Bicyclic heterocyclic derivatives as MNK1 and MNK2 modulators and uses thereof

1. A compound of Formula (Ib-i):

or a pharmaceutically acceptable salt thereof, wherein:

X 1 , X 2 , and X 3 are independently N or C;

X 4 and X 5 are independently N or CR 4 ;

wherein at least one of X 1 , X 2 , X 3 , X 4 , and X 5 is N;

X 7 is N or CH;

X 8 is N or CH;

is a single or double bond, as valency allows;

R 1 is —C(O)R, wherein R is an optionally substituted heterocyclyl;

R 2 , R 3 , R 6 , and R 7 are independently H, —F, —Cl, —CN, —CH 3 , —CF 3 , —CHF 2 , —C(O)NH 2 , —OH, OC 1-4 alkyl, or —OCF 3 ; or R 6 and R 7 are taken together to form a 5-6 membered fused heterocyclyl or heteroaryl; and

each R 4 is independently hydrogen or C 1-6 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 2 is C.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —C(O)R, wherein R is one of the following:

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof,

wherein R is of the formula:

5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein both R 2 and R 3 are hydrogen.

6. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 6 is —H.

7. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 7 is —F, —Cl, or —CN.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 3 is N.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 7 and X 8 are each CH.

10. The compound of claim 1 , wherein the compound is of Formula (Ib-ii):

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein the compound is of Formula (IIa), (IIIa), (IVa), (Va), (VIa), or (VIIa):

or a pharmaceutically acceptable salt thereof.

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

13. A kit comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and instructions for administering the compound to a subject.

14. A compound of formula:

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —C(O)R, wherein:

R is of the formula:

each R c is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R d is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, —COR c , S(O)R c , S(O) 2 R c , optionally substituted alkylaryl, or optionally substituted aryl;

each R e is independently hydrogen, halo, —OH, —OR c , —NH 2 , —NHR c , —NHSO 2 R c , —NR f SO 2 R c , —NR c R f , —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —COR c , or —NHCOR c ;

each R f is independently —H or C 1-6 alkyl;

each R g is independently hydrogen, halo, —OH, —OR c , —NH 2 , —NHR c , —NHSO 2 R c , —NR f SO 2 R c , —NR c R f , —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —COR c , or —NHCOR c ; and

n is 1, or 2.

16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof,

wherein R is of the formula: