BMP inhibitors and methods of use thereof
The present invention provides small molecule inhibitors of BMP signaling. These compounds may be used to modulate cell growth, differentiation, proliferation, and apoptosis, and thus may be useful for treating diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders, as well as for modulating cellular differentiation and/or proliferation. These compounds may also be used to reduce circulating levels of ApoB-100 or LDL and treat or prevent acquired or congenital hypercholesterolemia or hyperlipoproteinemia; diseases, disorders, or syndromes associated with defects in lipid absorption or metabolism; or diseases, disorders, or syndromes caused by hyperlipidemia.
1. A compound having a structure of Formula I or a pharmaceutically acceptable salt, ester, or prodrug thereof,
wherein
X and Y are independently selected from CR 15 and N;
Z is selected from CR 3 and N;
Ar is selected from substituted or unsubstituted aryl and heteroaryl;
L 1 is absent or selected from substituted or unsubstituted alkyl and heteroalkyl;
G, J, K, and M are all absent or, independently for each occurrence, are selected from CR 16 and N;
A, B, and E, independently for each occurrence, are selected from CR 16 and N;
provided that:
no more than three of A, B, E, G, J, K, and M are N,
at least one of E and M is N, and
that if G, J, K, and M are absent, then the carbon atom drawn as connected to variable M is optionally substituted with R 16 ;
R 3 is selected from H, halogen, cyano, and substituted or unsubstituted alkyl, cycloalkyl, acylamino, carbamate, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido;
R 4 is selected from hydroxyl, carboxyl, and substituted or unsubstituted alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, ester, alkoxyl, alkylthio, acyloxy, amino, acylamino, carbamate, amido, amidino, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido;
R 15 , independently for each occurrence, is selected from H, halogen, cyano, and substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acylamino, carbamate, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido; and
R 16 , independently for each occurrence, is absent or is selected from H, OH, halogen, cyano, carboxyl, and substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, cycloalkylalkyl, heterocyclylalkyl, acyl, ester, alkoxy, alkylthio, acyloxy, amino, acylamino, carbamate, amido, amidino, sulfonyl, sulfoxido, sulfamoyl, and sulfonamide;
provided that:
i) if Ar is a phenyl ring, it is substituted with at least one non-protium ( 1 H) substituent;
ii) B is C—R 25 when E is N, or K is C—R 25 when M is N, or both, such that at least one of B and K is C—R 25 , wherein
R 25 is selected from deuterium, halogen, hydroxyl, lower alkyl, and lower alkoxy; and/or
iii) R 4 is
W is N, CH, or CCH 3 ;
R 5 is selected from H and substituted or unsubstituted alkyl, acyl, and ester; and
R 6 and R 7 are each independently H or alkyl, or
R 6 forms a one- or two-carbon bridge to the carbon atom adjacent to R 7 and NR 5 ;
wherein either W is CH or CCH 3 , or R 6 and R 7 are not both H.
2. The compound according to claim 1 , wherein B is C—R 25 when E is N, or K is C—R 25 when M is N, or both, such that at least one of B and K is C—R 25 , wherein R 25 is selected from deuterium, fluorine, chlorine, methyl, ethyl, hydroxy, and methoxy.
3. The compound of claim 1 , wherein Ar is a substituted or unsubstituted nitrogen-containing heteroaryl group selected from pyridine, pyrazine, pyrimidine, oxazole, thiazole, thiadiazole and substituted or unsubstituted:
4. The compound of claim 1 , wherein when Ar is substituted, the substituent is selected from deuterium, halogen, hydroxy, cyano, lower alkyl, and lower alkoxy.
5. The compound of claim 1 , wherein Ar is a substituted or unsubstituted six-membered ring.
6. The compound of claim 5 , wherein:
L 1 , if present, is disposed on the para-position of Ar relative to the bicyclic core bearing X, Y, and Z; or
R 4 is disposed on the para-position of Ar relative to the bicyclic core bearing X, Y, and Z if L 1 is absent.
7. The compound of claim 5 , wherein when Ar is phenyl substituted with a non-protium substituent, either the substituent is halogen or cyano, or the substituent is positioned ortho to L 1 if L 1 is present or is positioned ortho to R 4 if L 1 is absent, or both.
8. The compound of claim 1 , wherein L 1 is absent.
9. The compound of claim 1 , wherein L 1 has a structure
wherein
Q is selected from CR 10 R 11 , NR 12 , O, S, S(O), and SO 2 ; and
R 10 and R 11 , independently for each occurrence, are selected from H and substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, amino, acylamino, carbamate, amido, amidino, cyano, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido;
R 12 is selected from H and substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, amino, acylamino, carbamate, amido, amidino, sulfonyl, sulfamoyl, and sulfonamido and
n is an integer from 0-4,
wherein any CH 2 subunit of L 1 is optionally substituted with one or two lower alkyl groups.
10. The compound of claim 1 , wherein R 4 is selected from
and wherein
L 1 is absent or selected from substituted or unsubstituted alkyl and heteroalkyl;
V is absent or is C(R 21 ) 2 , O, or NR 21 ;
R 20 is absent or represents from 1-4 substituents selected from substituted or unsubstituted alkyl, aralkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, cycloalkylalkyl, heterocyclylalkyl, acyl, sulfonyl, sulfoxido, sulfamoyl, and sulfonamido; and
R 21 , independently for each occurrence, is selected from H and substituted or unsubstituted alkyl, aralkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, cycloalkylalkyl, heterocyclylalkyl, acyl, sulfonyl, sulfamoyl, and sulfonamido.
11. The compound according to claim 1 , wherein
R 4 is
and
R 6 and R 7 are both methyl, optionally disposed in a syn relationship to each other.
12. The compound according to claim 1 , wherein
R 4 is
and
R 6 represents a one-carbon bridge, thereby forming a diazanorbornane bicycle.
13. The compound according to claim 1 , wherein A, G, and J are each CH.
14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient or solvent.
15. A method of treating a disease or condition in a subject that would benefit from inhibition of Bone Morphogenetic Protein (BMP) signaling, comprising administering to the subject a compound of claim 1 .
16. The method of claim 15 , wherein the disease or condition is selected from pulmonary hypertension, hereditary hemorrhagic telangiectasia syndrome, cardiac valvular malformations, cardiac structural malformations, fibrodysplasia ossificans progressiva, juvenile familial polyposis syndrome, parathyroid disease, anemia, vascular calcification, atherosclerosis, valve calcification, renal osteodystrophy, ankylosing spondylitis, vascular inflammation, anemia of inflammation, inflammatory bowel disease, seronegative spondyloarthropathies, psoriasis, atherosclerosis, infections with viruses, bacteria, fungi, tuberculosis, and parasites, breast carcinoma, prostate carcinoma, renal cell carcinoma, bone metastasis, lung metastasis, osteosarcoma, and multiple myeloma.
17. A method of reducing circulating levels of ApoB-100 and/or LDL and/or total cholesterol in a subject and thereby reducing risk of primary or secondary cardiovascular events, comprising administering an effective amount of a compound of claim 1 .
18. A method of treating hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia or hepatic steatosis in a subject, comprising administering an effective amount of a compound of claim 1 .
19. The method of claim 18 , wherein the hypercholesterolemia, hyperlipidemia, or hyperlipoproteinemia is autosomal dominant hypercholesterolemia (ADH), familial hypercholesterolemia (FH), polygenic hypercholesterolemia, familial combined hyperlipidemia (FCHL), hyperapobetalipoproteinemia, or small dense LDL syndrome (LDL phenotype B).