Macrocyclic kinase inhibitors and uses thereof
The present invention provides macrocyclic compounds of Formula (I): pharmaceutically acceptable salts thereof; and pharmaceutical compositions thereof, wherein R 1 , R 2 , R 3 , R 4 , R E , R F , R G , R H , R I , f, g, h, n, and m are as defined herein. The present invention further provides methods of synthesizing these macrocyclic compounds, and methods of their use and treatment. Certain aspects of the present invention relate to modulation of kinase activity, and in the treatment of kinase-associated diseases or disorders.
1. A compound of Formula (XV):
or a pharmaceutically acceptable salt thereof;
wherein:
n is 2 or 3;
m is 0;
represents a double bond in the cis or trans configuration;
p is an integer between 1 and 6, inclusive;
q is an integer between 1 and 5, inclusive;
each instance of R AA 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 A3 , —N(R A4 ) 2 , —SR A3 , —C(═O)R A3 , —C(═O)OR A3 , —C(═O)SR A3 , —C(═O)N(R A4 ) 2 , —OC(═O)R A3 , —OC(═O)OR A3 , —OC(═O)SR A3 , —OC(═O)N(R A4 ) 2 , —NR A4 C(═O)R A4 , —NR A4 C(═O)OR A3 , —NR A4 C(═O)SR A3 , —NR A4 C(═O)N(R A4 ) 2 , —SC(═O)R A3 , —SC(═O)OR A3 , —SC(═O)SR A3 , —SC(═O)N(R A4 ) 2 , —C(═NR A4 )R A3 , —C(═NR A4 )OR A3 , —C(═NR A4 )SR A3 , —C(═NR A4 )N(R A4 ) 2 , —OC(═NR A4 )R A3 , —OC(═NR A4 )OR A3 , —OC(═NR A4 )SR A3 , —OC(═NR A4 )N(R A4 ) 2 , —NR A4 C(═NR A4 )R A2 , —NR A4 C(═NR A4 )OR A3 , —NR A4 C(═NR A4 )SR A3 , —NR 4A C(═NR A4 )N(R A4 ) 2 , —SC(═NR A4 )R A3 , —SC(═NR A4 )OR A3 , —SC(═NR A4 )SR A3 , —SC(═NR A4 )N(R A4 ) 2 , —C(═S)R A3 , —C(═S)OR A3 , —C(═S)SR A3 , —C(═S)N(R A4 ) 2 , —OC(═S)R A3 , —OC(═S)OR A3 , —OC(═S)SR A3 , —OC(═S)N(R A4 ) 2 , —NR A4 C(═S)R A4 , —NR A4 C(═S)OR A3 , —NR A4 C(═S)SR A3 , —NR A4 C(═S)N(R A4 ) 2 , —SC(═S)R A3 , —SC(═S)OR A3 , —SC(═S)SR A3 , —SC(═S)N(R A4 ) 2 , —S(═O)R A3 , —SO 2 R A3 , —NR A4 SO 2 R A3 , —SO 2 N(R A4 ) 2 , —N 3 , —CN, —SCN, and —NO 2 , wherein each occurrence of R A3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each occurrence of R A4 is independently hydrogen, 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, or two R A4 groups are joined to form an substituted or unsubstituted heterocyclic ring,
provided at least one R AA is selected from the group consisting of halogen, perhaloalkyl, —C(═O)N(R A2 ) 2 , —CN, —SCN, and —NO 2 ;
a is an integer between 1 and 6, inclusive;
b is 0 or an integer between 1 and 5, inclusive;
each instance of R BB 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 B3 , —N(R B4 ) 2 , —SR B3 , —C(═O)R B3 , —C(═O)OR B3 , —C(═O)SR B3 , —C(═O)N(R B4 ) 2 , —OC(═O)R B3 , —OC(═O)OR B3 , —OC(═O)SR B3 , —OC(═O)N(R B4 ) 2 , —NR B4 C(═O)R B4 , —NR B4 C(═O)OR B3 , —NR B4 C(═O)SR B3 , —NR B4 C(═O)N(R B4 ) 2 , —SC(═O)R B3 , —SC(═O)OR B3 , —SC(═O)SR B3 , —SC(═O)N(R B4 ) 2 , —C(═NR B4 )R B3 , —C(═NR B4 )OR B3 , —C(═NR B4 )SR B3 , —C(═NR B4 )N(R B4 ) 2 , —OC(═NR B4 )R B3 , —OC(═NR B4 )OR B3 , —OC(═NR B4 )SR B3 , —OC(═NR B4 )N(R B4 ) 2 , —NR B4 C(═NR B4 )R B2 , —NR B4 C(═NR B4 )OR B3 , —NR B4 C(═NR B4 )SR B3 , —NR B4 C(═NR B4 )N(R B4 ) 2 , —SC(═NR B4 )R B3 , —SC(═NR B4 )OR B3 , —SC(═NR B4 )SR B3 , —SC(═NR B4 )N(R B4 ) 2 , —C(═S)R B3 , —C(═S)OR B3 , —C(═S)SR B3 , —C(═S)N(R B4 ) 2 , —OC(═S)R B3 , —OC(═S)OR B3 , —OC(═S)SR B3 , —OC(═S)N(R B4 ) 2 , —NR B4 C(═S)R B4 , —NR B4 C(═S)OR B3 , —NR B4 C(═S)SR B3 , —NR B4 C(═S)N(R B4 ) 2 , —SC(═S)R B3 , —SC(═S)OR B3 , —SC(═S)SR B3 , —SC(═S)N(R B4 ) 2 , —S(═O)R B3 , —SO 2 R B3 , —NR B4 SO 2 R B3 , —SO 2 N(R B4 ) 2 , —N 3 , —CN, —SCN, and —NO 2 , wherein each occurrence of R B3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each occurrence of R B4 is independently hydrogen, 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, or two R B4 groups are joined to form an substituted or unsubstituted heterocyclic ring;
s is an integer between 1 and 10, inclusive;
w is 3;
t is 0, 1, or 2;
each instance of R CC 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 C3 , —N(R C4 ) 2 , —SR C3 , —C(═O)R C3 , —C(═O)OR C3 , —C(═O)SR C3 , —C(═O)N(R C4 ) 2 , —OC(═O)R C3 , —OC(═O)OR C3 , —OC(═O)SR C3 , —OC(═O)N(R C4 ) 2 , —NR C4 C(═O)R C4 , —NR C4 C(═O)OR C3 , —NR C4 C(═O)SR C3 , —NR C4 C(═O)N(R C4 ) 2 , —SC(═O)R C3 , —SC(═O)OR C3 , —SC(═O)SR C3 , —SC(═O)N(R C4 ) 2 , —C(═NR C4 )R C3 , —C(═NR C4 )OR C3 , —C(═NR C4 )SR C3 , —C(═NR C4 )N(R C4 ) 2 , —OC(═NR C4 )R C3 , —OC(═NR C4 )OR C3 , —OC(═NR C4 )SR C3 , —OC(═NR C4 )N(R C4 ) 2 , NR C4 C(═NR C4 )R C2 , —NR C4 C(═NR C4 )OR C3 , —NR C4 C(═NR C4 )SR C3 , —NR C4 C(═NR C4 )N(R C4 ) 2 , —SC(═NR C4 )R C3 , —SC(═NR C4 )OR C3 , —SC(═NR C4 )SR C3 , —SC(═NR C4 )N(R C4 ) 2 , —C(═S)R C3 , —C(═S)OR C3 , —C(═S)SR C3 , —C(═S)N(R C4 ) 2 , —OC(═S)R C3 , —OC(═S)OR C3 , —OC(═S)SR C3 , —OC(═S)N(R C4 ) 2 , —NR C4 C(═S)R C4 , —NR C4 C(═S)OR C3 , —NR C4 C(═S)SR C3 , —NR C4 C(═S)N(R C4 ) 2 , —SC(═S)R C3 , —SC(═S)OR C3 , —SC(═S)SR C3 , —SC(═S)N(R C4 ) 2 , —S(═O)R C3 , —SO 2 R C3 , —NR C4 SO 2 R C3 , —SO 2 N(R C4 ) 2 , —N 3 , —CN, —SCN, or —NO 2 , wherein each occurrence of R C3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and each occurrence of R C4 is independently hydrogen, 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, or two R C4 groups are joined to form an substituted or unsubstituted heterocyclic ring;
R 4 is —N(R D ) 2 ; —OR D ; or —SR D ; wherein each occurrence of R D is independently independently hydrogen; a protecting group; substituted or unsubstituted aliphatic; substituted or unsubstituted heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or two R D groups are joined to form a substituted or unsubstituted heterocyclic group; optionally wherein at least one R D is a label, a resin, or a therapeutic agent, or at least one R D is substituted aliphatic, substituted heteroaliphatic, substituted aryl, or substituted heteroaryl, wherein the substituent covalently or non-covalently attached thereto is a resin, a label, or therapeutic agent; and
each instance of R E , R F , R G , R H , and R I is independently hydrogen; acyl; a nitrogen protecting group; or substituted or unsubstituted aliphatic.
2. The compound of claim 1 , wherein R 4 is —N(R D ) 2 .
3. The compound of claim 1 , wherein each occurrence of R E , R F , R G , R H , and R I is hydrogen.
4. The compound of claim 1 , wherein n is 3.
5. The compound of claim 1 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
7. The compound of claim 1 , wherein n is 2.
8. The compound of claim 1 , wherein q is 1; and R AA is halogen, perhaloalkyl, —C(═O)N(R A2 ) 2 , —CN, —SCN, or —NO 2 located at the para position relative to the point of attachment.
9. The compound of claim 8 , wherein R AA is —NO 2 .
10. The compound of claim 1 , wherein b is 1; and R BB is halogen located in the para position relative to the point of attachment.
11. The compound of claim 10 , wherein R BB is —F.
12. The compound of claim 1 , wherein t is 0.
13. The compound of claim 5 , wherein R 4 is —NH 2 , n is 3, and represents a double bond in the trans configuration.
14. The compound of claim 5 , wherein R 4 is —NH 2 , n is 3, and represents a double bond in the cis configuration.
15. The compound of claim 5 , wherein R 4 is —NH 2 , n is 2, and represents a double bond in the trans configuration.
16. The compound of claim 5 , wherein R 4 is —NH 2 , n is 2, and represents a double bond in the cis configuration.