Compositions useful for treating disorders related to kit
Compounds and compositions useful for treating disorders related to Kit are described herein.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from CH or N;
L is a bond, —(CR c R c ) n —, —(CR c R c ) n NR b —, —NR b (CR c R c ) n —, —S(O) 2 —, —S(O)—, —C(O)—, —OC(O)—, —C(O)O—, —(CR c R c ) n —OC(O)—, —OC(O)—(CR c R c ) n —, —(CR c R c ) n —C(O)—, —C(O)—(CR c R c ) n —, —NR b C(O)(CR c R c ), —C(O)NR b —(CR c R c ), where the two R c 's, together with the carbon to which they are attached, can form a carbocycle, —C(O)NR b —(CR c R b ), —(CR c R c ) n NR b —(CR c R c ), —NR b C(S)—, —C(S)NR b —, —NR b C(O)—, —C(O)NR b —, —NR b S(O) 2 , -or —S(O) 2 NR b —;
R 1 is alkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl each of which is substituted with 0-5 occurrences of R d ;
R 2 is H, halo, aryl, alkenyl, heteroaryl, carbocyclyl, or heterocyclyl, wherein each of aryl, alkenyl, heteroaryl, carbocyclyl, and heterocyclyl is substituted with 0-5 occurrences of R d ;
R 3 is H, alkyl, heteroalkyl, haloalkyl, haloalkoxyl, —OR c , —C(O)OR c , —C(O)NR a R b , —(CR c R c ) n NR b —(CR c R c )—H, —NR a R b , or cyano, wherein each of alkyl, heteroalkyl, haloalkyl, and haloalkoxyl is substituted with 0-5 occurrences of R d ;
R a and R b are each independently H, alkyl, heteroalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, wherein each of alkyl, heteroalkyl, aryl, aralkyl, heterocyclyl, and heterocyclylalkyl is substituted with 0-5 occurrences of R d ; or R a and R b together with the nitrogen atom to which they are attached form a heterocyclyl substituted with 0-5 occurrences of R d ;
R c is H or alkyl;
each R d is independently halo, heteroalkyl, haloalkyl, haloalkoxyl, alkyl, alkynyl, hydroxyalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, nitro, cyano, hydroxyl, —C(O)R a1 , —OC(O)R a1 , —C(O)OR a1 , —SR a1 , —S(O) 2 R a1 , —NR a1 R b1 , —C(O)NR a1 R b1 , —NR a1 S(O) 2 R a1 , or —OR a1 ; wherein each of heteroalkyl, haloalkyl, haloalkoxyl, alkyl, alkynyl, hydroxyalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, and heterocyclylalkyl is substituted with 0-5 occurrences of R c1 ; or two R d together with the atoms to which they are attached form a carbocyclyl or heterocyclyl, each optionally substituted with halo or alkyl;
R a1 and R b1 are each independently H, alkyl, aralkyl, carbocyclyl, heteroaryl, or heterocyclyl; or R a1 and R b1 together with the nitrogen atom to which they are attached form a heterocyclyl optionally substituted with halo or alkyl;
each R c1 is independently halo, —OR c2 , —NR a1 R b1 , alkyl, cyano, heteroalkyl, haloalkyl, haloalkoxyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, aryl, or aralkyl;
R c2 is H or alkyl;
p and r are each independently 1 or 2; and
n is 1, 2, 3 or 4.
2. The compound of claim 1 , wherein L is a bond, —(CR c R c ) n —, —(CR c R c ) n NR b —, —NR b (CR c R c ) n —, —(CR c R c ) n —C(O)—, —C(O)—(CR c R c ) n —, —C(O)NR b —(CR c R c ), where the two Rc's, together with the C to which they are attached, can form a carbocycle, —C(O)NR b —(CR c R b ), —(CR c R c ) n NR b —(CR c R c ), —NR b C(O)—, —C(O)NR b —, -or —S(O) 2 NR b —.
3. The compound of claim 1 , wherein L is —(CR c R c ) n NR b —, —NR b (CR c R c ) n —, —NR b C(O)—, or —C(O)NR b —.
4. The compound of claim 1 , wherein R 1 is aryl, carbocyclyl, carbocyclylalkyl, heterocyclyl, or heterocyclylalkyl, each of which is substituted with 0-5 occurrences of R d .
5. The compound of claim 1 , wherein R 2 is alkenyl, aryl, carbocyclyl, heteroaryl, or heterocyclyl, each of which is substituted with 0-5 occurrences of R d .
6. The compound of claim 1 , wherein R 2 is a 5- or 6-membered heterocyclyl substituted with 0-5 occurrences of R d .
7. The compound of claim 1 , wherein R 2 is a 5- or 6-membered heteroaryl substituted with 0-5 occurrences of R d .
8. The compound of claim 1 , wherein R 2 is selected from pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, thiophenyl, isoxazolyl, phenyl, dihydropyranyl, and tetrahydropyridinyl, each optionally substituted with 0-5 occurrences of R d .
9. The compound of claim 1 , wherein R 3 is H, alkyl, —OR c , or —NR a R b .
10. The compound of claim 1 , wherein each R d is independently selected from halo, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, hydroxyl, —C(O)R a1 , —C(O)OR a1 , —S(O) 2 R a1 , —NR a1 R b1 , —C(O) NR a1 R b1 , and —OR a1 ; wherein each of alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl is substituted with 0-5 occurrences of R c1 ; or two R d together with the atoms to which they are attached form a carbocyclyl or heterocyclyl, each optionally substituted with halo or alkyl.
11. The compound of claim 1 , wherein p is 1 and r is 1.
12. The compound of claim 1 , wherein the compound is a compound of Formula II:
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 , wherein the compound is a compound of Formula III:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 , wherein the compound is a compound of Formula IV:
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
16. A method of treating mastocytosis, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
17. A method of treating gastrointestinal stromal tumor, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
18. A method of treating acute myeloid leukemia, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
19. The method of claim 16 , wherein the mastocytosis is selected from cutaneous mastocytosis (CM) and systemic mastocytosis (SM).
20. The method of claim 19 , wherein the systemic mastocytosis is selected from indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), aggressive systemic mastocytosis (ASM), SM with associated hematologic non-mast cell lineage disease (SM-AHNMD), and mast cell leukemia (MCL).
21. The compound of claim 1 selected from any one of the compounds below, or a pharmaceutically acceptable salt thereof:
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