Substituted Imidazo[1,2-a]-pyridines as IRAK 1/4 and FLT3 inhibitors

1. A method for treating a disease or disorder in an individual, wherein the method comprises administering to the individual in need thereof a therapeutically effective amount of:

(i) a composition comprising a B-cell lymphoma 2 (BCL2) inhibitor:

wherein the BCL2 inhibitor is selected from the group consisting of:

apogossypol;

gossypol;

obatoclax;

navitoclax;

venetoclax, or a salt thereof;

2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-(3-(dimethylamino)prop-1-yn-1-yl)-2-fluorophenoxy)propyl)thiazole-4-carboxylic acid (A-1155463);

1,1′,6,6′,7,7′-hexahydroxy-5,5′-diisopropyl-3,3′-dimethyl-[2,2′-binaphthalene]-8,8′-dicarbaldehyde (AT-101);

4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide (AT-737);

(E)-3-((9-amino-7-ethoxyacridin-3-yl)diazenyl])pyridine-2,6-diamine (BXI-61);

2′-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-1H, 1′H-2,5′-bibenzo[d]imidazole (BXI-72);

ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA14-1);

(2R,3S,6S,7R,8R)-8-butyl-3-(3-formamido-2-methoxybenzamido)-2,6-dimethyl-4,9-dioxo-1,5-dioxonan-7-yl 3-methylbutanoate (2-methoxy antimycin A3);

4-((E)-(((Z)-2-(cyclohexylimino)-4-methylthiazol-3(2H)-yl)imino)methyl)benzene-1,2,3-triol (MIM1);

1-oxo-6-thiomorpholino-1H-phenalene-2,3-dicarbonitrile (S1);

N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide (TW37);

2-((4-((4-bromophenyl)sulfonamido)-1-hydroxynaphthalen-2-yl)thio)acetic acid (UMI-77); and

5-[3-[4-(aminomethyl)phenoxy]propyl]-2-[8-[2-(2-benzothiazolyl)hydrazinylidene]-5,6,7,8-tetrahydro-2-naphthalenyl]-4-thiazolecarboxylic acid (WEHI-539),

or a combination thereof; and

(ii) a composition comprising an interleukin receptor-associated kinase (IRAK) inhibiting compound of Formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

R 1 is H, halogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, OH, or C 1 -C 6 alkoxy, wherein the C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl or C 1 -C 6 alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO 2 , CN, CH 3 , CH 2 CH 3 , C≡CH, C(O)H, C(O)OH, OH, SO 3 H, and morpholinyl;

R 2 is H, halogen, CN, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C(O)H, C(O)OH, OH, C 1 -C 6 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C(O)H, C(O)OH, OH, C 1 -C 6 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO 2 , CN, C 1 -C 3 alkyl, C 1 -C 3 perfluorinated alkyl, C≡CH, CH 2 C≡CH, C≡CCH 3 , C(O)H, C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)OH, C(O)-morpholin-4-yl, NH 2 , N(CH 3 ) 2 , OH, C 1 -C 3 alkoxy, SO 3 H, heterocyclyl, aryl, and heteroaryl;

R 3 is H, halogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, OH, or C 1 -C 2 alkoxy, wherein the C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl or C 1 -C 2 alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, CH 3 , CH 2 CH 3 , C≡CH, C(O)H, C(O)OH, OH, and SO 3 H;

R 4 is H, halogen, CN, NO 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl C(O)H, C(O)OH, OH, C 1 -C 3 alkoxy, or SO 3 H, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl or C 1 -C 3 alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO 2 , CN, CH 3 , CH 2 CH 3 , C≡CH, C(O)H, C(O)OH, OH, and SO 3 H;

R 5 is H, halogen, CN, NO 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl C(O)H, C(O)OH, OH, C 1 -C 3 alkoxy, or SO 3 H, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl or C 1 -C 3 alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO 2 , CN, CH 3 , CH 2 CH 3 , C≡CH, C(O)H, C(O)OH, OH, and SO 3 H;

R 6 is H, halogen, CN, NO 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl C(O)H, C(O)OH, OH, C 1 -C 3 alkoxy, or SO 3 H, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl or C 1 -C 3 alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO 2 , CN, CH 3 , CH 2 CH 3 , C≡CH, C(O)H, C(O)OH, OH, and SO 3 H;

R 7 is

R 8 is H, CN, NO 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C(O)H, C(O)CH 3 , C(O)CH 2 CN, C(O)-phenyl, C(O)OH, or phenyl-CH 3 ;

Y is —NH—, —N(CH 3 )—, —N(CH 2 CH 3 )—, —N(CH 2 CH 2 CH 3 )—, —N[CH(CH 3 ) 2 ]—, or —O—;

m is 0, 1, 2, 3, 4, or 5; and

n is 0, 1, 2, 3, 4, or 5;

with the proviso that the sum of m and n is at least 1;

wherein the disease or disorder is selected from the group consisting of acute myeloid leukemia and a myelodysplastic syndrome, or a combination thereof.

2. The method of claim 1 , wherein the composition comprising a B-cell lymphoma 2 (BCL2) inhibitor and the composition comprising an interleukin receptor-associated kinase (IRAK) inhibiting compound are coformulated into one composition.

3. The method of claim 1 , wherein the composition comprising a B-cell lymphoma 2 (BCL2) inhibitor and the composition comprising an interleukin receptor-associated kinase (IRAK) inhibiting compound are coadministered as one composition.

4. The method of claim 1 , wherein the B-cell lymphoma 2 (BCL2) inhibitor is venetoclax, or a salt thereof.

5. The method of claim 1 , wherein the amount of the interleukin receptor-associated kinase (IRAK) inhibiting compound of Formula (I) in the composition is in the range of 0.005 mg/kg body weight of the individual to 50 mg/kg body weight of the individual.

6. The method of claim 1 , wherein R 1 is H, halogen, C 1 -C 7 alkyl, OH, or C 1 -C 6 alkoxy, wherein the C 1 -C 7 alkyl or C 1 -C 6 alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO 2 , CN, CH 3 , CH 2 CH 3 , C≡CH, C(O)H, C(O)OH, OH, SO 3 H, and morpholinyl.

7. The method of claim 6 , wherein R 1 is Cl, CH 3 , OCH 3 , or OCH 2 CH 2 -morpholinyl.

8. The method of claim 1 , wherein R 2 is H, halogen, CN, C 1 -C 7 alkyl, C(O)H, C(O)OH, OH, C 1 -C 6 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C 1 -C 7 alkyl, C(O)H, C(O)OH, OH, C 1 -C 6 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO 2 , CN, C 1 -C 3 alkyl, C 1 -C 3 perfluorinated alkyl, C≡CH, CH 2 C≡CH, C≡CCH 3 , C(O)H, C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)OH, C(O)-morpholin-4-yl, NH 2 , N(CH 3 ) 2 , OH, C 1 -C 3 alkoxy, SO 3 H, heterocyclyl, aryl, and heteroaryl.

9. The method of claim 1 , wherein R 2 is Cl, CN, CH 3 , CF 3 , CF 2 CF 3 , C≡CH, C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)-morpholin-4-yl, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 -morpholinyl, 4-ethylpiperazin-1-yl, 1H-pyrrol-3-yl, pyrazol-3-yl, 1H-pyrazol-4-yl, 1-methylpyrazol-4-yl, 1-(morpholin-4-yl)pyrazol-4-yl, 3,5-dimethylpyrazol-4-yl, 3,5-dimethylisoxazol-4-yl, tetrazol-5-yl, pyridin-3-yl, pyridin-4-yl, or 2-methoxypyridin-5-yl.

10. The method of claim 1 , wherein R 3 is H, halogen, C 1 -C 3 alkyl, OH, or C 1 -C 2 alkoxy, wherein the C 1 -C 3 alkyl or C 1 -C 2 alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, CH 3 , CH 2 CH 3 , C≡CH, C(O)H, C(O)OH, OH, and SO 3 H.

11. The method of claim 10 , wherein R 3 is H or OCH 3 , wherein the OCH 3 is optionally substituted with one, two, or three independently selected halogen substituents.

12. The method of claim 1 , wherein:

R 4 is H, halogen, CN, NO 2 , C 1 -C 4 alkyl, C(O)H, C(O)OH, OH, C 1 -C 3 alkoxy, or SO 3 H, wherein the C 1 -C 4 alkyl or C 1 -C 3 alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO 2 , CN, CH 3 , CH 2 CH 3 , C≡CH, C(O)H, C(O)OH, OH, and SO 3 H;

R 5 is H, halogen, CN, NO 2 , C 1 -C 4 alkyl, C(O)H, C(O)OH, OH, C 1 -C 3 alkoxy, or SO 3 H, wherein the C 1 -C 4 alkyl or C 1 -C 3 alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO 2 , CN, CH 3 , CH 2 CH 3 , C≡CH, C(O)H, C(O)OH, OH, and SO 3 H; and

R 6 is H, halogen, CN, NO 2 , C 1 -C 4 alkyl, C(O)H, C(O)OH, OH, C 1 -C 3 alkoxy, or SO 3 H, wherein the C 1 -C 4 alkyl or C 1 -C 3 alkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO 2 , CN, CH 3 , CH 2 CH 3 , C≡CH, C(O)H, C(O)OH, OH, and SO 3 H.

13. The method of claim 1 , wherein:

(i) R 4 is F, Cl, Br, CH 3 , CF 3 , or OCH 3 ; or

(ii) R 5 is F, Cl, Br, CH 3 , CH 2 CH 3 , or OCH 3 ; or

(iii) R 6 is F, Cl, Br, CH 3 , CF 3 , or OCH 3 , or any combination thereof.

14. The method of claim 1 , wherein R 7 is:

15. The method of claim 1 , wherein R 8 is H, C≡CH, C(O)CH 3 , C(O)CH 2 CN, or C(O)-phenyl.

16. The method of claim 1 , wherein Y is —NH—, —N(CH 3 )—, —N(CH2CH 3 )—, —N(CH 2 CH 2 CH 3 )—, or —N[CH(CH 3 ) 2 ]—.

17. The method of claim 1 , wherein:

(i) m is 1, 2, or 3; or

(ii) n is 1, 2, or 3,

or any combination thereof.

18. The method of claim 1 , wherein:

R 1 is H;

R 2 is F, Br, I, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C(O)H, C(O)OH, OH, C 2 -C 6 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C(O)H, C(O)OH, C 2 -C 6 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NO 2 , CN, C 1 -C 3 alkyl, C 1 -C 3 perfluorinated alkyl, C≡CH, CH 2 C≡CH, C≡CCH 3 , C(O)H, C(O)NH 2 , C(O)N(CH 3 ) 2 , C(O)OH, C(O)-morpholin-4-yl, NH 2 , N(CH 3 ) 2 , OH, C 1 -C 3 alkoxy, SO 3 H, heterocyclyl, aryl, and heteroaryl;

R 3 is H;

R 4 is H;

R 5 is H;

R 6 is H;

R 7 is

R 8 is H;

Y is —NH—;

m is 0, 1, 2, 3, 4, or 5; and

n is 0, 1, 3, 4, or 5;

with the proviso that the sum of m and n is at least 1.

19. The method of claim 1 , wherein the compound, or a stereoisomer thereof, is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.