(═NR.sup.1)N(R.sup.1).sub.2, —C(═O)R.sup.1, —C(═O)OR.sup.1, —C(═O)N(R.sup.1).sub.2, —NO.sub.2, —NR.sup.1C(═O)R.sup.1, —NR.sup.1C(═O)OR.sup.1, —NR.sup.1C(═O)N(R.sup.1).sub.2, —OC(═O)R.sup.1, —OC(═O)OR.sup.1, or —OC(═O)N(R.sup.1).sub.2;
[0104] R.sup.K is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.1, —N(R.sup.1).sub.2, —SR.sup.1, —CN, —SCN, —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, —C(═NR.sup.1)N(R.sup.1).sub.2, —C(═O)R.sup.1, —C(═O)OR.sup.1, —C(═O)N(R.sup.1).sub.2, —NO.sub.2, —NR.sup.1C(═O)R.sup.1, —NR.sup.1C(═O)OR.sup.1, —NR.sup.1C(═O)N(R.sup.1).sub.2, —OC(═O)R.sup.1, —OC(═O)OR.sup.1, or —OC(═O)N(R.sup.1).sub.2;
[0105] provided that: [0106] at least one of R.sup.A and R.sup.B is -(substituted or unsubstituted alkylene)-(substituted or unsubstituted heterocyclyl); or [0107] each of R.sup.B and R.sup.K is not hydrogen;
[0108] each instance of R.sup.C is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.1, —N(R.sup.1).sub.2, —SR.sup.1, —CN, —SCN, —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, —C(═NR.sup.1)N(R.sup.1).sub.2, —C(═O)R.sup.1, —C(═O)OR.sup.1, —C(═O)N(R.sup.1).sub.2, —NO.sub.2, —NR.sup.1C(═O)R.sup.1, —NR.sup.1C(═O)OR.sup.1, —NR.sup.1C(═O)N(R.sup.1).sub.2, —OC(═O)R.sup.1, —OC(═O)OR.sup.1, or —OC(═O)N(R.sup.1).sub.2;
[0109] k is 0, 1, or 2;
[0110] .sup.aL.sup.Ab is —C(═O)—, —N(R.sup.G)—, —NR.sup.GC(═O)—, —C(═O)NR.sup.G—, or —NR.sup.GC(═O)NR.sup.G—;
[0111] each instance of R.sup.G is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group;
##STR00008##
##STR00009##
is a monocyclic heterocyclyl ring or monocyclic heteroaryl ring;
[0112] each instance of R.sup.D is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.1, —N(R.sup.1).sub.2, —SR.sup.1, —CN, —SCN, —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, —C(═NR.sup.1)N(R.sup.1).sub.2, —C(═O)R.sup.1, —C(═O)OR.sup.1, —C(═O)N(R.sup.1).sub.2, —NO.sub.2, —NR.sup.1C(═O)R.sup.1, —NR.sup.1C(═O)OR.sup.1, —NR.sup.1C(═O)N(R.sup.1).sub.2, —OC(═O)R.sup.1, —OC(═O)OR.sup.1, or —OC(═O)N(R.sup.1).sub.2;
[0113] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, as valency permits;
[0114] L.sup.B is a single bond or O;
[0115] X is CR.sup.E or N;
[0116] each instance of R.sup.E is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.1, —N(R.sup.1).sub.2, —SR.sup.1, —CN, —SCN, —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, —C(═NR.sup.1)N(R.sup.1).sub.2, —C(═O)R.sup.1, —C(═O)OR.sup.1, —C(═O)N(R.sup.1).sub.2, —NO.sub.2, —NR.sup.1C(═O)R.sup.1, —NR.sup.1C(═O)OR.sup.1, —NR.sup.1C(═O)N(R.sup.1).sub.2, —OC(═O)R.sup.1, —OC(═O)OR.sup.1, or —OC(═O)N(R.sup.1).sub.2;
[0117] R.sup.F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, or a nitrogen protecting group;
[0118] each instance of R.sup.H is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.1, —N(R.sup.1).sub.2, —SR.sup.1, —CN, —SCN, —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, —C(═NR.sup.1)N(R.sup.1).sub.2, —C(═O)R.sup.1, —C(═O)OR.sup.1, —C(═O)N(R.sup.1).sub.2, —NO.sub.2, —NR.sup.1C(═O)R.sup.1, —NR.sup.1C(═O)OR.sup.1, —NR.sup.1C(═O)N(R.sup.1).sub.2, —OC(═O)R.sup.1, —OC(═O)OR.sup.1, or —OC(═O)N(R.sup.1).sub.2; and
[0119] n is 0, 1, 2, 3, 4, or 5.
[0120] When Formula (I) includes two or more instances of a moiety, unless otherwise provided, any two instances of the moiety may be the same or different from each other.
[0121] In certain embodiments,
##STR00010##
is of the formula:
##STR00011##
In certain embodiments,
##STR00012##
is of the formula:
##STR00013##
In certain embodiments,
##STR00014##
is of the formula:
##STR00015##
In certain embodiments,
##STR00016##
is of the formula:
##STR00017##
In certain embodiments,
##STR00018##
is of the formula:
##STR00019##
In certain embodiments
##STR00020##
is of the formula:
##STR00021##
[0122] In certain embodiments
##STR00022##
is of the formula:
##STR00023##
In certain embodiments
##STR00024##
is of the formula:
##STR00025##
In certain embodiments
##STR00026##
is of the formula:
##STR00027##
In certain embodiments
##STR00028##
is of the formula:
##STR00029##
In certain embodiments,
##STR00030##
In certain embodiments,
##STR00031##
is
##STR00032##
In certain embodiments,
##STR00033##
In certain embodiments, when L.sup.B is a bond,
##STR00034##
is not
##STR00035##
wherein:
[0123] R.sup.B is -(substituted or unsubstituted alkylene)-(substituted or unsubstituted heterocyclyl); and
[0124] R.sup.C is substituted or unsubstituted, C.sub.1-6 alkyl.
[0125] In certain embodiments, when L.sup.B is a bond,
##STR00036##
is not
##STR00037##
wherein:
[0126] R.sup.B is —CH.sub.2-(substituted or unsubstituted, piperazinyl or piperidinyl); and R.sup.C is substituted or unsubstituted methyl.
[0127] In certain embodiments, when L.sup.B is a bond,
##STR00038##
is not
##STR00039##
wherein:
[0128] R.sup.B is —CH.sub.2-(substituted 1- piperazinyl) or —CH.sub.2-(substituted 1-piperidinyl); and
[0129] R.sup.C is substituted methyl.
[0130] In certain embodiments, R.sup.A is hydrogen. In certain embodiments, R.sup.A is halogen (e.g., F, Cl, or Br). In certain embodiments, R.sup.A is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, R.sup.A is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A is substituted methyl. In certain embodiments, R.sup.A is —CH.sub.2F, —CHF.sub.2, or —CF.sub.3. In certain embodiments, R.sup.A is —CF.sub.3. In certain embodiments, R.sup.A is substituted ethyl (e.g., ethyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, R.sup.A is substituted propyl or substituted butyl. In certain embodiments, R.sup.A is -(substituted or unsubstituted alkylene)-(substituted or unsubstituted heterocyclyl). In certain embodiments, R.sup.A is —C(═O)-(substituted or unsubstituted heterocyclyl). In certain embodiments, R.sup.A is -(substituted or unsubstituted, C.sub.1-3 alkylene)-(substituted or unsubstituted, monocyclic, 5- or 6-membered heterocyclyl comprising in the heterocyclic system 1 or 2 heteroatoms independently selected from the group consisting of oxygen and nitrogen). In certain embodiments, R.sup.A is —C(═O)-(substituted or unsubstituted, monocyclic, 5- or 6-membered heterocyclyl comprising in the heterocyclic system 1 or 2 heteroatoms independently selected from the group consisting of oxygen and nitrogen). In certain embodiments, R.sup.A is —C(═O)-(substituted or unsubstituted piperazinyl). In certain embodiments, R.sup.A is —C(═O)-(substituted or unsubstituted pyrrolidinyl). In certain embodiments, R.sup.A is —C(═O)-(substituted or unsubstituted piperidinyl). In certain embodiments, R.sup.A is -(substituted or unsubstituted, C.sub.1-3 alkylene)-(substituted or unsubstituted piperazinyl). In certain embodiments, R.sup.A is -(substituted or unsubstituted, C.sub.1-3 alkylene)-(substituted or unsubstituted pyrrolidinyl). In certain embodiments, R.sup.A is -(substituted or unsubstituted, C.sub.1-3 alkylene)-(substituted or unsubstituted piperidinyl). In certain embodiments, R.sup.A is
##STR00040##
In certain embodiments, R.sup.A is
##STR00041##
In certain embodiments, R.sup.A is
##STR00042##
In certain embodiments, R.sup.A is
##STR00043##
In certain embodiments, R.sup.A is
##STR00044##
In certain embodiments, R.sup.A is
##STR00045##
In certain embodiments, R.sup.A is
##STR00046##
In certain embodiments, R.sup.A is
##STR00047##
In certain embodiments, R.sup.A is unsubstituted alkyl. In certain embodiments, R.sup.A is unsubstituted, C.sub.1-6 alkyl. In certain embodiments, R.sup.A is Me. In certain embodiments, R.sup.A is Et, Pr, or Bu. In certain embodiments, R.sup.A is substituted or unsubstituted alkenyl. In certain embodiments, R.sup.A is substituted or unsubstituted, C.sub.2-6 alkenyl (e.g., substituted or unsubstituted vinyl, substituted or unsubstituted allyl). In certain embodiments, R.sup.A is substituted or unsubstituted alkynyl. In certain embodiments, R.sup.A is substituted or unsubstituted, C.sub.2-6 alkynyl (substituted or unsubstituted ethynyl). In certain embodiments, R.sup.A is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, as valency permits). In certain embodiments, R.sup.A is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, R.sup.A is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R.sup.A is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R.sup.A is substituted or unsubstituted aryl. In certain embodiments, R.sup.A is substituted or unsubstituted phenyl. In certain embodiments, R.sup.A is substituted or unsubstituted naphthyl. In certain embodiments, R.sup.A is substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.A is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R.sup.A is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, R.sup.A is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R.sup.A is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, R.sup.A is —OR.sup.1 (e.g., —OH, —O(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —OMe, —OCF.sub.3, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certain embodiments, R.sup.A is —OMe. In certain embodiments, R.sup.A is —SR.sup.1 (e.g., —SH, —S(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —SMe, —SCF.sub.3, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstituted phenyl) (e.g., —SPh)). In certain embodiments, R.sup.A is —N(R.sup.1).sub.2 (e.g., —NH.sub.2, —NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHMe), or —N(substituted or unsubstituted, C.sub.1-6 alkyl)-(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NMe.sub.2)). In certain embodiments, R.sup.A is —CN or —SCN. In certain embodiments, R.sup.A is —NO.sub.2. In certain embodiments, R.sup.A is —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, or —C(═NR.sup.1)N(R.sup.1).sub.2. In certain embodiments, R.sup.A is —C(═O)R.sup.1 (e.g., —C(═O)(substituted or unsubstituted alkyl) (e.g., —C(═O)Me) or —C(═O)(substituted or unsubstituted phenyl)). In certain embodiments, R.sup.A is —C(═O)(heterocyclyl). In certain embodiments, R.sup.A is —C(═O)OR.sup.1 (e.g., —C(═O)OH, —C(═O)O(substituted or unsubstituted alkyl) (e.g., —C(═O)OMe), —C(═O)O(substituted or unsubstituted phenyl)). In certain embodiments, R.sup.A is —C(═O)N(R.sup.1).sub.2 (e.g., —C(═O)NH.sub.2, —C(═O)NH(substituted or unsubstituted alkyl) (e.g., —C(═O)NHMe), —C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), —C(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, R.sup.A is —NR.sup.1C(═O)R.sup.1 (e.g., —NHC(═O)(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)Me), —NHC(═O)(substituted or unsubstituted phenyl)). In certain embodiments, R.sup.A is —NR.sup.1C(═O)OR.sup.1. In certain embodiments, R.sup.A is —NR.sup.1C(═O)N(R.sup.1).sub.2 (e.g., —NHC(═O)NH.sub.2, —NHC(═O)NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)NHMe)). In certain embodiments, R.sup.A is —OC(═O)R.sup.1 (e.g., —OC(═O)(substituted or unsubstituted alkyl), —OC(═O)(substituted or unsubstituted phenyl)), —OC(═O)OR.sup.1 (e.g., —OC(═O)O(substituted or unsubstituted alkyl), —OC(═O)O(substituted or unsubstituted phenyl)), or —OC(═O)N(R.sup.1).sub.2 (e.g., —OC(═O)NH.sub.2, —OC(═O)NH(substituted or unsubstituted alkyl), —OC(═O)NH(substituted or unsubstituted phenyl), —OC(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), —OC(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)).
[0131] Each instance of R.sup.1 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 instances of R.sup.1 are joined to form a substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring. In certain embodiments, at least one instance of R.sup.1 is hydrogen. In certain embodiments, each instance of R.sup.1 is hydrogen. In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted acyl (e.g., acetyl). In certain embodiments, at least one instance of R.sup.1 is substituted or unsubstituted alkyl. In certain embodiments, R.sup.1 is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, R.sup.1 is unsubstituted alkyl. In certain embodiments, R.sup.1 is unsubstituted, C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is Me. In certain embodiments, R.sup.1 is Et, Pr, or Bu. In certain embodiments, R.sup.1 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is substituted methyl. In certain embodiments, R.sup.1 is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R.sup.1 is substituted or unsubstituted alkenyl. In certain embodiments, R.sup.1 is substituted or unsubstituted, C.sub.2-6 alkenyl (e.g., substituted or unsubstituted vinyl, substituted or unsubstituted allyl). In certain embodiments, R.sup.1 is substituted or unsubstituted alkynyl. In certain embodiments, R.sup.1 is substituted or unsubstituted, C.sub.2-6 alkynyl (substituted or unsubstituted ethynyl). In certain embodiments, R.sup.1 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, as valency permits). In certain embodiments, R.sup.1 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, R.sup.1 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R.sup.1 is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R.sup.1 is substituted or unsubstituted aryl. In certain embodiments, R.sup.1 is substituted or unsubstituted phenyl. In certain embodiments, R.sup.1 is substituted or unsubstituted naphthyl. In certain embodiments, R.sup.1 is substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.1 is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R.sup.1 is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, R.sup.1 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R.sup.1 is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, R.sup.1 is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, at least one instance of R.sup.1 is an oxygen protecting group (e.g., 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, at least one instance of R.sup.1 is a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom. In certain embodiments, two instances of R.sup.1 are joined to form a substituted or unsubstituted heterocyclic ring. In certain embodiments, two instances of R.sup.1 are joined to form a substituted or unsubstituted heteroaryl ring.
[0132] In certain embodiments, R.sup.B is hydrogen. In certain embodiments, R.sup.B is halogen (e.g., F, Cl, or Br). In certain embodiments, R.sup.B is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, R.sup.B is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.B is substituted methyl. In certain embodiments, R.sup.B is —CH.sub.2F, —CHF.sub.2, or —CF.sub.3. In certain embodiments, R.sup.B is —CF.sub.3. In certain embodiments, R.sup.B is substituted ethyl (e.g., ethyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, R.sup.B is substituted propyl or substituted butyl. In certain embodiments, R.sup.B is -(substituted or unsubstituted alkylene)-(substituted or unsubstituted heterocyclyl). In certain embodiments, R.sup.B is —C(═O)-(substituted or unsubstituted heterocyclyl). In certain embodiments, R.sup.B is -(substituted or unsubstituted, C.sub.1-3 alkylene)-(substituted or unsubstituted, monocyclic, 5- or 6-membered heterocyclyl comprising in the heterocyclic system 1 or 2 heteroatoms independently selected from the group consisting of oxygen and nitrogen). In certain embodiments, R.sup.B is —C(═O)-(substituted or unsubstituted, monocyclic, 5- or 6-membered heterocyclyl comprising in the heterocyclic system 1 or 2 heteroatoms independently selected from the group consisting of oxygen and nitrogen). In certain embodiments, R.sup.B is —C(═O)-(substituted or unsubstituted piperazinyl). In certain embodiments, R.sup.B is —C(═O)-(substituted or unsubstituted pyrrolidinyl). In certain embodiments, R.sup.B is —C(═O)-(substituted or unsubstituted piperidinyl). In certain embodiments, R.sup.B is -(substituted or unsubstituted, C.sub.1-3 alkylene)-(substituted or unsubstituted piperazinyl). In certain embodiments, R.sup.B is -(substituted or unsubstituted, C.sub.1-3 alkylene)-(substituted or unsubstituted pyrrolidinyl). In certain embodiments, R.sup.B is -(substituted or unsubstituted, C.sub.1-3 alkylene)-(substituted or unsubstituted piperidinyl). In certain embodiments, R.sup.B is
##STR00048##
In certain embodiments, R.sup.B is
##STR00049##
In certain embodiments, R.sup.B is
##STR00050##
In certain embodiments, R.sup.B is
##STR00051##
In certain embodiments, R.sup.B is
##STR00052##
In certain embodiments, R.sup.B is
##STR00053##
In certain embodiments, R.sup.B is
##STR00054##
In certain embodiments, R.sup.B is
##STR00055##
In certain embodiments, R.sup.B is unsubstituted alkyl. In certain embodiments, R.sup.B is unsubstituted, C.sub.1-6 alkyl. In certain embodiments, R.sup.B is Me. In certain embodiments, R.sup.B is Et, Pr, or Bu. In certain embodiments, R.sup.B is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.B is substituted methyl. In certain embodiments, R.sup.B is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R.sup.B is substituted or unsubstituted alkenyl. In certain embodiments, R.sup.B is substituted or unsubstituted, C.sub.2-6 alkenyl (e.g., substituted or unsubstituted vinyl, substituted or unsubstituted allyl). In certain embodiments, R.sup.B is substituted or unsubstituted alkynyl. In certain embodiments, R.sup.B is substituted or unsubstituted, C.sub.2-6 alkynyl (substituted or unsubstituted ethynyl). In certain embodiments, R.sup.B is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, as valency permits). In certain embodiments, R.sup.B is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, R.sup.B is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R.sup.B is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R.sup.B is substituted or unsubstituted aryl. In certain embodiments, R.sup.B is substituted or unsubstituted phenyl. In certain embodiments, R.sup.B is substituted or unsubstituted naphthyl. In certain embodiments, R.sup.B is substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.B is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R.sup.B is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, R.sup.B is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R.sup.B is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, R.sup.B is —OR.sup.1 (e.g., —OH, —O(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —OMe, —OCF.sub.3, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certain embodiments, R.sup.B is —OMe. In certain embodiments, R.sup.B is —SR.sup.1 (e.g., —SH, —S(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —SMe, —SCF.sub.3, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstituted phenyl) (e.g., —SPh)). In certain embodiments, R.sup.B is —N(R.sup.1).sub.2 (e.g., —NH.sub.2, —NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHMe), or —N(substituted or unsubstituted, C.sub.1-6 alkyl)-(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NMe.sub.2)). In certain embodiments, R.sup.B is —CN or —SCN. In certain embodiments, R.sup.B is —NO.sub.2. In certain embodiments, R.sup.B is —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, or —C(═NR.sup.1)N(R.sup.1).sub.2. In certain embodiments, R.sup.B is —C(═O)R.sup.1 (e.g., —C(═O)(substituted or unsubstituted alkyl) (e.g., —C(═O)Me) or —C(═O)(substituted or unsubstituted phenyl)). In certain embodiments, R.sup.B is —C(═O)(heterocyclyl). In certain embodiments, R.sup.B is —C(═O)OR.sup.1 (e.g., —C(═O)OH, —C(═O)O(substituted or unsubstituted alkyl) (e.g., —C(═O)OMe), —C(═O)O(substituted or unsubstituted phenyl)). In certain embodiments, R.sup.B is —C(═O)N(R.sup.1).sub.2 (e.g., —C(═O)NH.sub.2, —C(═O)NH(substituted or unsubstituted alkyl) (e.g., —C(═O)NHMe), —C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), —C(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, R.sup.B is —NR.sup.1C(═O)R.sup.1 (e.g., —NHC(═O)(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)Me), —NHC(═O)(substituted or unsubstituted phenyl)). In certain embodiments, R.sup.B is —NR.sup.1C(═O)OR.sup.1. In certain embodiments, R.sup.B is —NR.sup.1C(═O)N(R.sup.1).sub.2 (e.g., —NHC(═O)NH.sub.2, —NHC(═O)NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)NHMe)). In certain embodiments, R.sup.B is —OC(═O)R.sup.1 (e.g., —OC(═O)(substituted or unsubstituted alkyl), —OC(═O)(substituted or unsubstituted phenyl)), —OC(═O)OR.sup.1 (e.g., —OC(═O)O(substituted or unsubstituted alkyl), —OC(═O)O(substituted or unsubstituted phenyl)), or —OC(═O)N(R.sup.1).sub.2 (e.g., —OC(═O)NH.sub.2, —OC(═O)NH(substituted or unsubstituted alkyl), —OC(═O)NH(substituted or unsubstituted phenyl), —OC(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), —OC(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)).
[0133] In certain embodiments, R.sup.K is hydrogen. In certain embodiments, R.sup.K is halogen (e.g., F, Cl, or Br). In certain embodiments, R.sup.K is F. In certain embodiments, R.sup.K is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, R.sup.K is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.K is substituted methyl. In certain embodiments, R.sup.K is —CH.sub.2F, —CHF.sub.2, or —CF.sub.3. In certain embodiments, R.sup.K is —CF.sub.3. In certain embodiments, R.sup.K is substituted ethyl (e.g., ethyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, R.sup.K is substituted propyl or substituted butyl. In certain embodiments, R.sup.K is unsubstituted alkyl. In certain embodiments, R.sup.K is unsubstituted, C.sub.1-6 alkyl. In certain embodiments, R.sup.K is Me. In certain embodiments, R.sup.K is Et, Pr, or Bu. In certain embodiments, R.sup.K is substituted or unsubstituted alkenyl. In certain embodiments, R.sup.K is substituted or unsubstituted, C.sub.2-6 alkenyl (e.g., substituted or unsubstituted vinyl, substituted or unsubstituted allyl). In certain embodiments, R.sup.K is substituted or unsubstituted alkynyl. In certain embodiments, R.sup.K is substituted or unsubstituted, C.sub.2-6 alkynyl (substituted or unsubstituted ethynyl). In certain embodiments, R.sup.K is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, as valency permits). In certain embodiments, R.sup.K is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, R.sup.K is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R.sup.K is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R.sup.K is substituted or unsubstituted aryl. In certain embodiments, R.sup.K is substituted or unsubstituted phenyl. In certain embodiments, R.sup.K is substituted or unsubstituted naphthyl. In certain embodiments, R.sup.K is substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.K is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R.sup.K is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, R.sup.K is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R.sup.K is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, R.sup.K is —OR.sup.1 (e.g., —OH, —O(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —OMe, —OCF.sub.3, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certain embodiments, R.sup.K is —OMe. In certain embodiments, R.sup.K is —SR.sup.1 (e.g., —SH, —S(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —SMe, —SCF.sub.3, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstituted phenyl) (e.g., —SPh)). In certain embodiments, R.sup.K is —N(R.sup.1).sub.2 (e.g., —NH.sub.2, —NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHMe), or —N(substituted or unsubstituted, C.sub.1-6 alkyl)-(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NMe.sub.2)). In certain embodiments, R.sup.K is —CN or —SCN. In certain embodiments, R.sup.K is —NO.sub.2. In certain embodiments, R.sup.K is —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, or —C(═NR.sup.1)N(R.sup.1).sub.2. In certain embodiments, R.sup.K is —C(═O)R.sup.1 (e.g., —C(═O)(substituted or unsubstituted alkyl) (e.g., —C(═O)Me) or —C(═O)(substituted or unsubstituted phenyl)). In certain embodiments, R.sup.K is —C(═O)OR.sup.1 (e.g., —C(═O)OH, —C(═O)O(substituted or unsubstituted alkyl) (e.g., —C(═O)OMe), —C(═O)O(substituted or unsubstituted phenyl)). In certain embodiments, R.sup.K is —C(═O)N(R.sup.1).sub.2 (e.g., —C(═O)NH.sub.2, —C(═O)NH(substituted or unsubstituted alkyl) (e.g., —C(═O)NHMe), —C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), —C(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, R.sup.K is —NR.sup.1C(═O)R.sup.1 (e.g., —NHC(═O)(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)Me), —NHC(═O)(substituted or unsubstituted phenyl)). In certain embodiments, R.sup.K is —NR.sup.1C(═O)OR.sup.1. In certain embodiments, R.sup.K is —NR.sup.1C(═O)N(R.sup.1).sub.2 (e.g., —NHC(═O)NH.sub.2, —NHC(═O)NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)NHMe)). In certain embodiments, R.sup.K is —OC(═O)R.sup.1 (e.g., —OC(═O)(substituted or unsubstituted alkyl), —OC(═O)(substituted or unsubstituted phenyl)), —OC(═O)OR.sup.1 (e.g., —OC(═O)O(substituted or unsubstituted alkyl), —OC(═O)O(substituted or unsubstituted phenyl)), or —OC(═O)N(R.sup.1).sub.2 (e.g., —OC(═O)NH.sub.2, —OC(═O)NH(substituted or unsubstituted alkyl), —OC(═O)NH(substituted or unsubstituted phenyl), —OC(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), —OC(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)).
[0134] In certain embodiments, at least one of R.sup.A and R.sup.B is -(substituted or unsubstituted alkylene)-(substituted or unsubstituted heterocyclyl). In certain embodiments, at least one of R.sup.A and R.sup.B is —C(═O)-(substituted or unsubstituted heterocyclyl). In certain embodiments, at least one of R.sup.A and R.sup.B is -(substituted or unsubstituted, C.sub.1-3 alkylene)-(substituted or unsubstituted, monocyclic, 5- or 6-membered heterocyclyl comprising in the heterocyclic system 1 or 2 heteroatoms independently selected from the group consisting of oxygen and nitrogen). In certain embodiments, at least one of R.sup.A and R.sup.B is —C(═O)-(substituted or unsubstituted, monocyclic, 5- or 6-membered heterocyclyl comprising in the heterocyclic system 1 or 2 heteroatoms independently selected from the group consisting of oxygen and nitrogen). In certain embodiments, at least one of R.sup.A and R.sup.B is —C(═O)-(substituted or unsubstituted piperazinyl). In certain embodiments, at least one of R.sup.A and R.sup.B is —C(═O)-(substituted or unsubstituted pyrrolidinyl). In certain embodiments, at least one of R.sup.A and R.sup.B is —C(═O)-(substituted or unsubstituted piperidinyl). In certain embodiments, at least one of R.sup.A and R.sup.B is -(substituted or unsubstituted, C.sub.1-3 alkylene)-(substituted or unsubstituted piperazinyl). In certain embodiments, at least one of R.sup.A and R.sup.B is -(substituted or unsubstituted, C.sub.1-3 alkylene)-(substituted or unsubstituted pyrrolidinyl). In certain embodiments, at least one of R.sup.A and R.sup.B is -(substituted or unsubstituted, C.sub.1-3 alkylene)-(substituted or unsubstituted piperidinyl).
[0135] In certain embodiments, each of R.sup.B and R.sup.K is not hydrogen. In certain embodiments, each of R.sup.B and R.sup.K is independently substituted or unsubstituted alkyl or halogen. In certain embodiments, each of R.sup.B and R.sup.K is halogen (e.g., F).
[0136] In certain embodiments, at least one instance of R.sup.C is halogen (e.g., F, Cl, or Br). In certain embodiments, at least one instance of R.sup.C is F. In certain embodiments, at least one instance of R.sup.C is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, at least one instance of R.sup.C is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.C is substituted methyl. In certain embodiments, at least one instance of R.sup.C is —CH.sub.2F, —CHF.sub.2, or —CF.sub.3. In certain embodiments, at least one instance of R.sup.C is —CF.sub.3. In certain embodiments, at least one instance of R.sup.C is substituted ethyl (e.g., ethyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, at least one instance of R.sup.C is substituted propyl or substituted butyl. In certain embodiments, at least one instance of R.sup.C is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.C is unsubstituted, C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.C is Me. In certain embodiments, at least one instance of R.sup.C is Et, Pr, or Bu. In certain embodiments, at least one instance of R.sup.C is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.C is substituted or unsubstituted, C.sub.2-6 alkenyl (e.g., substituted or unsubstituted vinyl, substituted or unsubstituted allyl). In certain embodiments, at least one instance of R.sup.C is substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.C is substituted or unsubstituted, C.sub.2-6 alkynyl (e.g., substituted or unsubstituted ethynyl). In certain embodiments, at least one instance of R.sup.C is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, as valency permits). In certain embodiments, at least one instance of R.sup.C is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of R.sup.C is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R.sup.C is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R.sup.C is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.C is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.C is substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of R.sup.C is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.C is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.C is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of R.sup.C is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of R.sup.C is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.C is —OR.sup.1 (e.g., —OH, —O(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —OMe, —OCF.sub.3, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certain embodiments, at least one instance of R.sup.C is —OMe. In certain embodiments, at least one instance of R.sup.C is —SR.sup.1 (e.g., —SH, —S(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —SMe, —SCF.sub.3, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstituted phenyl) (e.g., —SPh)). In certain embodiments, at least one instance of R.sup.C is —N(R.sup.1).sub.2 (e.g., —NH.sub.2, —NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHMe), or —N(substituted or unsubstituted, C.sub.1-6 alkyl)-(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NMe.sub.2)). In certain embodiments, at least one instance of R.sup.C is —CN or —SCN. In certain embodiments, at least one instance of R.sup.C is —NO.sub.2. In certain embodiments, at least one instance of R.sup.C is —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, or —C(═NR.sup.1)N(R.sup.1).sub.2. In certain embodiments, at least one instance of R.sup.C is —C(═O)R.sup.1 (e.g., —C(═O)(substituted or unsubstituted alkyl) (e.g., —C(═O)Me) or —C(═O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.C is —C(═O)OR.sup.1 (e.g., —C(═O)OH, —C(═O)O(substituted or unsubstituted alkyl) (e.g., —C(═O)OMe), —C(═O)O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.C is —C(═O)N(R.sup.1).sub.2 (e.g., —C(═O)NH.sub.2, —C(═O)NH(substituted or unsubstituted alkyl) (e.g., —C(═O)NHMe), —C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), —C(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of R.sup.C is —NR.sup.1C(═O)R.sup.1 (e.g., —NHC(═O)(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)Me), —NHC(═O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.C is —NR.sup.1C(═O)OR.sup.1. In certain embodiments, at least one instance of R.sup.C is —NR.sup.1C(═O)N(R.sup.1).sub.2 (e.g., —NHC(═O)NH.sub.2, —NHC(═O)NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)NHMe)). In certain embodiments, at least one instance of R.sup.C is —OC(═O)R.sup.1 (e.g., —OC(═O)(substituted or unsubstituted alkyl), —OC(═O)(substituted or unsubstituted phenyl)), —OC(═O)OR.sup.1 (e.g., —OC(═O)O(substituted or unsubstituted alkyl), —OC(═O)O(substituted or unsubstituted phenyl)), or —OC(═O)N(R.sup.1).sub.2 (e.g., —OC(═O)NH.sub.2, —OC(═O)NH(substituted or unsubstituted alkyl), —OC(═O)NH(substituted or unsubstituted phenyl), —OC(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), —OC(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)).
[0137] In certain embodiments, k is 0. In certain embodiments, k is 1. In certain embodiments, k is 2.
[0138] In certain embodiments, .sup.aL.sup.Ab is —C(═O)—. In certain embodiments, .sup.aL.sup.Ab is —N(R.sup.G)—. In certain embodiments, .sup.aL.sup.Ab is —N(H)—. In certain embodiments, .sup.aL.sup.Ab is —NR.sup.GC(═O)—. In certain embodiments, .sup.aL.sup.Ab is —N(H)C(═O)—. In certain embodiments, .sup.aL.sup.Ab is —C(═O)NR.sup.G—. In certain embodiments, .sup.aL.sup.Ab is —C(═O)N(H)—. In certain embodiments, .sup.aL.sup.Ab is —NR.sup.GC(═O)NR.sup.G—. In certain embodiments, .sup.aL.sup.Ab is —N(H)C(═O)N(H)—.
[0139] In certain embodiments,
##STR00056##
In certain embodiments, when
##STR00057##
In certain embodiments,
##STR00058##
In certain embodiments,
##STR00059##
In certain embodiments,
##STR00060##
In certain embodiments,
##STR00061##
[0140] In certain embodiments, at least one instance of R.sup.G is hydrogen. In certain embodiments, each instance of R.sup.G is hydrogen. In certain embodiments, at least one instance of R.sup.G is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted, C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.G is Me. In certain embodiments, at least one instance of R.sup.G is Et, Pr, Bu, substituted methyl, substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R.sup.G is substituted or unsubstituted acyl (e.g., acetyl). In certain embodiments, at least one instance of R.sup.G is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Gmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).
[0141] In certain embodiments,
##STR00062##
In certain embodiments,
##STR00063##
is a monocyclic heterocyclyl ring. In certain embodiments,
##STR00064##
is monocyclic heteroaryl ring. In certain embodiments,
##STR00065##
is a nitrogen-containing heterocyclyl ring. In certain embodiments,
##STR00066##
is a nitrogen-containing heteroaryl ring. In certain embodiments,
##STR00067##
is a five-membered heterocyclyl ring. In certain embodiments,
##STR00068##
is a five-membered heteroaryl ring. In certain embodiments,
##STR00069##
is a six-membered heterocyclyl ring. In certain embodiments,
##STR00070##
is a six-membered heteroaryl ring. In certain embodiments,
##STR00071##
is of the formula:
##STR00072##
In certain embodiments,
##STR00073##
is of the formula:
##STR00074##
In certain embodiments,
##STR00075##
is of the formula:
##STR00076##
In certain embodiments,
##STR00077##
is of the formula:
##STR00078##
In certain embodiments,
##STR00079##
is of the formula:
##STR00080##
In certain embodiments,
##STR00081##
is of the formula:
##STR00082##
In certain embodiments,
##STR00083##
is of the formula:
##STR00084##
In certain embodiments,
##STR00085##
is of the formula:
##STR00086##
In certain embodiments,
##STR00087##
is of the formula:
##STR00088##
In certain embodiments,
##STR00089##
is of the formula:
##STR00090##
In certain embodiments,
##STR00091##
is of the formula:
##STR00092##
In certain embodiments,
##STR00093##
is of the formula:
##STR00094##
In certain embodiments,
##STR00095##
is of the formula:
##STR00096##
In certain embodiments,
##STR00097##
is of the formula:
##STR00098##
In certain embodiments
##STR00099##
is of the formula:
##STR00100##
In certain embodiments,
##STR00101##
is of the formula:
##STR00102##
In certain embodiments,
##STR00103##
is of the formula:
##STR00104##
In certain embodiments,
##STR00105##
is of the formula:
##STR00106##
In certain embodiments,
##STR00107##
is of the formula:
##STR00108##
In certain embodiments,
##STR00109##
is of the formula:
##STR00110##
In certain embodiments,
##STR00111##
is of the formula:
##STR00112##
[0142] In certain embodiments, at least one instance of R.sup.D is halogen (e.g., F, Cl, or Br). In certain embodiments, at least one instance of R.sup.D is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, at least one instance of R.sup.D is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.D is unsubstituted, C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.D is Me. In certain embodiments, at least one instance of R.sup.D is Et, Pr, or Bu. In certain embodiments, at least one instance of R.sup.D is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.D is substituted methyl. In certain embodiments, at least one instance of R.sup.D is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, at least one instance of R.sup.D is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.D is substituted or unsubstituted, C.sub.2-6 alkenyl (e.g., substituted or unsubstituted vinyl, substituted or unsubstituted allyl). In certain embodiments, at least one instance of R.sup.D is substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.D is substituted or unsubstituted, C.sub.2-6 alkynyl (substituted or unsubstituted ethynyl). In certain embodiments, at least one instance of R.sup.D is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, as valency permits). In certain embodiments, at least one instance of R.sup.D is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of R.sup.D is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R.sup.D is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R.sup.D is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.D is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.D is substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of R.sup.D is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.D is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.D is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of R.sup.D is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of R.sup.D is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.D is —OR.sup.1 (e.g., —OH, —O(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —OMe, —OCF.sub.3, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certain embodiments, at least one instance of R.sup.D is —OMe. In certain embodiments, at least one instance of R.sup.D is —SR.sup.1 (e.g., —SH, —S(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —SMe, —SCF.sub.3, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstituted phenyl) (e.g., —SPh)). In certain embodiments, at least one instance of R.sup.D is —N(R.sup.1).sub.2 (e.g., —NH.sub.2, —NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHMe), or —N(substituted or unsubstituted, C.sub.1-6 alkyl)-(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NMe.sub.2)). In certain embodiments, at least one instance of R.sup.D is —CN or —SCN. In certain embodiments, at least one instance of R.sup.D is —NO.sub.2. In certain embodiments, at least one instance of R.sup.D is —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, or —C(═NR.sup.1)N(R.sup.1).sub.2. In certain embodiments, at least one instance of R.sup.D is —C(═O)R.sup.1 (e.g., —C(═O)(substituted or unsubstituted alkyl) (e.g., —C(═O)Me) or —C(═O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.D is —C(═O)OR.sup.1 (e.g., —C(═O)OH, —C(═O)O(substituted or unsubstituted alkyl) (e.g., —C(═O)OMe), —C(═O)O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.D is —C(═O)N(R.sup.1).sub.2 (e.g., —C(═O)NH.sub.2, —C(═O)NH(substituted or unsubstituted alkyl) (e.g., —C(═O)NHMe), —C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), —C(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of R.sup.D is —NR.sup.1C(═O)R.sup.1 (e.g., —NHC(═O)(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)Me), —NHC(═O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.D is —NR.sup.1C(═O)OR.sup.1. In certain embodiments, at least one instance of R.sup.D is —NR.sup.1C(═O)N(R.sup.1).sub.2 (e.g., —NHC(═O)NH.sub.2, —NHC(═O)NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)NHMe)). In certain embodiments, at least one instance of R.sup.D is —OC(═O)R.sup.1 (e.g., —OC(═O)(substituted or unsubstituted alkyl), —OC(═O)(substituted or unsubstituted phenyl)), —OC(═O)OR.sup.1 (e.g., —OC(═O)O(substituted or unsubstituted alkyl), —OC(═O)O(substituted or unsubstituted phenyl)), or —OC(═O)N(R.sup.1).sub.2 (e.g., —OC(═O)NH.sub.2, —OC(═O)NH(substituted or unsubstituted alkyl), —OC(═O)NH(substituted or unsubstituted phenyl), —OC(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), —OC(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)).
[0143] In certain embodiments, m is 0 or 1. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, m is 7. In certain embodiments, m is 8. In certain embodiments, m is 9. In certain embodiments, m is 10. In certain embodiments, m is 11.
[0144] In certain embodiments, L.sup.B is a single bond. In certain embodiments, L.sup.B is O. In certain embodiments, when L.sup.B is a bond, R.sup.B is H. In certain embodiments, when L.sup.B is a bond, R.sup.B is not -(substituted or unsubstituted alkylene)-(substituted or unsubstituted heterocyclyl). In certain embodiments, when L.sup.B is a bond, R.sup.B is not —CH.sub.2-(substituted or unsubstituted, piperazinyl or piperidinyl). In certain embodiments, when L.sup.B is a bond, R.sup.B is not —CH.sub.2-(substituted 1-piperazinyl) or —CH.sub.2-(substituted 1-piperidinyl). In certain embodiments, when L.sup.B is a bond, R.sup.B is not
##STR00113##
In certain embodiments, when L.sup.B is a bond, R.sup.C is —CF.sub.3. In certain embodiments, when L.sup.B is O, R.sup.C is substituted or unsubstituted alkyl. In certain embodiments, when L.sup.B is O, R.sup.C is perhaloalkyl. In certain embodiments, when L.sup.B is O, R.sup.C is CF.sub.3. In certain embodiments, when L.sup.B is O, R.sup.B is H.
[0145] In certain embodiments, X is CR.sup.E. In certain embodiments, X is C—H. In certain embodiments, X is C-(substituted or unsubstituted alkyl) (e.g., C-Me). In certain embodiments, X is C-halogen (e.g., C—F). In certain embodiments, X is N.
[0146] In certain embodiments, R.sup.E is hydrogen. In certain embodiments, each instance of R.sup.E is hydrogen. In certain embodiments, no instance of R.sup.E is hydrogen. In certain embodiments, R.sup.E is halogen (e.g., F, Cl, or Br). In certain embodiments, R.sup.E is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, R.sup.E is unsubstituted alkyl. In certain embodiments, R.sup.E is unsubstituted, C.sub.1-6 alkyl. In certain embodiments, R.sup.E is Me. In certain embodiments, R.sup.E is Et, Pr, or Bu. In certain embodiments, R.sup.E is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.E is substituted methyl. In certain embodiments, R.sup.E is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R.sup.E is substituted or unsubstituted alkenyl. In certain embodiments, R.sup.E is substituted or unsubstituted, C.sub.2-6 alkenyl (e.g., substituted or unsubstituted vinyl, substituted or unsubstituted allyl). In certain embodiments, R.sup.E is substituted or unsubstituted alkynyl. In certain embodiments, R.sup.E is substituted or unsubstituted, C.sub.2-6 alkynyl (substituted or unsubstituted ethynyl). In certain embodiments, R.sup.E is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, as valency permits). In certain embodiments, R.sup.E is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, R.sup.E is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R.sup.E is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R.sup.E is substituted or unsubstituted aryl. In certain embodiments, R.sup.E is substituted or unsubstituted phenyl. In certain embodiments, R.sup.E is substituted or unsubstituted naphthyl. In certain embodiments, R.sup.E is substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.E is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R.sup.E is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, R.sup.E is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R.sup.E is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, R.sup.E is —OR.sup.1 (e.g., —OH, —O(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —OMe, —OCF.sub.3, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certain embodiments, R.sup.E is —OMe. In certain embodiments, R.sup.E is —SR.sup.1 (e.g., —SH, —S(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —SMe, —SCF.sub.3, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstituted phenyl) (e.g., —SPh)). In certain embodiments, R.sup.E is —N(R.sup.1).sub.2 (e.g., —NH.sub.2, —NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHMe), or —N(substituted or unsubstituted, C.sub.1-6 alkyl)-(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NMe.sub.2)). In certain embodiments, R.sup.E is —CN or —SCN. In certain embodiments, R.sup.E is —NO.sub.2. In certain embodiments, R.sup.E is —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, or —C(═NR.sup.1)N(R.sup.1).sub.2. In certain embodiments, R.sup.E is —C(═O)R.sup.1 (e.g., —C(═O)(substituted or unsubstituted alkyl) (e.g., —C(═O)Me) or —C(═O)(substituted or unsubstituted phenyl)). In certain embodiments, R.sup.E is —C(═O)OR.sup.1 (e.g., —C(═O)OH, —C(═O)O(substituted or unsubstituted alkyl) (e.g., —C(═O)OMe), —C(═O)O(substituted or unsubstituted phenyl)). In certain embodiments, R.sup.E is —C(═O)N(R.sup.1).sub.2 (e.g., —C(═O)NH.sub.2, —C(═O)NH(substituted or unsubstituted alkyl) (e.g., —C(═O)NHMe), —C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), —C(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, R.sup.E is —NR.sup.1C(═O)R.sup.1 (e.g., —NHC(═O)(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)Me), —NHC(═O)(substituted or unsubstituted phenyl)). In certain embodiments, R.sup.E is —NR.sup.1C(═O)OR.sup.1. In certain embodiments, R.sup.E is —NR.sup.1C(═O)N(R.sup.1).sub.2 (e.g., —NHC(═O)NH.sub.2, —NHC(═O)NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)NHMe)). In certain embodiments, R.sup.E is —OC(═O)R.sup.1 (e.g., —OC(═O)(substituted or unsubstituted alkyl), —OC(═O)(substituted or unsubstituted phenyl)), —OC(═O)OR.sup.1 (e.g., —OC(═O)O(substituted or unsubstituted alkyl), —OC(═O)O(substituted or unsubstituted phenyl)), or —OC(═O)N(R.sup.1).sub.2 (e.g., —OC(═O)NH.sub.2, —OC(═O)NH(substituted or unsubstituted alkyl), —OC(═O)NH(substituted or unsubstituted phenyl), —OC(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), —OC(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)).
[0147] In certain embodiments,
##STR00114##
In certain embodiments,
##STR00115##
[0148] In certain embodiments, R.sup.F is hydrogen. In certain embodiments, R.sup.F is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted, C.sub.1-6 alkyl). In certain embodiments, R.sup.F is Me. In certain embodiments, R.sup.F is Et, Pr, Bu, substituted methyl, substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R.sup.F is substituted or unsubstituted acyl (e.g., acetyl). In certain embodiments, R.sup.F is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).
[0149] In certain embodiments, at least one instance of R.sup.H is halogen (e.g., F, Cl, or Br). In certain embodiments, at least one instance of R.sup.H is F. In certain embodiments, at least one instance of R.sup.H is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, at least one instance of R.sup.H is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.H is substituted methyl. In certain embodiments, at least one instance of R.sup.H is —CH.sub.2F, —CHF.sub.2, or —CF.sub.3. In certain embodiments, at least one instance of R.sup.H is —CF.sub.3. In certain embodiments, at least one instance of R.sup.H is substituted ethyl (e.g., ethyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, at least one instance of R.sup.H is substituted propyl or substituted butyl. In certain embodiments, at least one instance of R.sup.H is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.H is unsubstituted, C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.H is Me. In certain embodiments, at least one instance of R.sup.H is Et, Pr, or Bu. In certain embodiments, at least one instance of R.sup.H is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.H is substituted or unsubstituted, C.sub.2-6 alkenyl (e.g., substituted or unsubstituted vinyl, substituted or unsubstituted allyl). In certain embodiments, at least one instance of R.sup.H is substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.H is substituted or unsubstituted, C.sub.2-6 alkynyl (substituted or unsubstituted ethynyl). In certain embodiments, at least one instance of R.sup.H is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, as valency permits). In certain embodiments, at least one instance of R.sup.H is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of R.sup.H is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R.sup.H is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R.sup.H is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.H is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.H is substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of R.sup.H is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.H is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.H is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of R.sup.H is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of R.sup.H is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.H is —OR.sup.1 (e.g., —OH, —O(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —OMe, —OCF.sub.3, —OEt, —OPr, —OBu, or —OBn), or —O(substituted or unsubstituted phenyl) (e.g., —OPh)). In certain embodiments, at least one instance of R.sup.H is —OMe. In certain embodiments, at least one instance of R.sup.H is —SR.sup.1 (e.g., —SH, —S(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —SMe, —SCF.sub.3, —SEt, —SPr, —SBu, or —SBn), or —S(substituted or unsubstituted phenyl) (e.g., —SPh)). In certain embodiments, at least one instance of R.sup.H is —N(R.sup.1).sub.2 (e.g., —NH.sub.2, —NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHMe), or —N(substituted or unsubstituted, C.sub.1-6 alkyl)-(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NMe.sub.2)). In certain embodiments, at least one instance of R.sup.H is —CN or —SCN. In certain embodiments, at least one instance of R.sup.H is —NO.sub.2. In certain embodiments, at least one instance of R.sup.H is —C(═NR.sup.1)R.sup.1, —C(═NR.sup.1)OR.sup.1, or —C(═NR.sup.1)N(R.sup.1).sub.2. In certain embodiments, at least one instance of R.sup.H is —C(═O)R.sup.1 (e.g., —C(═O)(substituted or unsubstituted alkyl) (e.g., —C(═O)Me) or —C(═O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.H is —C(═O)OR.sup.1 (e.g., —C(═O)OH, —C(═O)O(substituted or unsubstituted alkyl) (e.g., —C(═O)OMe), —C(═O)O(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.H is —C(═O)N(R.sup.1).sub.2 (e.g., —C(═O)NH.sub.2, —C(═O)NH(substituted or unsubstituted alkyl) (e.g., —C(═O)NHMe), —C(═O)NH(substituted or unsubstituted phenyl), —C(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), —C(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, at least one instance of R.sup.H is —NR.sup.1C(═O)R.sup.1 (e.g., —NHC(═O)(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)Me), —NHC(═O)(substituted or unsubstituted phenyl)). In certain embodiments, at least one instance of R.sup.H is —NR.sup.1C(═O)OR.sup.1. In certain embodiments, at least one instance of R.sup.H is —NR.sup.1C(═O)N(R.sup.1).sub.2 (e.g., —NHC(═O)NH.sub.2, —NHC(═O)NH(substituted or unsubstituted, C.sub.1-6 alkyl) (e.g., —NHC(═O)NHMe)). In certain embodiments, at least one instance of R.sup.H is —OC(═O)R.sup.1 (e.g., —OC(═O)(substituted or unsubstituted alkyl), —OC(═O)(substituted or unsubstituted phenyl)), —OC(═O)OR.sup.1 (e.g., —OC(═O)O(substituted or unsubstituted alkyl), —OC(═O)O(substituted or unsubstituted phenyl)), or —OC(═O)N(R.sup.1).sub.2 (e.g., —OC(═O)NH.sub.2, —OC(═O)NH(substituted or unsubstituted alkyl), —OC(═O)NH(substituted or unsubstituted phenyl), —OC(═O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), —OC(═O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)).
[0150] In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5.
[0151] In certain embodiments, the compound is of the formula:
##STR00116##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0152] In certain embodiments, the compound is of the formula:
##STR00117##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0153] In certain embodiments, the compound is of the formula:
##STR00118##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0154] In certain embodiments, the compound is of the formula:
##STR00119##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0155] In certain embodiments, the compound is of the formula:
##STR00120##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0156] In certain embodiments, the compound is of the formula:
##STR00121##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0157] In certain embodiments, the compound is of the formula:
##STR00122##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0158] In certain embodiments, the compound is of the formula:
##STR00123##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0159] In certain embodiments, the compound is of the formula:
##STR00124##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0160] In certain embodiments, the compound is of the formula:
##STR00125##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0161] R.sup.J is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group. In certain embodiments, R.sup.J is hydrogen. In certain embodiments, R.sup.J is substituted or unsubstituted acyl (e.g., acetyl). In certain embodiments, R.sup.J is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In certain embodiments, R.sup.J is unsubstituted alkyl. In certain embodiments, R.sup.J is unsubstituted, C.sub.1-6 alkyl. In certain embodiments, R.sup.J is Me. In certain embodiments, R.sup.J is Et, Pr, or Bu. In certain embodiments, R.sup.J is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.J is substituted methyl. In certain embodiments, R.sup.J is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, R.sup.J is substituted or unsubstituted alkenyl. In certain embodiments, R.sup.J is substituted or unsubstituted, C.sub.2-6 alkenyl (e.g., substituted or unsubstituted vinyl, substituted or unsubstituted allyl). In certain embodiments, R.sup.J is substituted or unsubstituted alkynyl. In certain embodiments, R.sup.J is substituted or unsubstituted, C.sub.2-6 alkynyl (substituted or unsubstituted ethynyl). In certain embodiments, R.sup.J is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, as valency permits). In certain embodiments, R.sup.J is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, R.sup.J is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, R.sup.J is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R.sup.J is substituted or unsubstituted aryl. In certain embodiments, R.sup.J is substituted or unsubstituted phenyl. In certain embodiments, R.sup.J is substituted or unsubstituted naphthyl. In certain embodiments, R.sup.J is substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.J is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R.sup.J is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, R.sup.J is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R.sup.J is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, R.sup.J is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).
[0162] In certain embodiments, the compound is of the formula:
##STR00126##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0163] In certain embodiments, the compound is of the formula:
##STR00127##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0164] In certain embodiments, the compound is of the formula:
##STR00128##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0165] In certain embodiments, the compound is of the formula:
##STR00129##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0166] In certain embodiments, the compound is of the formula:
##STR00130##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0167] In certain embodiments, the compound is of the formula:
##STR00131##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0168] In certain embodiments, the compound is of the formula:
##STR00132##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0169] In certain embodiments, the compound is of the formula:
##STR00133##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0170] In certain embodiments, the compound is of the formula:
##STR00134##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0171] In certain embodiments, the compound is of the formula:
##STR00135##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0172] In certain embodiments, the compound is of the formula:
##STR00136##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0173] In certain embodiments, the compound is of the formula:
##STR00137##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0174] In certain embodiments, the compound is not of the formula:
##STR00138## ##STR00139##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0175] In certain embodiments, the compound is of the formula:
##STR00140##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0176] In certain embodiments, the compound is of the formula:
##STR00141##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0177] In certain embodiments, the compound is of the formula:
##STR00142##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0178] In certain embodiments, the compound is of the formula:
##STR00143##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
[0179] In certain embodiments, the compound is of Formula (I-5), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof).
[0180] In certain embodiments, a provided compound (a compound described herein) is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, a provided compound is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, a provided compound is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In certain embodiments, a provided compound is a compound of Formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, a provided compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, a provided compound is a mixture (e.g., a racemic mixture) of enantiomers and/or diastereomers.
[0181] In certain embodiments, a provided compound is a compound of the formula:
##STR00144##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof (e.g., pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof). In certain embodiments, a provided compound is a compound of Formula (I-2), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof (e.g., pharmaceutically acceptable salt thereof).
[0182] In certain embodiments, the molecular weight of a provide compound that is not in the form of a salt, solvate, hydrate, co-crystal, or prodrug is lower than 2,000, lower than 1,500, lower than 1,200, lower than 1,000, lower than 800, lower than 700, or lower than 600 g/mol. In certain embodiments, the molecular weight of a provide compound that is not in the form of a salt, solvate, hydrate, co-crystal, or prodrug is lower than 1000 g/mol. In certain embodiments, the molecular weight of a provide compound that is not in the form of a salt, solvate, hydrate, co-crystal, or prodrug is lower than 700 g/mol.
[0183] In certain embodiments, a provided compound inhibits a kinase. In certain embodiments, a provided compound inhibits the activity (e.g., aberrant activity (e.g., higher-than-normal activity, increase activity)) of a kinase. In certain embodiments, a provided compound inhibits the overexpression of a kinase. In certain embodiments, the kinase is a JAK, ABL1(Q252H), ABL1(T315I), ABL2, BRAF(V600E), CDC2L2, CDKL3, CIT, CSF1R, EPHA4, EPHA6, EPHA8, EPHB1, EPHB2, EPHB4, FES, FGR, FLT4, HPK1, INSRR, ITK, KIT, KIT(L576P), KIT(V559D), LYN, MAP4K2, MERTK, p38-delta, PDGFRA, PDGFRB, PFTAIRE2, PFTK1, RAF1, RET, RET(M918T), RET(V804L), RET(V804M), RIPK1, SRC, TAK1, TAOK3, TIE1, TIE2, TRKB, TRKC, or a combination thereof. In certain embodiments, the kinase is a JAK, ABL1, ABL2, BRAF, CDC2L2, CDKL3, CIT, CSF1R, EPHA4, EPHA6, EPHA8, EPHB1, EPHB2, EPHB4, FES, FGR, FLT4, HPK1, INSRR, ITK, KIT, LYN, MAP4K2, MERTK, p38-delta, PDGFRA, PDGFRB, PFTAIRE2, PFTK1, RAF1, RET, RIPK1, SRC, TAK1, TAOK3, TIE1, TIE2, TRKB, TRKC, or a combination thereof. In certain embodiments, the kinase is a JAK. In certain embodiments, the JAK is JAK1 (e.g., wild-type or mutant JAK1). In certain embodiments, the JAK is JAK2 (e.g., wild-type or mutant JAK2). In certain embodiments, the JAK is JAK3 (e.g., wild-type or mutant JAK3). In certain embodiments, the JAK is TYK2 (e.g., wild-type or mutant TYK2). In certain embodiments, the JAK is a human JAK. In certain embodiments, the JAK is a non-human mammal (e.g., dog) JAK. In certain embodiments, the kinase is a wild type kinase. In certain embodiments, the kinase is a mutant kinase. In certain embodiments, a provided compound inhibits a kinase as measured in an assay described herein or known in the art. In certain embodiments, a provided compound inhibits the kinase at an IC.sub.50 less than or equal to 30 μM, less than or equal to 10 μM, less than or equal to 3 μM, less than or equal to 1 μM, less than or equal to 0.3 μM, or less than or equal to 0.1 μM. In certain embodiments, a provided compound is selective for inhibiting a first kinase over a second kinase, wherein the first and second kinases are different from each other. In certain embodiments, the first kinase is a JAK, ABL1(Q252H), ABL1(T315I), ABL2, BRAF(V600E), CDC2L2, CDKL3, CIT, CSF1R, EPHA4, EPHA6, EPHA8, EPHB1, EPHB2, EPHB4, FES, FGR, FLT4, HPK1, INSRR, ITK, KIT, KIT(L576P), KIT(V559D), LYN, MAP4K2, MERTK, p38-delta, PDGFRA, PDGFRB, PFTAIRE2, PFTK1, RAF1, RET, RET(M918T), RET(V804L), RET(V804M), RIPK1, SRC, TAK1, TAOK3, TIE1, TIE2, TRKB, TRKC, or a combination thereof. In certain embodiments, the first kinase is a JAK, ABL1, ABL2, BRAF, CDC2L2, CDKL3, CIT, CSF1R, EPHA4, EPHA6, EPHA8, EPHB1, EPHB2, EPHB4, FES, FGR, FLT4, HPK1, INSRR, ITK, KIT, LYN, MAP4K2, MERTK, p38-delta, PDGFRA, PDGFRB, PFTAIRE2, PFTK1, RAF1, RET, RIPK1, SRC, TAK1, TAOK3, TIE1, TIE2, TRKB, TRKC, or a combination thereof. In certain embodiments, the first kinase is a JAK (e.g., JAK1, JAK2, JAK3, TYK2). In certain embodiments, the first kinase is JAK2. In certain embodiments, the first kinase is JAK3. In certain embodiments, a provided compound is selective for inhibiting the first kinase over the second kinase by at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 7-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 300-fold, or at least 1,000-fold (e.g., in an in vitro assay or an assay described herein). In certain embodiments, a provided compound reversibly binds to a kinase. In certain embodiments, a provided compound irreversibly binds to a kinase.
[0184] In another aspect, the present disclosure provides methods of preparing a compound described herein. In certain embodiments, the method of preparing is a method described herein (e.g., a method described in Example 1).
Pharmaceutical Compositions, Administration, and Kits
[0185] The present disclosure also provides pharmaceutical compositions comprising a compound described herein and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition further comprises an additional pharmaceutical agent.
[0186] In certain embodiments, the compound described herein is provided in an effective (e.g., effective for inhibiting a kinase, such as a JAK (e.g., JAK2)) amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, a therapeutically effective amount is an amount effective for inhibiting a kinase. In certain embodiments, a therapeutically effective amount is an amount effective for treating a disease (e.g., a disease associated with aberrant activity of a kinase (e.g., proliferative disease)). In certain embodiments, a therapeutically effective amount is an amount effective for inhibiting the activity of a kinase and treating a disease (e.g., a disease associated with aberrant activity of a kinase (e.g., proliferative disease)). In certain embodiments, a therapeutically effective amount is an amount effective for inducing apoptosis in a cell (e.g., malignant cell, premalignant cell).
[0187] In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a kinase by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a kinase by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%.
[0188] In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human (e.g., an adult, juvenile, or child). In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a dog. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the subject is a genetically engineered animal. In certain embodiments, the subject is a transgenic animal (e.g., transgenic mice, transgenic pigs). In certain embodiments, the subject is a fish or reptile.
[0189] In certain embodiments, the biological sample or cell (e.g., the biological sample or cell being contacted with a compound or pharmaceutical composition described herein) is in vitro. In certain embodiments, the biological sample or cell is in vivo or ex vivo. In certain embodiments, the cell is a malignant cell or premalignant cell.
[0190] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.
[0191] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.
[0192] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.
[0193] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
[0194] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
[0195] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
[0196] Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
[0197] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.
[0198] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.
[0199] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
[0200] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
[0201] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
[0202] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
[0203] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
[0204] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.
[0205] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.
[0206] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
[0207] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, Litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
[0208] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
[0209] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[0210] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
[0211] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.
[0212] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
[0213] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.
[0214] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragées, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
[0215] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragées, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.
[0216] Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
[0217] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.
[0218] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
[0219] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
[0220] Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
[0221] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
[0222] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
[0223] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
[0224] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other ophthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.
[0225] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
[0226] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
[0227] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.
[0228] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 μg and 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.
[0229] 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.
[0230] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in inhibiting the activity of a kinase (e.g., JAK) in a subject, biological sample, or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject, biological sample, or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.
[0231] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., proliferative disease, cancer, inflammatory disease, autoimmune disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) or premalignant condition. Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
[0232] The additional pharmaceutical agents include, but are not limited to, cytotoxic chemotherapeutic agents, epigenetic modifiers, glucocorticoids, immunotherapeutic agents, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, and a combination thereof. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent (e.g., anti-cancer agent). In certain embodiments, the additional pharmaceutical agent is an anti-leukemia agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ADE, Adriamycin RDF (doxorubicin hydrochloride), Ambochlorin (chlorambucil), ARRANON (nelarabine), ARZERRA (ofatumumab), BOSULIF (bosutinib), BUSULFEX (busulfan), CAMPATH (alemtuzumab), CERUBIDINE (daunorubicin hydrochloride), CLAFEN (cyclophosphamide), CLOFAREX (clofarabine), CLOLAR (clofarabine), CVP, CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), ERWINAZE (Asparaginase Erwinia Chrysanthemi), FLUDARA (fludarabine phosphate), FOLEX (methotrexate), FOLEX PFS (methotrexate), GAZYVA (obinutuzumab), GLEEVEC (imatinib mesylate), Hyper-CVAD, ICLUSIG (ponatinib hydrochloride), IMBRUVICA (ibrutinib), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), MARQIBO (vincristine sulfate liposome), METHOTREXATE LPF (methorexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), mitoxantrone hydrochloride, MUSTARGEN (mechlorethamine hydrochloride), MYLERAN (busulfan), NEOSAR (cyclophosphamide), ONCASPAR (Pegaspargase), PURINETHOL (mercaptopurine), PURIXAN (mercaptopurine), Rubidomycin (daunorubicin hydrochloride), SPRYCEL (dasatinib), SYNRIBO (omacetaxine mepesuccinate), TARABINE PFS (cytarabine), TASIGNA (nilotinib), TREANDA (bendamustine hydrochloride), TRISENOX (arsenic trioxide), VINCASAR PFS (vincristine sulfate), ZYDELIG (idelalisib), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is an anti-lymphoma agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABVD, ABVE, ABVE-PC, ADCETRIS (brentuximab vedotin), ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride), AMBOCHLORIN (chlorambucil), AMBOCLORIN (chlorambucil), ARRANON (nelarabine), BEACOPP, BECENUM (carmustine), BELEODAQ (belinostat), BEXXAR (tositumomab and iodine I 131 tositumomab), BICNU (carmustine), BLENOXANE (bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN (cyclophosphamide), COPP, COPP-ABV, CVP, CYTOXAN (cyclophosphamide), DEPOCYT (liposomal cytarabine), DTIC-DOME (dacarbazine), EPOCH, FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLOTYN (pralatrexate), HYPER-CVAD, ICE, IMBRUVICA (ibrutinib), INTRON A (recombinant interferon alfa-2b), ISTODAX (romidepsin), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), Lomustine, MATULANE (procarbazine hydrochloride), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MOPP, MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), NEOSAR (cyclophosphamide), OEPA, ONTAK (denileukin diftitox), OPPA, R-CHOP, REVLIMID (lenalidomide), RITUXAN (rituximab), STANFORD V, TREANDA (bendamustine hydrochloride), VAMP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VINCASAR PFS (vincristine sulfate), ZEVALIN (ibritumomab tiuxetan), ZOLINZA (vorinostat), ZYDELIG (idelalisib), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is REVLIMID (lenalidomide), DACOGEN (decitabine), VIDAZA (azacitidine), CYTOSAR-U (cytarabine), IDAMYCIN (idarubicin), CERUBIDINE (daunorubicin), LEUKERAN (chlorambucil), NEOSAR (cyclophosphamide), FLUDARA (fludarabine), LEUSTATIN (cladribine), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABRAXANE (paclitaxel albumin-stabilized nanoparticle formulation), AC, AC-T, ADE, ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRUCIL (fluorouracil), AFINITOR (everolimus), AFINITOR DISPERZ (everolimus), ALDARA (imiquimod), ALIMTA (pemetrexed disodium), AREDIA (pamidronate disodium), ARIMIDEX (anastrozole), AROMASIN (exemestane), AVASTIN (bevacizumab), BECENUM (carmustine), BEP, BICNU (carmustine), BLENOXANE (bleomycin), CAF, CAMPTOSAR (irinotecan hydrochloride), CAPOX, CAPRELSA (vandetanib), CARBOPLATIN-TAXOL, CARMUBRIS (carmustine), CASODEX (bicalutamide), CEENU (lomustine), CERUBIDINE (daunorubicin hydrochloride), CERVARIX (recombinant HPV bivalent vaccine), CLAFEN (cyclophosphamide), CMF, COMETRIQ (cabozantinib-s-malate), COSMEGEN (dactinomycin), CYFOS (ifosfamide), CYRAMZA (ramucirumab), CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), DACOGEN (decitabine), DEGARELIX, DOXIL (doxorubicin hydrochloride liposome), DOXORUBICIN HYDROCHLORIDE, DOX-SL (doxorubicin hydrochloride liposome), DTIC-DOME (dacarbazine), EFUDEX (fluorouracil), ELLENCE (epirubicin hydrochloride), ELOXATIN (oxaliplatin), ERBITUX (cetuximab), ERIVEDGE (vismodegib), ETOPOPHOS (etoposide phosphate), EVACET (doxorubicin hydrochloride liposome), FARESTON (toremifene), FASLODEX (fulvestrant), FEC, FEMARA (letrozole), FLUOROPLEX (fluorouracil), FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, GARDASIL (recombinant human papillomavirus (HPV) quadrivalent vaccine), GEMCITABINE-CISPLATIN, GEMCITABINE-OXALIPLATIN, GEMZAR (gemcitabine hydrochloride), GILOTRIF (afatinib dimaleate), GLEEVEC (imatinib mesylate), GLIADEL (carmustine implant), GLIADEL WAFER (carmustine implant), HERCEPTIN (trastuzumab), HYCAMTIN (topotecan hydrochloride), IFEX (ifosfamide), IFOSFAMIDUM (ifosfamide), INLYTA (axitinib), INTRON A (recombinant interferon alfa-2b), IRESSA (gefitinib), IXEMPRA (ixabepilone), JAKAFI (ruxolitinib phosphate), JEVTANA (cabazitaxel), KADCYLA (ado-trastuzumab emtansine), KEYTRUDA (pembrolizumab), KYPROLIS (carfilzomib), LIPODOX (doxorubicin hydrochloride liposome), LUPRON (leuprolide acetate), LUPRON DEPOT (leuprolide acetate), LUPRON DEPOT-3 MONTH (leuprolide acetate), LUPRON DEPOT-4 MONTH (leuprolide acetate), LUPRON DEPOT-PED (leuprolide acetate), MEGACE (megestrol acetate), MEKINIST (trametinib), METHAZOLASTONE (temozolomide), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MITOXANTRONE HYDROCHLORIDE, MITOZYTREX (mitomycin c), MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), MUTAMYCIN (mitomycin c), MYLOSAR (azacitidine), NAVELBINE (vinorelbine tartrate), NEOSAR (cyclophosphamide), NEXAVAR (sorafenib tosylate), NOLVADEX (tamoxifen citrate), NOVALDEX (tamoxifen citrate), OFF, PAD, PARAPLAT (carboplatin), PARAPLATIN (carboplatin), PEG-INTRON (peginterferon alfa-2b), PEMETREXED DISODIUM, PERJETA (pertuzumab), PLATINOL (cisplatin), PLATINOL-AQ (cisplatin), POMALYST (pomalidomide), prednisone, PROLEUKIN (aldesleukin), PROLIA (denosumab), PROVENGE (sipuleucel-t), REVLIMID (lenalidomide), RUBIDOMYCIN (daunorubicin hydrochloride), SPRYCEL (dasatinib), STIVARGA (regorafenib), SUTENT (sunitinib malate), SYLATRON (peginterferon alfa-2b), SYLVANT (siltuximab), SYNOVIR (thalidomide), TAC, TAFINLAR (dabrafenib), TARABINE PFS (cytarabine), TARCEVA (erlotinib hydrochloride), TASIGNA (nilotinib), TAXOL (paclitaxel), TAXOTERE (docetaxel), TEMODAR (temozolomide), THALOMID (thalidomide), TOPOSAR (etoposide), TORISEL (temsirolimus), TPF, TRISENOX (arsenic trioxide), TYKERB (lapatinib ditosylate), VECTIBIX (panitumumab), VEIP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VEPESID (etoposide), VIADUR (leuprolide acetate), VIDAZA (azacitidine), VINCASAR PFS (vincristine sulfate), VOTRIENT (pazopanib hydrochloride), WELLCOVORIN (leucovorin calcium), XALKORI (crizotinib), XELODA (capecitabine), XELOX, XGEVA (denosumab), XOFIGO (radium 223 dichloride), XTANDI (enzalutamide), YERVOY (ipilimumab), ZALTRAP (ziv-aflibercept), ZELBORAF (vemurafenib), ZOLADEX (goserelin acetate), ZOMETA (zoledronic acid), ZYKADIA (ceritinib), ZYTIGA (abiraterone acetate), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TK1258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055, BEZ235, BGT226, XL765, PF-4691502, GDCO.sub.980, SF1126, and OSI-027), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethyl melamine, or a combination thereof. In certain embodiments, the additional pharmaceutical agent is a cytotoxic chemotherapeutic agent (e.g., gemcitabine, cytarabine, daunorubicin, doxorubicin, vincristine, 1-asparaginase, cyclophosphamide, or etoposide). In certain embodiments, the additional pharmaceutical agent is an epigenetic modifier such as azacitidine or romidepsin. In certain embodiments, the additional pharmaceutical agent is ruxolitinib, BBT594, CHZ868, CYT387, or BMS911543. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a tyrosine kinase. In some embodiments, the additional pharmaceutical agent is a topoisomerase inhibitor, a MCL1 inhibitor, a BCL-2 inhibitor, a BCL-xL inhibitor, a BRD4 inhibitor, a BRCA1 inhibitor, BRCA2 inhibitor, HER1 inhibitor, HER2 inhibitor, a CDK9 inhibitor, a Jumonji histone demethylase inhibitor, or a DNA damage inducer. In some embodiments, the additional pharmaceutical agent is etoposide, obatoclax, navitoclax, JQ1, 4-(((5′-chloro-2′-(((1R,4R)-4-(((R)-1-methoxypropan-2-yl)amino)cyclohexyl)amino)-[2,4′-bipyridin]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile, JIB04, or cisplatin. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of a kinase (e.g., JAK, ABL1, ABL2, BRAF, CDC2L2, CDKL3, CIT, CSF1R, EPHA4, EPHA6, EPHA8, EPHB1, EPHB2, EPHB4, FES, FGR, FLT4, HPK1, INSRR, ITK, KIT, LYN, MAP4K2, MERTK, p38-delta, PDGFRA, PDGFRB, PFTAIRE2, PFTK1, RAF1, RET, RIPK1, SRC, TAK1, TAOK3, TIE1, TIE2, TRKB, TRKC, or a combination thereof). In certain embodiments, the additional pharmaceutical agent is an antibody or a fragment thereof (e.g., monoclonal antibody). In certain embodiments, the additional pharmaceutical agent is a tyrosine kinase inhibitor. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the additional pharmaceutical agent is a glucocorticoid (e.g., cortisol, cortisone, prednisone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone acetate, or deoxycorticosterone acetate). In certain embodiments, the additional therapy is an immunotherapy (e.g., an immunotherapeutic monoclonal antibody). In certain embodiments, the additional pharmaceutical agent is an immunomodulator. In certain embodiments, the additional pharmaceutical agent is an immune checkpoint inhibitor. In certain embodiments, the additional pharmaceutical agent is a programmed cell death 1 protein (PD-1) inhibitor. In certain embodiments, the additional pharmaceutical agent is a programmed cell death 1 protein ligand 1 (PD-L1) inhibitor. In certain embodiments, the additional pharmaceutical agent is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor. In certain embodiments, the additional pharmaceutical agent is a T-cell immunoglobulin domain and mucin domain 3 (TIM3) inhibitor, lymphocyte activation gene-3 (LAG3) inhibitor, V-set domain-containing T-cell activation inhibitor 1 (VTCN1 or B7-H4) inhibitor, cluster of differentiation 276 (CD276 or B7-H3) inhibitor, B and T lymphocyte attenuator (BTLA) inhibitor, galectin-9 (GAL9) inhibitor, checkpoint kinase 1 (Chk1) inhibitor, adenosine A2A receptor (A2AR) inhibitor, indoleamine 2,3-dioxygenase (IDO) inhibitor, killer-cell immunoglobulin-like receptor (KIR) inhibitor, or V-domain Ig suppressor of T cell activation (VISTA) inhibitor. In certain embodiments, the PD-1 inhibitor is nivolumab, pidilizumab, pembrolizumab, MEDI-0680, REGN2810, or AMP-224. In certain embodiments, the PD-L1 inhibitor is atezolizumab, durvalumab, BMS-936559, avelumab, or CA-170. In certain embodiments, the CTLA-4 inhibitor is ipilimumab or tremelimumab. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, and transplantation (e.g., stem cell transplantation, bone marrow transplantation).
[0233] Also encompassed by the present disclosure are kits (e.g., pharmaceutical packs). In certain embodiments, the kit comprises a compound or pharmaceutical composition described herein, and instructions for using the compound or pharmaceutical composition. In certain embodiments, the kit comprises a first container, wherein the first container includes the compound or pharmaceutical composition. In some embodiments, the kit further comprises a second container. In certain embodiments, the second container includes an excipient (e.g., an excipient for dilution or suspension of the compound or pharmaceutical composition). In certain embodiments, the second container includes an additional pharmaceutical agent. In some embodiments, the kit further comprises a third container. In certain embodiments, the third container includes an additional pharmaceutical agent. In some embodiments, the compound or pharmaceutical composition included in the first container and the excipient or additional pharmaceutical agent included in the second container are combined to form one unit dosage form. In some embodiments, the compound or pharmaceutical composition included in the first container, the excipient included in the second container, and the additional pharmaceutical agent included in the third container are combined to form one unit dosage form. In certain embodiments, each of the first, second, and third containers is independently a vial, ampule, bottle, syringe, dispenser package, tube, or inhaler.
[0234] In certain embodiments, the instructions are for administering the compound or pharmaceutical composition to a subject (e.g., a subject in need of treatment or prevention of a disease described herein). In certain embodiments, the instructions are for contacting a biological sample or cell with the compound or pharmaceutical composition. In certain embodiments, the instructions comprise information required by a regulatory agency, such as the U.S. Food and Drug Administration (FDA) or the European Agency for the Evaluation of Medicinal Products (EMA). In certain embodiments, the instructions comprise prescribing information.
Methods of Use and Uses
[0235] The present disclosure provides methods of modulating (e.g., inhibiting or increasing) the activity (e.g., aberrant activity, such as increased or decreased activity) of a kinase (e.g., JAK (e.g., JAK2)). The present disclosure provides methods of modulating (e.g., inhibiting or increasing) the activity (e.g., undesired or aberrant activity, such as increased activity (e.g., activity above normal levels) or decreased activity (e.g., activity below normal levels)), of a kinase in a subject, biological sample, or cell. The present disclosure also provides methods for the treatment of a range of diseases and conditions, such as diseases and conditions associated with undesired or aberrant activity (e.g., increased activity) or overexpression of a kinase. In certain embodiments, the diseases include proliferative diseases, musculoskeletal diseases, genetic diseases, hematological diseases, neurological diseases, painful conditions, psychiatric disorders, metabolic disorders, benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, autoimmune diseases, and premalignant conditions.
[0236] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount (e.g., therapeutically effective amount) of a compound described herein or a pharmaceutical composition described herein.
[0237] In another aspect, the present disclosure provides methods of preventing a disease in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount (e.g., prophylactically effective amount) of a compound described herein or a pharmaceutical composition described herein.
[0238] In another aspect, the present disclosure provides methods of inhibiting the activity of a kinase in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound described herein or a pharmaceutical composition described herein.
[0239] In another aspect, the present disclosure provides methods of inhibiting the activity of a kinase in a biological sample (e.g., an in vitro biological sample), the method comprising contacting the biological sample with an effective amount of a compound described herein or a pharmaceutical composition described herein.
[0240] In another aspect, the present disclosure provides methods of inhibiting the activity of a kinase in a cell (e.g., an in vitro cell), the method comprising contacting the cell with an effective amount of a compound described herein or a pharmaceutical composition described herein.
[0241] Without wishing to be bound by any particular theory, in certain embodiments the compounds described herein are able to bind (e.g., covalently modify) the kinase being inhibited. In certain embodiments, a compound described herein is able to bind (e.g., covalently modify) to the kinase. In certain embodiments, the kinase is JAK. In certain embodiments, the kinase is JAK2. In certain embodiments, the kinase is JAK3. In certain embodiments, the kinase is JAK1. In certain embodiments, the kinase is TYK2.
[0242] In certain embodiments, provided are methods of decreasing the activity of a kinase (e.g., JAK (e.g., JAK2)) in a subject, biological sample, or cell by at least about 1%, at least about 3%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In certain embodiments, the activity of a kinase in a subject, biological sample, or cell is decreased by at least about 1%, at least about 3%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the activity of a kinase in a subject, biological sample, or cell is selectively inhibited by the method. In some embodiments, the activity of a kinase (e.g., JAK2) in a subject, biological sample, or cell is selectively decreased by a compound or pharmaceutical composition described herein.
[0243] A disease, including proliferative disease, may be associated with aberrant or undesired activity of a kinase, and/or overexpression of the kinase. Aberrant or undesired activity of a kinase may be an increased or a decreased level of activity of the kinase. Proliferative diseases are sometimes associate with abnormal levels of JAK activity, frequently through increased or decreased JAK activation. Inhibition of the activity of JAK2 would be expected to inhibit phosphorylation. In certain embodiments, JAK2 is not overexpressed, but the activity of JAK2 is increased. In certain embodiments, JAK2 is overexpressed, and the activity of JAK2 is increased. The compounds and pharmaceutical compositions described herein may inhibit the activity of JAK2 and be useful in treating and/or preventing diseases, such as diseases associated with the aberrant, increased, or undesired activity of a kinase, overactivation of the kinase, and/or overexpression of the kinase.
[0244] JAK1 has been implicated in the signaling of the common gamma chain (γc) of type I cytokine receptors, to elicit signals from the IL-2 receptor family (e.g. IL-2R, IL-7R, IL-9R and IL-15R), the IL-4 receptor family (e.g. IL-4R and IL-13R), the gp130 receptor family (e.g. IL-6R, IL-11R, LIF-R, OSM-R, cardiotrophin-1 receptor (CT-1R), ciliary neurotrophic factor receptor (CNTF-R), and neurotrophin-1 receptor (NNT-1R) and Leptin-R.
[0245] JAK2 has been implicated in signaling by members of the type II cytokine receptor family (e.g. interferon receptors), the GM-CSF receptor family (IL-3R, IL-5R and GM-CSF-R), the gp130 receptor family (e.g., IL-6R), and the single chain receptors (e.g. Epo-R, Tpo-R, GH-R, PRL-R). JAK3 has been implicated in the signaling of the common gamma chain (γc) of the type I cytokine receptor family (e.g. IL-2R, IL-4R, IL-7R, IL-9R, IL-15R, and IL-21R). TYK2 has been implicated in the signaling of IFN-α, IL-6, IL-10, and IL-12.
[0246] Ruxolitinib, a dual JAK1 and JAK2 inhibitor, first gained FDA approval for treatment of myelofibrosis in 2011. While the phase III Controlled Myelofibrosis Study with Oral JAK Inhibitor (COMFORT-I and -II) trials showed that the medication can reduce abnormal splenomegaly and constitutional symptoms, the majority of patients did not achieve a molecular response with reduced mutant allele burden, and improvement in survival was minimal (Harrison, C. et al. N Engl J Med 366, 787-798, (2012); Koppikar, P. et al. Nature 489, 155-159, (2012); Verstovsek, S. et al. N Engl J Med 366, 799-807, (2012)). Thus, there is a significant unmet medical need in the MPN population. Ruxolitinib has essentially no activity (IC.sub.50>20 μM) against cell lines or patient-derived xenografts from patients with CRLF2-rearranged B-ALL, but it can induce remarkable remissions in the rare subset of leukemias with TEL-JAK2 fusions (Roberts, K. G. et al. N Engl J Med 371, 1005-1015, (2014)). A major advance in this field came from the Levine laboratory, which demonstrated that persistent JAK2 signaling in the presence of an ATP-competitive type I JAK2 inhibitor, such as ruxolitinib, may result from heterodimerization and trans-phosphorylation of JAK2 with JAK1 or TYK2 (Koppikar, P. et al. Nature 489, 155-159, (2012)). This helps explain the commonly observed phenomenon that activation loop phosphorylation of JAK2 increases in the presence of type I JAK2 inhibitors. In the setting of JAK2 fusions, obligate homodimerization between TEL domains prevents heterodimerization, and thus these leukemias remain sensitive to type I inhibitors. Of note, CRLF2 signaling involves heterodimerization with the IL7Rα subunit and signaling through JAK2 (bound to CRLF2) and JAK1 (bound to IL7Rα) (Pandey, A. et al. Nat Immunol 1, 59-64 (2000)). Thus, persistent trans-phosphorylation of JAK2 is likely to explain the resistance of these B-ALLs to type I JAK2 inhibitors (Wu, S. C. et al. Cancer Cell 28, 29-41, (2015)).
[0247] Type II inhibitors lock the kinase domain in a closed conformation and therefore should overcome trans-phosphorylation of JAK2 by JAK1 or TYK2. In fact, the Levine lab demonstrated that BBT594, a type II inhibitor initially developed to target BCR-ABL T315I (Andraos, R. et al. Cancer discovery 2, 512-523, (2012)), abrogated persistent JAK2 signaling in myeloid cells refractory to treatment with a type I JAK2 inhibitor (Koppikar, P. et al. Nature 489, 155-159, (2012)). BBT594 has limitations in potency and selectivity for JAK2, and its pharmacokinetic properties preclude in vivo use. Mining the Novartis database for type II kinase inhibitors and cellular screening in JAK2 V617F-mutant SET2 cells to identify compounds that inhibit JAK2 and STAT5 phosphorylation revealed arylamino-benzimidazoles, originally described as RAF kinase inhibitors (Shiels, M. S. et al., Journal of the National Cancer Institute 103, 753-762, (2011)), as a starting point for drug design. Medicinal chemistry efforts led to the development of CHZ868, the first type II JAK2 inhibitor amenable to in vivo testing in transgenic and xenograft mouse models (Wu, S. C. et al., Cancer cell 28, 29-41, (2015)).
[0248] In certain embodiments, the disease (e.g., the disease to be treated or prevented by a method described herein) is associated with the increased activity of a kinase (e.g., JAK (e.g., JAK2)). In certain embodiments, the disease is associated with overexpression of a kinase (e.g., JAK (e.g., JAK2)). In certain embodiments, the disease is a proliferative disease. In certain embodiments, the disease is cancer. In certain embodiments, the cancer is a JAK-STAT-dependent cancer.
[0249] In certain embodiments, the cancer is a hematological malignancy. In certain embodiments, the proliferative disease is a leukemia. In certain embodiments, the proliferative disease is chronic lymphocytic leukemia (CLL). In certain embodiments, the proliferative disease is acute lymphoblastic leukemia (ALL). In certain embodiments, the proliferative disease is T-cell acute lymphoblastic leukemia (T-ALL). In certain embodiments, the proliferative disease is chronic myelogenous leukemia (CML). In certain embodiments, the proliferative disease is acute myelogenous leukemia (AML). In certain embodiments, the proliferative disease is acute monocytic leukemia (AMoL). In certain embodiments, the proliferative disease is lymphoma. In some embodiments, the proliferative disease is Burkitt's lymphoma. In certain embodiments, the proliferative disease is a Hodgkin's lymphoma. In certain embodiments, the proliferative disease is a non-Hodgkin's lymphoma. In certain embodiments, the cancer is essential thrombocythemia.
[0250] In certain embodiments, the cancer is a myeloma. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the cancer is myelofibrosis, myeloproliferative neoplasm, myeloid malignancy, or polycythemia vera.
[0251] In certain embodiments, the cancer is an adenocarcinoma. In certain embodiments, the cancer is a blastoma. In certain embodiments, the cancer is a carcinoma. In certain embodiments, the cancer is a sarcoma. In certain embodiments, the cancer is brain cancer. In certain embodiments, the cancer is pancreatic cancer.
[0252] In some embodiments, the disease is a benign neoplasm.
[0253] In certain embodiments, the disease is an inflammatory disease.
[0254] In some embodiments, the disease is an autoinflammatory disease. In certain embodiments, the autoimmune disease is psoriasis, rheumatoid arthritis, graft-versus-host disease, alopecia, alopecia universalis, or vitiligo.
[0255] In certain embodiments, the disease is myelodysplastic syndrome.
[0256] In certain embodiments, the disease is causing a syndrome of wasting that comprises weight loss as a symptom.
[0257] In certain embodiments, the disease is a premalignant condition (e.g., clonal hematopoiesis).
[0258] In certain embodiments, the method described herein superior (e.g., showing improved safety and/or therapeutic effects) or comparable to existing therapy (e.g., chemotherapy).
[0259] In certain embodiments, the biological sample or cell (e.g., the biological sample or cell being contacted with a compound or pharmaceutical composition described herein) is in vitro. In certain embodiments, the biological sample or cell is in vivo. In certain embodiments, the biological sample or cell is ex vivo.
[0260] In certain embodiments, the cell is a malignant cell (e.g., cancer cell). In certain embodiments, the cell is a malignant blood cell. In certain embodiments, the cell is a malignant bone marrow cell. In certain embodiments, the cell is an adenocarcinoma cell, blastoma cell, carcinoma cell, or sarcoma cell. In certain embodiments, the cell is a pre-malignant cell (e.g., pre-cancerous cell).
[0261] In certain embodiments, the method described herein further comprises administering to the subject in need thereof an additional therapy. In certain embodiments, the additional therapy is an additional pharmaceutical agent described herein. In certain embodiments, the additional therapy is a cytotoxic chemotherapy (e.g., gemcitabine, cytarabine, daunorubicin, doxorubicin, vincristine, 1-asparaginase, cyclophosphamide, or etoposide). In certain embodiments, the additional therapy is an epigenetic modifier (e.g., azacitidine or romidepsin). In certain embodiments, the additional therapy is a glucocorticoid. In certain embodiments, the additional therapy is an immunotherapy (e.g., an immunotherapeutic monoclonal antibody). In some embodiments, the additional pharmaceutical agent is etoposide, obatoclax, or navitoclax, and optionally the disease is breast cancer, e.g., triple-negative breast cancer, HER2 positive breast cancer, HER2 negative breast cancer, ER-positive breast cancer, ER-negative breast cancer, or ER/PR-positive breast cancer. In some embodiments, the additional pharmaceutical agent is etoposide, JIB04, or cisplatin, and optionally the disease is Ewing's sarcoma. In some embodiments, the additional pharmaceutical agent is JQ1 or NVP2, and optionally the disease is leukemia, e.g., acute myelogenous leukemia, myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, monoblastic leukemia, or megakaryoblastic leukemia.
[0262] In yet another aspect, the present invention provides compounds and pharmaceutical compositions described herein for use in the treatment of a disease (e.g., a proliferative disease, such as cancer) in a subject in need thereof.
[0263] In yet another aspect, the present invention provides compounds and pharmaceutical compositions described herein for use in the prevention of a disease (e.g., a proliferative disease, such as cancer) in a subject in need thereof.
[0264] In another aspect, the present disclosure provides compounds and pharmaceutical compositions described herein for use in inhibiting the activity of a kinase in a subject in need thereof.
[0265] In another aspect, the present disclosure provides compounds and pharmaceutical compositions described herein for use in inhibiting the activity of a kinase in a biological sample (e.g., an in vivo or ex vivo biological sample).
[0266] In another aspect, the present disclosure provides compounds and pharmaceutical compositions described herein for use in inhibiting the activity of a kinase in a cell (e.g., an in vivo or ex vivo cell).
[0267] In another aspect, the present disclosure provides uses of compounds and pharmaceutical compositions described herein in the manufacture of a medicament for treating a disease in a subject in need thereof.
[0268] In another aspect, the present disclosure provides uses of compounds and pharmaceutical compositions described herein in the manufacture of a medicament for preventing a disease in a subject in need thereof.
[0269] The compounds, pharmaceutical compositions, and kits described herein may synergistically augment inhibition of a kinase (e.g., JAK (e.g., JAK2)) induced by the additional pharmaceutical agent(s) in the biological sample or subject. Thus, the combination of the compounds, pharmaceutical compositions, or kits with additional pharmaceutical agent(s) may be useful in treating diseases resistant to a treatment using the additional pharmaceutical agent(s) without the compounds, pharmaceutical compositions, or kits described herein.
EXAMPLES
[0270] 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 of the Present Disclosure
[0271] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance spectra were obtained on Bruker AVANCE spectrometer at 400 MHz or 500 MHz for proton. Spectra are given in ppm (S) and coupling constants, J, are reported in Hertz. The solvent peak was used as the reference peak for proton spectra. LC-MS spectra were obtained on Waters UPLC or Agilent 1100 HPLC LC-MS ion trap electrospray ionization (ESI) mass spectrometer.
##STR00145##
N-(5-bromothiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide
[0272] To a mixture of 5-bromothiazolo[5,4-b]pyridin-2-amine (230 mg, 1.0 mmol, 1.0 eq) and TEA (606 mg, 6 mmol, 6 eq) in 5 mL DCM was added cyclopropanecarbonyl chloride (520 mg, 5 mmol, 5 eq) in 2 mL DCM at 0° C. The mixture was stirred at 80° C. for 12 h. After cooling down, the solvent was removed under reduced pressure. 80 mL of H.sub.2O was added, and the mixture was extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with brine, dried over Na.sub.2SO.sub.4, and then purified with silica gel column to give the product as a light-yellow solid (120 mg, 40%). LCMS (m/z): 298 [M+H].sup.+.
Methyl 3-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)-4-methylbenzoate
[0273] The mixture of N-(5-bromothiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide (100 mg, 0.34 mmol, 1.0 eq), methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (65 mg, 0.34 mmol, 1.0 eq), Pd(dppf)Cl.sub.2 (8.3 mg, 0.01 mmol, 0.03 eq) and Cs.sub.2CO.sub.3 (170 mg, 0.51 mmol) in dioxane/water (4 mL/0.4 mL) was stirred for 8 h at 100° C. under N.sub.2. The mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure and the residue was purified with silica gel column to give the product as a light yellow solid (93 mg, 78%). LCMS (m/z): 368 [M+H].sup.+.
3-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)-4-methylbenzoic acid
[0274] To a solution of methyl 3-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)-4-methylbenzoate (93 mg, 0.25 mmol) in THF (4 mL) was add 2 mL of 3 N LiOH aqueous solution. The reaction mixture was stirred at room temperature overnight, then purified by prep-HPLC (Cis column, CH.sub.3CN/H.sub.2O, containing 0.05% NH.sub.4HCO.sub.3) to obtain the target compound (white solid, 61 mg, yield 69%). LCMS (m/z): 354 [M+H].sup.+.
3-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)-N-(2,4-difluorophenyl)-4-methylbenzamide
[0275] To a mixture of 3-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)-4-methyl benzoic acid (20 mg, 0.056 mmol), 2,4-difluoroaniline (10 mg, 0.068 mmol) in DMF (1 mL) was added HATU (32 mg, 0.084 mmol) and DIPEA (0.03 mL, 0.168 mmol). The reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried with Na.sub.2SO.sub.4, and concentrated. The residue was purified by prep-HPLC to obtain the target compound (white solid, 7.6 mg, yield 29%). LCMS (m/z): 465 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.83 (s, 1H), 10.18 (s, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.95 (dd, J=8.0, 2.0 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.59 (td, J=8.8, 6.1 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.36 (ddd, J=10.7, 9.0, 2.9 Hz, 1H), 7.16-7.08 (m, 1H), 2.44 (s, 3H), 2.10-1.97 (m, 1H), 1.00 (m, 4H).
##STR00146##
3-(2-acetamidothiazolo[5,4-b]pyridin-5-yl)-N-(2,4-difluorophenyl)-4-methylbenzamide
[0276] Compound I-2 is prepared by using essentially the same procedure with Compound I-1, except that acetyl chloride was used in the first step. LCMS (m/z): 439 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.49 (s, 1H), 10.19 (s, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.08 (s, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.58 (m, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.34 (m, 1H), 7.12 (m, 1H), 2.44 (s, 3H), 2.24 (s, 3H).
##STR00147##
N-(5-(2-methyl-5-nitrophenyl)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide
[0277] The mixture of N-(5-bromothiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide (45 mg, 0.15 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(2-methyl-5-nitrophenyl)-1,3,2-dioxaborolane (45 mg, 0.17 mmol, 1.1 eq), Pd(dppf)Cl.sub.2 (6 mg, 0.015 mmol, 0.05 eq) and Cs.sub.2CO.sub.3 (100 mg, 0.3 mmol) in dioxane/water (4 mL/0.4 mL) was stirred for 8 h at 100° C. under N.sub.2. The mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure, and the residue was purified with silica gel column to give the product as a light-yellow solid (23 mg, 43%). LCMS (m/z): 355 [M+H].sup.+.
N-(5-(5-amino-2-methylphenyl)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide
[0278] The mixture of N-(5-(2-methyl-5-nitrophenyl)thiazolo[5,4-b]pyridin-2-yl)cyclopropane carboxamide (23 mg, 0.065 mmol), Pd/C (5 mg) in MeOH (10 mL) was stirred at room temperature under H.sub.2 (1 atm) for 16 h. The resulting mixture was filtered. The filtrate was concentrated to provide the title compound (light brown solid, 9 mg, 43%), which was used in the next step without further purification. LCMS: 325 [M+H].sup.+.
N-(5-(5-(3-(2,4-difluorophenyl)ureido)-2-methylphenyl)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide
[0279] The mixture of N-(5-(5-amino-2-methylphenyl)thiazolo[5,4-b]pyridin-2-yl)cyclopropane carboxamide (9 mg, 0.03 mmol), 2,4-difluoro-1-isocyanatobenzene (5 mg, 0.03 mmol) in THF (2 mL) was stirred reflux overnight. After completion, the mixture was diluted with water, extracted with DCM (50 mL×3). The organic phase was washed with brine (20 mL×3), dried with Na.sub.2SO.sub.4, filtered, concentrated to remove the solvent, and the residue was purified by Prep-HPLC to obtain the desire compound (white solid, 5.7 mg, yield 42%). LCMS (m/z): 480 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.81 (s, 1H), 9.08 (s, 1H), 8.47 (d, J=2.3 Hz, 1H), 8.17 (d, J=8.3 Hz, 1H), 8.06 (td, J=9.3, 6.1 Hz, 1H), 7.66-7.58 (m, 2H), 7.38 (dd, J=8.2, 2.4 Hz, 1H), 7.30 (ddd, J=11.6, 8.9, 2.9 Hz, 1H), 7.26-7.19 (m, 1H), 7.03 (td, J=9.0, 3.0 Hz, 1H), 2.30 (s, 3H), 2.09-2.00 (m, 1H), 1.05-0.95 (m, 4H),
##STR00148##
N-(6-(2-methyl-5-nitrophenyl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide
[0280] The mixture of N-(6-bromobenzo[d]thiazol-2-yl)cyclopropanecarboxamide (90 mg, 0.3 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(2-methyl-5-nitrophenyl)-1,3,2-dioxaborolane (90 mg, 0.33 mmol, 1.1 eq), Pd(dppf)Cl.sub.2 (13 mg, 0.015 mmol, 0.05 eq) and Cs.sub.2CO.sub.3 (200 mg, 0.6 mmol) in dioxane/water (4 mL/0.4 mL) was stirred for 8 h at 100° C. under N.sub.2. The mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure and the residue was purified with silica gel column to give the product as a light-yellow solid (90 mg, 85%). LCMS (m/z): 354 [M+H].sup.+.
N-(6-(5-amino-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide
[0281] The mixture of N-(6-(2-methyl-5-nitrophenyl)benzo[d]thiazol-2-yl)cyclopropane carboxamide (90 mg, 0.26 mmol), iron (88 mg, 1.58 mmol) and NH.sub.4Cl (70 mg, 1.32 mmol) in iPrOH/H.sub.2O (3 mL/1 mL) was stirred at 60° C. for 1 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column to get title compound (light brown solid, 78 mg, 92%). LCMS: 324 [M+H].sup.+.
N-(3-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-4-methylphenyl)-3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide
[0282] To a mixture of N-(6-(5-amino-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane carboxamide (20 mg, 0.05 mmol), 3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl) benzoic acid (15 mg, 0.05 mmol) in DMF (2 mL) was added HATU (35 mg, 0.092 mmol) and DIPEA (0.05 mL). The reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried with Na.sub.2SO.sub.4, and concentrated. The residue was purified by prep-HPLC to obtain the product (white solid, 8.4 mg, yield 29%). LCMS: 622 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.62 (s, 1H), 10.38 (s, 1H), 8.12 (d, J=15.1 Hz, 2H), 7.90 (d, J=1.8 Hz, 1H), 7.79-7.71 (m, 2H), 7.67 (dd, J=8.2, 2.3 Hz, 1H), 7.63 (d, J=2.3 Hz, 1H), 7.36 (dd, J=8.3, 1.8 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 3.57 (s, 2H), 2.34 (m, 7H), 2.24 (q, J=7.2 Hz, 3H), 2.18 (s, 3H), 2.00-1.91 (m, 1H), 0.90 (m, 7H).
Compound I-6
3-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)-N-(3-(4-ethylpiperazine-1-carbonyl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide
[0283] Compound I-6 is prepared by using essentially the same procedure with Compound I-1, except that (3-amino-5-(trifluoromethyl)phenyl)(4-ethylpiperazin-1-yl)methanone was used in the last step. LCMS (m/z): 637 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.86 (s, 1H), 10.73 (s, 1H), 8.27-8.20 (m, 3H), 8.12 (d, J=2.0 Hz, 1H), 7.98 (dd, J=7.9, 2.0 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.8 Hz, 2H), 4.14-3.53 (m, 4H), 3.19-3.14 (m, 2H), 2.45 (s, 3H), 2.11-2.01 (m, 1H), 1.53-1.46 (m, 1H), 1.40-1.20 (m, 5H), 1.06-0.91 (m, 5H), 0.91-0.83 (m, 1H).
##STR00149##
N-(3-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)phenyl)-3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide
[0284] To a mixture of N-(5-(3-aminophenyl)thiazolo[5,4-b]pyridin-2-yl)cyclopropane carboxamide (16 mg, 0.05 mmol), 3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl) benzoic acid (22 mg, 0.05 mmol) in DMF (2 mL) was added HATU (38 mg, 0.1 mmol) and DIPEA (0.03 mL). The reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried with Na.sub.2SO.sub.4, and concentrated. The residue was purified by prep-HPLC to obtain the product (white solid, 6.8 mg, yield 22%). LCMS (m/z): 609 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ 12.85 (s, 1H), 10.67 (s, 1H), 8.52 (s, 1H), 8.36 (s, 1H), 8.30 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 8.02-7.94 (m, 2H), 7.87 (d, J=7.9 Hz, 1H), 7.53 (t, J=7.9 Hz, 1H), 3.90 (s, 2H), 3.18-3.10 (m, 3H), 3.07 (s, 1H), 2.67-2.53 (m, 1H), 2.51 (br, 5H), 2.09-2.00 (m, 1H), 1.21 (t, J=7.3 Hz, 3H), 1.05-0.95 (m, 4H).
##STR00150##
N-(3-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)-4-methylphenyl)-3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide
[0285] To a mixture of N-(5-(5-amino-2-methylphenyl)thiazolo[5,4-b]pyridin-2-yl)cyclopropane carboxamide (20 mg, 0.05 mmol), 3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl) benzoic acid (15 mg, 0.05 mmol) in DMF (2 mL) was added HATU (35 mg, 0.092 mmol) and DIPEA (0.05 mL). The reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried with Na.sub.2SO.sub.4, and concentrated. The residue was purified by prep-HPLC to obtain the product (white solid, 18.8 mg, yield 66%). LCMS (m/z): 623 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.77 (s, 1H), 10.47 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.85 (s, 1H), 7.83-7.74 (m, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 3.74 (s, 2H), 3.06 (q, J=7.4 Hz, 2H), 2.97-2.91 (m, 2H), 2.44 (s, 5H), 2.39-2.35 (m, 1H), 2.29 (s, 3H), 2.02-1.94 (m, 1H), 1.13 (t, J=7.3 Hz, 3H), 0.98-0.88 (m, 4H).
##STR00151##
N-(5-(5-(3-(3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)ureido)-2-methylphenyl)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide
[0286] Compound I-9 is prepared by using essentially the same procedure with Compound I-3, except that 3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl) aniline was used in the last step. LCMS (m/z): 638 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.82 (s, 1H), 9.38 (s, 1H), 9.18 (s, 1H), 8.17 (d, J=8.4 Hz, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.66 (d, J=2.3 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.41 (dd, J=8.2, 2.3 Hz, 1H), 7.31 (s, 1H), 7.25 (d, J=8.7 Hz, 1H), 3.82 (s, 2H), 3.26-2.91 (m, 7H), 2.58-2.52 (m, 3H), 2.29 (s, 3H), 2.05 (m, 1H), 1.20 (t, J=7.3 Hz, 3H), 1.05-0.95 (m, 4H).
##STR00152##
N-(5-(indolin-6-yl)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide
[0287] The mixture of N-(5-bromothiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide (100 mg, 0.34 mmol, 1.0 eq), indolin-6-ylboronic acid (60 mg, 0.37 mmol, 1.1 eq), Pd(dppf)Cl.sub.2 (14 mg, 0.017 mmol, 0.05 eq) and Cs.sub.2CO.sub.3 (166 mg, 0.51 mmol) in dioxane/water (5 mL/0.5 mL) was stirred for 8 h at 100° C. under N.sub.2. The mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure and the residue was purified with silica gel column to give the product as a light-yellow solid (80 mg, 70%). LCMS (m/z): 337 [M+H].sup.+.
6-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)-N-(2,4-difluorophenyl)indoline-1-carboxamide
[0288] The mixture of N-(5-(indolin-6-yl)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide (20 mg, 0.035 mmol), 2,4-difluoro-1-isocyanatobenzene (6.5 mg, 0.042 mmol) in THF (2 mL) was stirred reflux overnight. The resulting mixture was diluted with water, extracted with DCM (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried with Na.sub.2SO.sub.4, and concentrated. The residue was purified by Prep-HPLC to obtain the desire compound (white solid, 15.4 mg, yield 75%). LCMS (m/z): 492 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.78 (s, 1H), 8.61 (d, J=1.7 Hz, 1H), 8.48 (s, 1H), 8.12 (d, J=8.5 Hz, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.67 (dd, J=7.7, 1.7 Hz, 1H), 7.52 (td, J=8.9, 6.2 Hz, 1H), 7.37-7.29 (m, 2H), 7.14-7.06 (m, 1H), 4.18 (t, J=8.6 Hz, 2H), 3.26 (t, J=8.6 Hz, 2H), 2.08-1.99 (m, 1H), 1.02-0.96 (m, 4H).
##STR00153##
N-(5-(1-(3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzoyl)indolin-6-yl)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide
[0289] The mixture of N-(5-(indolin-6-yl)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide (17 mg, 0.05 mmol), 3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl) benzoic acid (22 mg, 0.05 mmol) in DMF (2 mL) was added HATU (29 mg, 0.076 mmol) and DIPEA (0.03 mL). The reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried with Na.sub.2SO.sub.4, and concentrated. The residue was purified by prep-HPLC to obtain the product(white solid, 8.1 mg, yield 26%). LCMS: 635 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ 12.82 (s, −1H), 8.89 (s, 1H), 8.49-7.06 (m, 6H), 6.65 (s, 1H), 3.98 (m, 7H), 3.25-2.84 (m, 7H), 2.53 (m, 2H), 2.05 (m, 1H), 1.63-0.60 (m, 7H).
Compound I-12
6-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)-N-(3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-1-carboxamide
[0290] Compound I-12 is prepared by using essentially the same procedure with Compound I-10, except that 1-ethyl-4-(3-isocyanato-5-(trifluoromethyl) benzyl)piperazine was used in the last step. LCMS: 650 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.81 (s, 1H), 8.95 (s, 1H), 8.68 (s, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.06 (s, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.92 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.39-7.32 (m, 2H), 4.23 (t, J=8.6 Hz, 2H), 3.84-3.77 (m, 2H), 3.27 (t, J=8.5 Hz, 2H), 3.14 (q, J=7.3 Hz, 3H), 3.06 (s, 1H), 2.57-2.51 (m, 6H), 2.09-2.00 (m, 1H), 1.21 (t, J=7.3 Hz, 3H), 1.05-0.95 (m, 4H).
##STR00154##
N-(5-(2-(3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzoyl)isoindolin-5-yl)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide
[0291] The mixture of N-(5-(isoindolin-5-yl)thiazolo[5,4-b]pyridin-2-yl)cyclopropane carboxamide (15 mg, 0.03 mmol), 3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl) benzoic acid (15 mg, 0.03 mmol) in DMF (2 mL) was added HATU (20 mg, 0.045 mmol) and DIPEA (0.03 mL). The reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by prep-HPLC to obtain the product(white solid, 5.2 mg, yield 27%). LCMS: 635 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ 12.89-12.79 (m, 1H), 8.30-8.13 (m, 3H), 8.13-8.01 (m, 2H), 8.01-7.82 (m, 3H), 5.14-5.08 (m, 1H), 5.03-4.91 (m, 1H), 4.90-4.71 (m, 1H), 3.81 (s, 2H), 3.26-2.84 (m, 9H), 2.49-2.29 (m, 2H), 2.09-2.00 (m, 1H), 1.32-1.10 (m, 3H), 1.05-0.95 (m, 4H).
##STR00155##
5-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)-N-(3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)isoindoline-2-carboxamide
[0292] Compound I-14 is prepared by using essentially the same procedure with Compound I-15, except that 1-ethyl-4-(3-isocyanato-5-(trifluoromethyl) benzyl)piperazine was used in the last step. LCMS: 650 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.91 (s, 1H), 8.94 (s, 1H), 8.28-8.21 (m, 2H), 8.17 (dd, J=8.5, 2.9 Hz, 2H), 8.03 (d, J=4.8 Hz, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.40 (s, 1H), 4.94 (d, J=11.6 Hz, 4H), 3.90 (s, 3H), 3.36-2.87 (m, 9H), 2.16-2.08 (m, 1H), 1.29 (t, J=7.3 Hz, 3H), 1.13-1.03 (m, 4H).
##STR00156##
Tert-butyl 5-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)isoindoline-2-carboxylate
[0293] A mixture of N-(5-bromothiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide (90 mg, 0.3 mmol, 1.0 eq), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate (104 mg, 0.3 mmol, 1 eq), Pd(dppf)Cl.sub.2 (12 mg, 0.015 mmol, 0.05 eq), and Cs.sub.2CO.sub.3 (145 mg, 0.45 mmol) in in dioxane/water (5 mL/0.5 mL) was stirred for 8 h at 100° C. under N.sub.2. The mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure, and the residue was purified with silica gel column to give the product as a light-yellow solid (20 mg, 15%). LCMS (m/z): 437 [M+H].sup.+.
N-(5-(isoindolin-5-yl)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide
[0294] A solution of tert-butyl 5-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl) isoindoline-2-carboxylate (20 mg, 0.046 mmol) in dioxane (0.5 mL) was added 4 N HCl in dioxane (1 mL). The reaction mixture was stirred at rt for 2 h. The reaction mixture was filtered and the solid was dried under reduced pressure to afford desire compound as a HCl salt (13 mg, 84%). LCMS (m/z): 337 [M+H].sup.+.
5-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)-N-(2,4-difluorophenyl)isoindoline-2-carboxamide
[0295] A mixture of N-(5-(isoindolin-5-yl)thiazolo[5,4-b]pyridin-2-yl)cyclopropane carboxamide (13 mg, 0.036 mmol), 2,4-difluoro-1-isocyanatobenzene (6.6 mg, 0.043 mmol) in THF (2 mL) was stirred reflux overnight. The resulting solution was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by prep-HPLC to obtain the product (white solid, 1.1 mg, yield 6%). LCMS (m/z): 492 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.24 (s, 1H), 8.17-8.10 (m, 2H), 8.07 (m, 2H), 7.74-7.65 (m, 1H), 7.52 (m, 2H), 7.26 (m, 1H), 7.05 (m, 1H), 4.82 (d, 4H), 2.05-1.97 (m, 1H), 1.01-0.94 (m, 4H).
##STR00157##
Tert-butyl (4-methyl-3-((5-nitropyridin-2-yl)oxy)phenyl)carbamate
[0296] The mixture of 2-chloro-5-nitropyridine (200 mg, 1.26 mmol), tert-butyl (3-hydroxy-4-methylphenyl)carbamate (282 mg, 1.26 mmol), K.sub.2CO.sub.3 (261 mg, 1.89 mmol) and DMF (2 mL) was stirred at 100° C. overnight in a seal tube. The resulting solution was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated to give the crude compound (510 mg). LCMS (m/z): 346 [M+H].sup.+.
Tert-butyl (3-((5-aminopyridin-2-yl)oxy)-4-methylphenyl)carbamate
[0297] The mixture of tert-butyl (4-methyl-3-((5-nitropyridin-2-yl)oxy)phenyl)carbamate (510 mg, 1.47 mmol), Pd/C (50 mg) in MeOH (50 mL was stirred at room temperature under H.sub.2 (1 atm) for 16 h. The resulting mixture was filtered. The filtrate was concentrated to give the crude product (light brown solid, 400 mg, 86%) which was put into next step without further purification. LCMS: 316 [M+H].sup.+.
Tert-butyl (3-((2-aminothiazolo[5,4-b]pyridin-5-yl)oxy)-4-methylphenyl)carbamate
[0298] To a solution of tert-butyl (3-((5-aminopyridin-2-yl)oxy)-4-methylphenyl)carbamate (400 mg, 1.27 mmol) in acetic acid (5 mL) was added potassium thiocyanate (740 mg, 7.6 mmol). The resulting mixture was cooled to 0-15° C., and then bromine (203 mg, 1.27 mmol) solution in acetic acid (1 mL) was added drop-wise over a period of 3 min. The reaction mixture was stirred at room temperature for 5 h, and then concentrated under reduced pressure. The residue was suspended in water (100 mL), and then basified with sodium carbonate solution to pH=9. The resulting mixture was extracted with dichloromethane (3×150 mL). The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure to give the crude product as a light brown solid (380 mg, yield 80%). LCMS: 373 [M+H].sup.+.
Tert-butyl (3-((2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)oxy)-4-methyl phenyl)carbamate
[0299] To a mixture of tert-butyl (3-((2-aminothiazolo[5,4-b]pyridin-5-yl)oxy)-4-methylphenyl) carbamate (380 mg, 1.02 mmol) and DIPEA (659 mg, 5.1 mmol) in 6 mL of THF was added cyclopropanecarbonyl chloride (427 mg, 4.08 mmol) in THF (2 mL). The mixture was stirred at 80° C. for 12 h. The resulting solution was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated. The crude product was purified by silica gel column (hexane/ethyl acetate=10/1 to 100%) to give the product as a light-yellow solid (200 mg, 44%). LCMS (m/z): 441 [M+H].sup.+.
N-(5-(5-amino-2-methylphenoxy)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide
[0300] The mixture of tert-butyl (3-((2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl) oxy)-4-methylphenyl)carbamate (200 mg, 0.45 mmol) and TFA (2 mL) in DCM (4 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified by prep-HPLC to get the desire product (off-white solid, 99 mg, 65%). LCMS (m/z): 341 [M+H].sup.+.
N-(5-(5-(3-(2,4-difluorophenyl)ureido)-2-methylphenoxy)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide
[0301] The mixture of N-(5-(5-amino-2-methylphenoxy)thiazolo[5,4-b]pyridin-2-yl)cyclopropane carboxamide (21 mg, 0.08 mmol) and 2,4-difluoro-1-isocyanatobenzene (15 mg, 0.095 mmol) in toluene (3 mL) was stirred reflux overnight. The resulting solution was diluted with water (50 mL), and then extracted with DCM (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by Prep-HPLC to obtain the desire compound (white solid, 2 mg, yield 5%). LCMS (m/z): 496 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.73 (s, 1H), 9.14 (s, 1H), 8.53 (m, 1H), 8.22 (m, 1H), 8.06 (m, 1H), 7.46-7.21 (m, 3H), 7.24-6.92 (m, 3H), 2.11 (s, 3H), 2.05 (m, 1H), 1.04-0.97 (m, 4H).
##STR00158##
N-(5-(5-(3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)-2-methylphenoxy)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide
[0302] Compound I-17 is prepared by using essentially the same procedure with Compound I-16 except that 1-ethyl-4-(4-isocyanato-2-(trifluoromethyl)benzyl) piperazine was used in the last step. LCMS (m/z): 654 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.43 (s, 2H), 9.24 (s, 1H), 8.33 (d, J=8.7 Hz, 1H), 8.03 (s, 1H), 7.69 (s, 2H), 7.47 (m, 1H), 7.36-7.26 (m, 2H), 7.19 (d, J=8.8 Hz, 1H), 4.20 (t, J=7.2 Hz, 2H), 3.22 (m, 2H), 3.08-2.99 (m, 2H), 2.76 (m, 2H), 2.46 (m, 3H), 2.28 (m, 2H), 2.13 (s, 3H), 1.29 (m, 4H).
##STR00159##
N-(5-(5-(3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)-2-methylphenoxy)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide
[0303] Compound I-18 is prepared by using essentially the same procedure with Compound I-16 except that 1-ethyl-4-(3-isocyanato-5-(trifluoromethyl)benzyl) piperazine was used in the last step. LCMS (m/z): 654 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 9.37 (s, 1H), 9.18 (s, 1H), 8.17 (d, J=8.7 Hz, 1H), 7.80 (d, J=2.2 Hz, 1H), 7.67 (s, 1H), 7.38 (d, J=2.1 Hz, 1H), 7.33-7.16 (m, 3H), 7.09 (d, J=8.7 Hz, 1H), 3.46 (s, 2H), 3.16-2.95 (m, 8H), 2.41 (m, 2H), 2.05 (s, 3H), 2.02-1.97 (m, 1H), 1.19 (t, J=7.3 Hz, 3H), 0.95 (m, 4H).
##STR00160##
N-(3-((2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)oxy)-4-methylphenyl)-3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide
[0304] To a mixture of N-(5-(5-amino-2-methylphenoxy)thiazolo[5,4-b]pyridin-2-yl)cyclopropane carboxamide (40 mg, 0.12 mmol), 3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl) benzoic acid (37 mg, 0.12 mmol) in DCM (4 mL) was added EDCI (34 mg, 0.18 mmol), HOBt (24 mg, 0.18 mmol) and DMAP (22 mg, 0.18 mmol). The reaction mixture was stirred at 50° C. overnight. The resulting solution was diluted with water (50 mL), and then extracted with DCM (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by prep-HPLC to obtain Compound I-19 (white solid, 6.4 mg, yield 8%). LCMS (m/z): 639 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.70 (s, 1H), 10.51 (s, 1H), 8.24 (s, 1H), 8.22-8.16 (m, 2H), 7.91 (s, 1H), 7.62-7.55 (m, 2H), 7.34 (d, J=8.3 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H), 3.83 (s, 2H), 3.47 (m, 2H), 3.19-3.09 (m, 2H), 3.04-2.98 (m, 4H), 2.49-2.37 (m, 2H), 2.11 (s, 3H), 2.00 (m, 1H), 1.20 (t, J=7.3 Hz, 3H), 1.01-0.90 (m, 4H).
##STR00161##
Methyl 4-methyl-3-((5-nitropyridin-2-yl)oxy)benzoate
[0305] The mixture of 2-chloro-5-nitropyridine (200 mg, 1.26 mmol), methyl 3-hydroxy-4-methylbenzoate (210 mg, 1.26 mmol) and K.sub.2CO.sub.3 (261 mg, 1.89 mmol) in DMF (2 mL) was stirred at 100° C. for 6 h in a sealed tube. The resulting solution was diluted with water (50 mL), and then extracted with DCM (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated to give the crude compound (380 mg). LCMS (m/z): 289 [M+H].sup.+.
Methyl 3-((5-aminopyridin-2-yl)oxy)-4-methylbenzoate
[0306] The mixture of methyl 4-methyl-3-((5-nitropyridin-2-yl)oxy)benzoate (380 mg, 1.31 mmol) and Pd/C (10%, 50 mg) in MeOH (10 mL) was stirred at room temperature under H.sub.2 (1 atm) for 16 h. The resulting mixture was filtered. The filtrate was concentrated to give the crude product (light brown solid, 130 mg, 38%), which was used in the next step without further purification. LCMS: 259 [M+H].sup.+.
Methyl 3-((2-aminothiazolo[5,4-b]pyridin-5-yl)oxy)-4-methylbenzoate
[0307] To a solution of Methyl 3-((5-aminopyridin-2-yl)oxy)-4-methylbenzoate (130 mg, 0.50 mmol) in acetic acid (4 mL) was added potassium thiocyanate (245 mg, 2.52 mmol). The mixture was cooled to 0-15° C., and then a bromine (81 mg, 0.50 mmol) solution in acetic acid (1 mL) was added drop-wise over a period of 3 min. The reaction mixture was stirred at room temperature for 5 h, and then concentrated under reduced pressure to remove acetic acid. The residue was suspended in water (100 mL) and basified with sodium carbonate solution to pH=9. The resulting mixture was extracted with DCM (100 mL×3). The combined organic phase was washed with brine (50 mL×3), dried over Na.sub.2SO.sub.4, and concentrated to give target compound as a light brown solid (150 mg, yield 95%). LCMS: 316 [M+H].sup.+.
Methyl 3-((2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)oxy)-4-methyl benzoate
[0308] To a mixture of methyl 3-((2-aminothiazolo[5,4-b]pyridin-5-yl)oxy)-4-methylbenzoate (150 mg, 0.48 mmol) and DIPEA (308 mg, 2.38 mmol) in 6 mL of THF was added cyclopropanecarbonyl chloride (176 mg, 1.68 mmol) in THF (2 mL). The mixture was stirred at 80° C. for 12 h. The resulting solution was diluted with water (50 mL), and then extracted with DCM (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by silica gel column (hexane/ethyl acetate=10/1 to 100%) to give the product as a light yellow solid (50 mg, 27%). LCMS (m/z): 284 [M+H].sup.+.
3-((2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)oxy)-4-methylbenzoic acid
[0309] To a solution of methyl 3-((2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)oxy)-4-methylbenzoate (50 mg, 0.13 mmol) in THF (2 mL) was add 1 mL of 3 N LiOH aqueous solution. The reaction mixture was stirred at room temperature overnight, and then purified by prep-HPLC (Cis column, CH.sub.3CN/H.sub.2O, containing 0.05% NH.sub.4HCO.sub.3) to obtain the desire compounds (white solid, 25 mg, yield 52%). LCMS (m/z): 370 [M+H].sup.+.
3-((2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)oxy)-N-(3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide
[0310] To a mixture of 3-((2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)oxy)-4-methylbenzoic acid (18 mg, 0.048 mmol) and 3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoro methyl)aniline (15 mg, 0.052 mmol) in DMF (0.5 mL) was added HATU (27 mg, 0.072 mmol) and DIPEA (19 mg, 0.144 mmol). The reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by prep-HPLC to obtain Compound I-20 (white solid, 4.8 mg, yield 7%). LCMS (m/z): 639 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.47 (s, 1H), 8.25-8.07 (m, 2H), 7.98 (s, 1H), 7.86 (dd, J=7.9, 1.8 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.34 (s, 1H), 7.17 (d, J=8.7 Hz, 1H), 3.53 (s, 3H), 2.48-2.24 (m, 10H), 2.21 (s, 3H), 2.02-1.94 (m, 1H), 1.24 (s, 3H), 0.95 (m, 4H).
##STR00162##
Tert-butyl 5-((5-nitropyridin-2-yl)oxy)isoindoline-2-carboxylate
[0311] The mixture of 2-chloro-5-nitropyridine (125 mg, 0.79 mmol), tert-butyl 5-hydroxy isoindoline-2-carboxylate (187 mg, 0.8 mmol), K.sub.2CO.sub.3 (167 mg, 1.2 mmol) in DMF (2 mL) was stirred at 100° C. for 3 h in sealing tube. The resulting solution was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated to give the crude compound (320 mg). LCMS (m/z): 358 [M+H].sup.+.
Tert-butyl 5-((5-aminopyridin-2-yl)oxy)isoindoline-2-carboxylate
[0312] The mixture of tert-butyl 5-((5-nitropyridin-2-yl)oxy)isoindoline-2-carboxylate (320 mg, 0.89 mmol) and Pd/C (10%, 50 mg) in MeOH (10 mL) was stirred at room temperature under H.sub.2 (1 atm) for 16 h, and then filtered. The filtrate was concentrated to give title compound (light brown solid, 256 mg, 88%) which was used in the next step directly. LCMS: 328 [M+H].sup.+.
Tert-butyl 5-((2-aminothiazolo[5,4-b]pyridin-5-yl)oxy)isoindoline-2-carboxylate
[0313] To a solution of tert-butyl 5-((5-aminopyridin-2-yl)oxy)isoindoline-2-carboxylate (256 mg, 0.78 mmol) in acetic acid (4 mL) was added potassium thiocyanate (456 mg, 4.69 mmol). The mixture was cooled to 0-15° C., and then a bromine (124 mg, 0.78 mmol) solution in acetic acid (1 mL) was added drop-wise over a period of 3 min. The reaction mixture was stirred at room temperature for 5 h, then concentrated under reduced pressure to remove acetic acid. The residue was suspended in water (100 mL) and basified with saturated sodium carbonate solution to pH=9. The resulting mixture was diluted with water (50 mL), and then extracted with DCM (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated to give the target compound as a light brown solid (220 mg, yield 73%). LCMS: 385 [M+H].sup.+.
Tert-butyl 5-((2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)oxy)isoindoline-2-carboxylate
[0314] To a mixture of tert-butyl 5-((2-aminothiazolo[5,4-b]pyridin-5-yl)oxy)isoindoline-2-carboxylate (220 mg, 0.57 mmol) and DIPEA (372 mg, 2.86 mmol) in 6 mL of THF was added cyclopropanecarbonyl chloride (180 mg, 1.71 mmol) in THF (2 mL). The mixture was stirred at 80° C. for 12 h. The resulting mixture was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by silica gel column (hexane/ethyl acetate=10/1 to 100%) to give the product as a light yellow solid (190 mg, 74%). LCMS (m/z): 453 [M+H].sup.+.
N-(5-(isoindolin-5-yloxy)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide
[0315] The mixture of tert-butyl 5-((2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl) oxy)isoindoline-2-carboxylate (190 mg, 0.42 mmol) and TFA (2 mL) in DCM (4 mL) was stirred at room temperature overnight. The resulting mixture was concentrated. The residue was purified by prep-HPLC to get the desire product (off-white solid, 140 mg, 95%). LCMS (m/z): 353 [M+H].sup.+.
5-((2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)oxy)-N-(2,4-difluorophenyl)isoindoline-2-carboxamide
[0316] The mixture of N-(5-(isoindolin-5-yloxy)thiazolo[5,4-b]pyridin-2-yl)cyclopropane carboxamide (25 mg, 0.071 mmol) and 2,4-difluoro-1-isocyanatobenzene (14 mg, 0.085 mmol) in DCM (3 mL) was stirred at room temperature overnight. The resulting mixture was diluted with water (50 mL), and then extracted with DCM (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by silica gel column to obtain the desire compound (white solid, 15.1 mg, yield 42%). LCMS (m/z): 508 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.22-8.13 (m, 2H), 7.56 (td, J=9.0, 6.3 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.28 (ddd, J=10.6, 9.1, 2.9 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 7.16-7.10 (m, 2H), 7.05 (tdd, J=8.7, 2.9, 1.3 Hz, 1H), 4.77 (s, 4H), 2.05-1.94 (m, 1H), 0.99-0.90 (m, 4H).
##STR00163##
5-((2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)oxy)-N-(3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)isoindoline-2-carboxamide
[0317] Compound I-22 is prepared by using essentially the similar procedure with Compound I-23 except that 1-ethyl-4-(3-isocyanato-5-(trifluoromethyl) benzyl)piperazine was used in the last step. LCMS (m/z): 666 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.79 (s, 1H), 8.18 (d, J=8.7 Hz, 1H), 7.95 (s, 2H), 7.43 (d, J=8.3 Hz, 1H), 7.29 (s, 1H), 7.27-7.16 (m, 1H), 7.19-7.11 (m, 2H), 4.80 (s, 4H), 3.75 (s, 2H), 3.51-3.46 (m, 2H), 3.15 (m, 2H), 3.03 (m, 4H), 2.46 (m, 2H), 2.00 (m, 1H), 1.21 (t, J=7.3 Hz, 3H), 1.01-0.91 (m, 4H).
##STR00164##
5-((2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)isoindoline-2-carboxamide
[0318] Compound I-21 is prepared by using essentially the similar procedure with Compound I-23 except that 1-ethyl-4-(4-isocyanato-2-(trifluoromethyl) benzyl)piperazine was used in last step. LCMS (m/z): 666 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.70 (s, 1H), 8.74 (s, 1H), 8.18 (d, J=8.7 Hz, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.90 (dd, J=8.6, 2.2 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.22 (d, J=2.3 Hz, 1H), 7.14 (dd, J=8.4, 5.0 Hz, 2H), 4.80 (s, 4H), 3.67 (s, 2H), 3.47 (d, J=12.0 Hz, 2H), 3.15 (m, 2H), 2.95 (m, 2H), 2.40 (m, 2H), 2.00 (m, 1H), 1.21 (t, J=7.3 Hz, 3H), 1.01-0.91 (m, 4H).
##STR00165## ##STR00166##
Di-tert-butyl (4-hydroxy-1,2-phenylene)dicarbamate
[0319] A mixture of 3,4-diaminophenol (1 g, 8.1 mmol), TEA (1.48 g, 12.1 mmol) and di-tert-butyl dicarbonate (2.11 g, 9.67 mmol) in THF (10 mL) was stirred for 12 hours at room temperature. The resulting solution was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by silica gel column to give the target compound (1.3 g, yield 50%). LCMS (m/z): 325 [M+H].sup.+.
Di-tert-butyl (4-((5-nitropyridin-2-yl)oxy)-1,2-phenylene)dicarbamate
[0320] The mixture of 2-chloro-5-nitropyridine (146 mg, 0.93 mmol), di-tert-butyl (4-hydroxy-1, 2-phenylene)dicarbamate (300 mg, 0.93 mmol) and K.sub.2CO.sub.3 (191 mg, 1.39 mmol) in DMF (2 mL) was stirred at room temperature overnight. The resulting solution was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by silica gel column to give the target compound (90 mg, yield 22%). LCMS (m/z): 447 [M+H].sup.+.
4-((5-nitropyridin-2-yl)oxy)benzene-1,2-diamine
[0321] To a solution of di-tert-butyl (4-((5-nitropyridin-2-yl)oxy)-1,2-phenylene)dicarbamate (450 mg, 1 mmol) in dioxane (5 mL) was added 4N HCl in dioxane (5 mL). The reaction mixture was stirred at room temperature for 2 h, and then filtered. The solid was dried under reduced pressure to afford desire compound (217 mg, yield 88%) LCMS (m/z): 247 [M+H].sup.+.
N-(2,4-difluorophenyl)-6-((5-nitropyridin-2-yl)oxy)-1H-benzo[d]imidazol-2-amine
[0322] The mixture of 4-((5-nitropyridin-2-yl)oxy)benzene-1,2-diamine (217 mg, 0.88 mmol) and 2,4-difluoro-1-isothiocyanatobenzene (151 mg, 0.88 mmol) in THF (5 mL) was stirred at room temperature for 3 h. Then EDCI (253 mg, 1.32 mmol) was added. The reaction mixture was further stirred at 70° C. for 4 h. The resulting solution was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by silica gel column to obtain desire compound (200 mg, yield 59%) LCMS (m/z): 384 [M+H].sup.+.
6-((5-aminopyridin-2-yl)oxy)-N-(2,4-difluorophenyl)-1H-benzo[d]imidazol-2-amine
[0323] The mixture of N-(2,4-difluorophenyl)-6-((5-nitropyridin-2-yl)oxy)-1H-benzo[d]imidazole-2-amine (200 mg, 0.52 mmol) and Fe (234 mg, 4.17 mmol) in HOAc (10 mL) was stirred at 60° C. for 5 h, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column to obtain desire compound (110 mg, yield 60%) LCMS (m/z): 354 [M+H].sup.+.
5-((2-((2,4-difluorophenyl)amino)-1H-benzo[d]imidazol-6-yl)oxy)thiazolo[5,4-b]pyridin-2-amine
[0324] To a solution of 6-((5-aminopyridin-2-yl)oxy)-N-(2,4-difluorophenyl)-1H-benzo[d]imidazol-2-amine (110 mg, 0.31 mmol) in acetic acid (4 mL) was added potassium thiocyanate (151 mg, 1.56 mmol). The mixture was cooled to 0-15° C., and bromine (50 mg, 0.31 mmol) solution in acetic acid (1 mL) was added drop-wise over a period of 3 min. The reaction mixture was stirred at room temperature for 5 h, and then concentrated. The residue was suspended in water (100 mL) and basified with saturated sodium carbonate solution to pH=9. The resulting mixture was extracted with DCM (150 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by silica gel column to obtain desire compound (light brown solid, 60 mg, yield 47%). LCMS: 411 [M+H].sup.+.
tert-butyl 6-((2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)oxy)-2-((2,4-difluorophenyl)amino)-1H-benzo[d]imidazole-1-carboxylate
[0325] A mixture of 5-((2-((2,4-difluorophenyl)amino)-1H-benzo[d]imidazol-6-yl)oxy)thiazolo [5,4-b]pyridin-2-amine (60 mg, 0.15 mmol), TEA (60 mg, 0.59 mmol) and di-tert-butyl dicarbonate (35 mg, 0.16 mmol) in THF (2 mL) was stirred for 12 hours at room temperature. Then a solution of cyclopropanecarbonyl chloride (78 mg, 0.75 mmol) in 2 mL THF was added. The result mixture was stirred for 3 days at room temperature. Then 3 mL of NaOH aq. (3 M) was added for further 30 min. The resulting mixture was extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na.sub.2SO.sub.4, and concentrated. The residue was used in the next step directly without further purification. LCMS: 579 [M+H].sup.+.
N-(5-((2-((2,4-difluorophenyl)amino)-1H-benzo[d]imidazol-6-yl)oxy)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide
[0326] The mixture of tert-butyl 6-((2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl) oxy)-2-((2,4-difluorophenyl)amino)-1H-benzo[d]imidazole-1-carboxylate (crude from last step) and TFA (1 mL) in DCM (1 mL) was stirred at room temperature overnight. The resulting mixture was concentrated. The residue was purified by prep-HPLC to get the desire product (off-white solid, 29.6 mg, 41% for two steps). LCMS (m/z): 479 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 13.12 (s, 1H), 12.70 (s, 1H), 10.94 (s, 1H), 8.18 (d, J=8.7 Hz, 1H), 7.81 (m, 1H), 7.56 (m, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.32-7.24 (m, 2H), 7.15 (d, J=8.7 Hz, 1H), 7.10 (dd, J=8.6, 2.3 Hz, 1H), 2.00 (m, 1H), 1.01-0.90 (m, 4H).
##STR00167## ##STR00168##
N-(5-((2-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)amino)-1H-benzo[d]imidazol-6-yl)oxy)thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide
[0327] Compound I-25 is prepared by using essentially the similar procedure with Compound I-24 except that 1-ethyl-4-(4-isothiocyanato-2-(trifluoromethyl)benzyl)piperazine replaced 2,4-difluoro-1-isothiocyanatobenzene. LCMS (m/z): 637 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.69 (s, 1H), 10.83 (s, 1H), 9.46 (s, 1H), 8.17 (d, J=8.7 Hz, 1H), 8.00 (s, 1H), 7.92-7.87 (m, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.24 (d, J=2.2 Hz, 1H), 7.12 (d, J=8.7 Hz, 1H), 7.02 (dd, J=8.5, 2.3 Hz, 1H), 4.03 (d, J=7.2 Hz, 2H), 3.49 (m, 2H), 3.16 (m, 2H), 2.99-2.95 (m, 4H), 2.43 (m, 2H), 2.00 (m, 1H), 1.22 (t, J=7.3 Hz, 3H), 1.01-0.90 (m, 4H).
Example 2. Biochemical Assay of the Compounds of the Present Disclosure
[0328] The JAK2 Z-Lyte biochemical assay was performed according to manufacturer's instructions (Life Technologies).
TABLE-US-00001 TABLE 1 Biochemical IC.sub.50 by a commercial JAK2 Z-Lyte assay from Invitrogen. JAK2 Compound Z-lyte IC.sub.50 No. Compound Formula (nM) I-1
Example 3. In Vitro Kinase Selectivity Profiling of the Compounds of the Present Disclosure
[0329]
TABLE-US-00002 TABLE 2 In vitro kinase selectivity profiling by a commercial KINOMEscan .sup.® assay from DiscoverX (Eurofins). Ambit KINOMEscan of compound I-5 at 10 μM Kinase (percent control %) ABL1(Q252H) 0 ABL1(T315I) 0 ABL2 0 BRAF(V600E) 0 CDC2L2 0 CDKL3 0 CIT 0 CSF1R 0 EPHA4 0 EPHA6 0 EPHA8 0 EPHB1 0 EPHB2 0 EPHB4 0 FES 0 FGR 0 FLT4 0 HPK1 0 INSRR 0 ITK 0 KIT 0 KIT(L576P) 0 KIT(V559D) 0 LYN 0 MAP4K2 0 MERTK 0 p38-delta 0 PDGFRA 0 PDGFRB 0 PFTAIRE2 0 PFTK1 0 RAF1 0 RET 0 RET(M918T) 0 RET(V804L) 0 RET(V804M) 0 RIPK1 0 SRC 0 TAK1 0 TAOK3 0 TIE1 0 TIE2 0 TRKB 0 TRKC 0
EQUIVALENTS AND SCOPE
[0330] 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 present disclosure 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 present disclosure 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.
[0331] Furthermore, the present disclosure 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 present disclosure, or aspects of the present disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the present disclosure or aspects of the present disclosure 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 present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
[0332] 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 present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
[0333] 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.