JAK2 AND ALK2 INHIBITORS AND METHODS FOR THEIR USE
Compounds having activity as inhibitors of ALK2 kinase and/or JAK2 kinase are disclosed. The compounds have the following structure (I): including stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, z and A are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
1 . A compound having the following structure (I):
or a stereoisomer, pharmaceutically acceptable salt, tautomer or prodrug thereof,
wherein:
A represents a 6-membered aromatic ring or a 5 or 6-membered heteroaryl ring;
X is —NH—, —O—, —S(O) m —, —CH 2 —, —CHOH— or —C(═O)—;
R 1 is H, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —S(O) m C 1 -C 6 alkyl, C 1 -C 6 hydroxylalkyl, —OCH 2 CH 2 R 9 , —(CH 2 ) n NR a R b , or —CONR a R b ;
R 2 is halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —S(O) m C 1 -C 6 alkyl, C 1 -C 6 hydroxylalkyl, —OCH 2 CH 2 R 9 , —(CH 2 ) n NR a R b , or —CONR a R b ;
R 3 is halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —S(O) m C 1 -C 6 alkyl, C 1 -C 6 hydroxylalkyl, —OCH 2 CH 2 R 9 , —(CH 2 ) n NR a R b , —CONR a R b or —NHCHR a R b ;
R 4 is H or C 1 -C 6 alkyl;
R 5 is, at each occurrence, independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, —CN, C 1 -C 6 nitrilylalkyl or C 3 -C 6 nitrilylcycloalkyl;
R 6 and R 7 are each independently H, halo,hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 1 -C 6 nitrilylalkyl, C 3 -C 6 nitrilylcycloalkyl, C 3 -C 6 nitrilylcycloalkylalkyl or —(CH 2 ) n NR a R b ;
R 8 is H, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 1 -C 6 nitrilylalkyl, C 3 -C 6 nitrilylcycloalkyl, C 3 -C 6 nitrilylcycloalkylalkyl, (CH 2 ) n NR a R b , aryl or heteroaryl;
R 9 is —H, —F, —Cl, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 3 -C 4 cycloalkyl, —CH 2 OH, —OCH 3 , —OCH 2 CH 3 , —S(O) m CH 3 , —CH 2 CN, —CH 2 OCH 3 , —CH 2 S(O) m CH 3 , —CN, —CHCH 3 CN, —C(CH 3 ) 2 CN of
R a and R b are each independently —H, C 1 -C 6 alkyl, C 1 -C 6 hydroxylalkyl, or R a and R b together with the nitrogen or carbon atom to which they are attached form an optionally substituted 5 or 6 membered saturated carbocyclic or heterocyclic ring;
m is 0, 1 or 2;
n is 0, 1, 2 or 3; and
z is 0,1 or 2
provided that:
either R 5 is not H or none of R 6 , R 7 or R 8 are —CH 2 CN when X is NH, A is a 6-membered aromatic ring and one of R 1 , R 2 or R 3 is 4-methylpiperazin-1-yl and another of R 1 , R 2 or R 3 is F or CF 3 ; and
C 1 -C 6 alkoxy is not substituted with heterocyclyl.
2 . The compound of claim 1 , wherein the compound has the following structure (II):
wherein:
X is —NH—;
Y is N or CH;
R 1 is H or C 1 -C 6 alkoxy;
R 2 is halo or C 1 -C 6 alkoxy;
R 3 is C 1 -C 6 alkoxy or —NHCHR a R b ;
R 4 is H;
R 5 is, at each occurrence, independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —CN or C 1 -C 6 nitrilylalkyl;
R 6 is H, C 1 -C 6 alkyl, C 1 -C 6 nitrilylalkyl or C 3 -C 6 nitrilylcycloalky
R 7 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 nitrilylalkyl or C 3 -C 6 nitrilylcycloalky;
R 8 is H or heteroaryl; and
z is 0, 1 or 2.
3 . The compound of any one of claim 1 or 2 , wherein X is —NH—.
4 . The compound of any one of claims 1 - 3 , wherein Y is CH.
5 . The compound of any one of claims 1 - 3 , wherein Y is N.
6 . The compound of any one of claims 1 - 5 , wherein R 1 is H.
7 . The compound of any one of claims 1 - 5 , wherein R 1 is C 1 -C 6 alkoxy.
8 . The compound of claim 7 , wherein R 1 is methoxy.
9 . The compound of any one of claims 1 - 8 , wherein R 2 is halo.
10 . The compound of claim 9 , wherein R 2 is F or Cl.
11 . The compound of any one of claims 1 - 8 , wherein R 2 is C 1 -C 6 alkoxy.
12 . The compound of claim 11 , wherein R 2 is methoxy.
13 . The compound of any one of claims 1 - 12 , wherein R 3 is —NHCHR a R b and R a and R b join to form a heterocyclic ring.
14 . The compound of claim 13 , wherein the heterocyclic ring is a substituted or unsubstituted piperazinyl ring.
15 . The compound of claim 14 , wherein the substituted piperizinyl ring is an N-substituted piperizinyl ring, and the substituted is selected from C 1 -C 6 alkly, C 1 -C 6 carboxyalkylcarbonyl and C 1 -C 6 hydroxylalkyl.
16 . The compound of any one of claims 1 - 12 , wherein R 3 is C 1 -C 6 alkoxy.
17 . The compound of claim 16 , wherein R 3 is methoxy.
18 . The compound of any one of claim 1 or 2 , wherein the compound has one of the following structures:
19 . The compound of any one of claims 1 - 18 , wherein R 5 is H.
20 . The compound of any one of claims 1 - 18 , wherein R 5 is methyl.
21 . The compound of any one of claims 1 - 18 , wherein R 5 is chloro or fluoro.
22 . The compound of any one of claims 1 - 18 , wherein R 5 is nitrilyl.
23 . The compound of any one of claims 1 - 18 , wherein R 5 is methoxy.
24 . The compound of any one of claim 1 - 23 , wherein at least one of R 6 and R 7 is H.
25 . The compound of any one of claim 1 - 23 , wherein at least one of R 6 and R 7 is fluoro or chloro.
26 . The compound of any one of claims 1 - 23 , wherein at least one of R 6 and R 7 is C 1 -C 6 alkyl.
27 . The compound of claim 26 , wherein the C 1 -C 6 alkyl is methyl.
28 . The compound of any one of claims 1 - 27 , wherein one of R 6 or R 7 is C 1 -C 6 nitrilylalkyl.
29 . The compound of claim 28 , wherein the C 1 -C 6 nitrilylalkyl is —CH 2 CN.
30 . The compound of any one of claims 1 - 27 , wherein one of R 6 or R 7 is C 3 -C 6 nitrilylcycloalky.
31 . The compound of claim 30 , wherein the C 3 -C 6 nitrilylcycloalky is
32 . The compound of any one of claims 1 - 31 , wherein R 8 is H.
33 . The compound of any one of claims 1 - 31 , wherein R 8 is heteroaryl.
34 . The compound of claim 33 , wherein the heteroaryl is substituted or unsubstituted pyridinyl.
35 . The compound of any one of claim 1 - 17 or 19 - 23 , wherein the compound has one of the following structures:
36 . The compound of claim 1 , wherein the compound is selected from a compound in Table 1.
37 . A pharmaceutical composition comprising a compound of any one of claims 1 - 36 , or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
38 . A method of inhibiting ALK2 kinase or JAK2 kinase, or combinations thereof, in a mammal in need thereof, the method comprising administering to the mammal an effective amount of a compound of any one of claims 1 - 36 or a composition of claim 37 .
39 . The method of claim 38 , wherein the method is for inhibiting ALK2 Kinase.
40 . The method of claim 38 , wherein the method is for inhibiting JAK2 kinase.
41 . The method of any one of claims 38 - 40 , wherein the inhibition is for treatment of cancer.
42 . The method of any one of claims 38 - 40 , wherein the inhibition is for treatment of anemia of chronic disease, anemia of chronic inflammation, anemia of cancer or fibrodysplasia ossificans progressive.
43 . A method for treating cancer in a mammal in need thereof, the method comprising administering to the mammal an effective amount of a compound of any one of claims 1 - 36 or a composition of claim 37 .
44 . The method of claim 41 or 43 , wherein the cancer is a myeloproliferative disorder, a lymphoma or a solid tumor.
45 . The method of claim 42 , wherein the myeloproliferative disorder is myelofibrosis, polycythemia vera or essential thrombocytosis.
46 . The method of claim 42 , wherein the solid tumor is a breast, prostate or pancreatic tumor.
47 . The method of claim 41 or 43 , wherein the cancer is prostate, ovarian or head and neck cancer.
48 . A method for providing supportive care to a cancer patient in need thereof, the method comprising administering to the patient an effective amount of a compound of any one of claims 1 - 36 or a composition of claim 37 .
49 . The method of claim 48 , wherein the method is for treating anemia, or fatigue associated with cancer.