Tricyclic lactams for use in HSPC-sparing treatments for RB-positive abnormal cellular proliferation
View Patent ↗This invention is in the area of tricyclic lactam compounds for and methods of treating selected Rb-positive cancers and other Rb-positive abnormal cellular proliferative disorders while minimizing the deleterious effects on healthy cells, for example healthy Hematopoietic Stem Cells and Progenitor Cells (HSPCs), associated with current treatment modalities. In one aspect, treatment of select Rb-positive cancers is disclosed using specific compounds disclosed herein. In certain embodiments, the compounds described herein act as selective cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors when administered to subjects.
1. A compound of Formula VI:
wherein
Z is —(CH 2 ) x — wherein x is 1, 2, 3, or 4 or —O—(CH 2 ) z — wherein z is 2, 3, or 4;
each X is independently CH or N;
R is H, C 1 -C 3 alkyl or haloalkyl, cycloalkyl, cycloalkyl containing one or more heteroatoms selected from N, O, or S, -(alkylene) m C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene)-heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)-NR 3 R 4 , -(alkylene) m —O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 ;
each R 1 is independently aryl, alkyl, cycloalkyl, or haloalkyl, wherein each of said alkyl, cycloalkyl, and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and two R 1 s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle;
y is 0, 1, 2, 3, or 4;
R 2 is -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 , -(alkylene) m -C(O)—O-alkyl, -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n -R 5 , or -(alkylene) m -S(O) n -NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valance;
R 3 and R 4 at each occurrence are independently:
(i) hydrogen or
(ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl; or R 3 and R 4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring;
R 5 is:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarvlalkyl;
R x at each occurrence is independently, halo, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkyl;
n is 0, 1, or 2;
m is 0, 1, or 2;
R 6 is H, lower alkyl, -(alkylene)m-heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)-NR 3 R 4 , -(alkylene) m -O—R 5 , -(alkylene) m -S(O)n-R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 ;
each R 14 is independently H, C 1 -C 3 alkyl or haloalkyl, cycloalkyl, cycloalkyl containing one or more heteroatoms selected from N, O, or S, -(alkylene) m -C 3 -C 8 cycloalkyl, -(alkylene)m-aryl, -(alkylene)m-heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 , -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 ;
or two R 14 groups bonded to the same carbon form an exocyclic double bond;
or two R 14 groups bonded to the same carbon form a carbonyl group; and
when the compound of Formula VI has a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, two R 14 groups are present as allowed for in Formula VI above; or
when the compound of Formula VI does not include a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, four R 14 groups are present as allowed for in Formula VI above;
or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
3. A compound of Formula VI:
wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R x , Z, m, n, and y are as defined in claim 1 ;
each R 14 is independently H, C 1 -C 3 alkyl or haloalkyl, cycloalkyl, cycloalkyl containing one or more heteroatoms selected from N, O, or S, -(alkylene) m -C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclo, -(alkylene) m - heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 , -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 ;
or two R 14 groups bonded to the same carbon form an exocyclic double bond;
or two R 14 groups bonded to the same carbon form a carbonyl group; and
when the compound of Formula VI has a double bond, as indicated by the (----), in the6-membered ring fused to the pyrimidine ring, two R 14 groups are present as allowed for in Formula VI above; or
when the compound of Formula VI does not include a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, four R 14 groups are present as allowed for in Formula VI above;
wherein each heteroaryl is an aryl ring system that contains one or more heteroatoms selected from the group O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized;
wherein each aryl is a carbocyclic aromatic system containing one or two rings, wherein such rings may be attached together in a fused manner, and wherein each aryl may have 1 or more R x sub stituents;
wherein each heterocyclo is a saturated or partially saturated heteroatom-containing ring radical, where the heteroatoms may be selected from nitrogen, sulfur and oxygen, wherein each heterocyclo is a monocyclic 6-8 membered ring or a 5-16 membered bicyclic ring system, and wherein each heterocyclo may have 1 to 3 R x substituents;
or a pharmaceutically acceptable salt thereof.
4. A compound having the structure:
5. The compound of claim 1 , wherein the compound is:
6. The compound of claim 1 , wherein the compound is:
7. The compound of claim 1 , wherein the compound is:
8. The compound of claim 1 , wherein the compound is:
9. The compound of claim 1 , wherein the compound is:
10. The compound of claim 1 , wherein R is H.
11. The compound of claim 3 , wherein R is H.
12. The compound of claim 10 , wherein two R 14 groups bonded to the same carbon form an exocyclic double bond, or two R 14 groups bonded to the same carbon form a carbonyl group.
13. The compound of claim 11 , wherein two R 14 groups bonded to the same carbon form an exocyclic double bond, or two R 14 groups bonded to the same carbon form a carbonyl group.
14. The compound of claim 12 , wherein one X is N and the other X is CH.
15. The compound of claim 13 , wherein one X is N and the other X is CH.
16. The compound of claim 14 , wherein R 2 is -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 , -(alkylene) m -C(O)—O-alkyl, or -(alkylene) m -O—R 5 .
17. The compound of claim 15 , wherein R 2 is -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 , -(alkylene) m -C(O)—O-alkyl, or -(alkylene) m -O—R 5 .
18. The compound of claim 16 , wherein m is 0.
19. The compound of claim 17 , wherein m is 0.
20. The compound of claim 14 , wherein R 2 is -(alkylene) m -heterocyclo, or -(alkylene) m -heteroaryl.
21. The compound of claim 15 , wherein R 2 is -(alkylene) m -heterocyclo, or -(alkylene) m -heteroaryl.
22. The compound of claim 20 , wherein heterocyclo is piperazine, piperidine, morpholine, pyrolidine, azetidine, or oxetane.
23. The compound of claim 21 , wherein heterocyclo is piperazine, piperidine, morpholine, pyrolidine, azetidine, or oxetane.
24. The compound of claim 20 , wherein heterocyclo is piperazine.
25. The compound of claim 21 , wherein heterocyclo is piperazine.
26. The compound of claim 24 , wherein R x is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkyl.
27. The compound of claim 25 , wherein R x is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkyl.
28. The compound of claim 24 , wherein R x is alkyl, cycloalkyl, heterocyclo, aryl, or heteroaryl.
29. The compound of claim 25 , wherein R x is alkyl, cycloalkyl, heterocyclo, aryl, or heteroaryl.
30. The compound of claim 24 , wherein R x is alkyl.
31. The compound of claim 25 , wherein R x is alkyl.
32. The compound of claim 26 , wherein Z is -(CH 2 ) x —.
33. The compound of claim 32 , wherein x is 1 or 2.
34. The compound of claim 33 , wherein y is 2.
35. The compound of claim 34 , wherein R 1 is aryl, alkyl, or cycloalkyl.
36. The compound of claim 34 , wherein R 1 is alkyl.
37. The compound of claim 34 , wherein two R 1 s on the same ring atom together with the ring atom to which they are attached form a 3-8-membered cycle.
38. The compound of claim 33 , wherein y is 0.
39. The compound of claim 33 , wherein y is 1.
40. The compound of claim 1 , wherein two R 14 groups bonded to the same carbon form an exocyclic double bond, or two R 14 groups bonded to the same carbon form a carbonyl group.
41. The compound of claim 1 , wherein one X is N and the other X is CH.
42. The compound of claim 1 , wherein R 2 is -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 , -(alkylene) m -C(O)—O-alkyl, or -(alkylene) m -O—R 5 .
43. The compound of claim 1 , wherein m is 0.
44. The compound of claim 1 , wherein R 2 is -(alkylene) m -heterocyclo, or -(alkylene) m -heteroaryl.
45. The compound of claim 1 , wherein heterocyclo is piperazine, piperidine, morpholine, pyrolidine, azetidine, or oxetane.
46. The compound of claim 1 , wherein heterocyclo is piperazine.
47. The compound of claim 1 , wherein R x is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkyl.
48. The compound of claim 1 , wherein R x is alkyl, cycloalkyl, heterocyclo, aryl, or heteroaryl.
49. The compound of claim 1 , wherein R x is alkyl.
50. The compound of claim 1 , wherein Z is -(CH 2 ) x —.
51. The compound of claim 1 , wherein x is 1 or 2.
52. The compound of claim 1 , wherein y is 2.
53. The compound of claim 1 , wherein R 1 is aryl, alkyl, or cycloalkyl.
54. The compound of claim 1 , wherein R 1 is alkyl.
55. The compound of claim 1 , wherein two R 1 s on the same ring atom together with the ring atom to which they are attached form a 3-8-membered cycle.
56. The compound of claim 1 , wherein y is 0.
57. The compound of claim 1 , wherein y is 1.
58. A compound of Formula VI:
wherein Z is -(CH 2 ), wherein x is 1, 2, 3, or 4 or —O—(CH 2 ) z — wherein z is 2, 3, or 4;
each X is independently CH or N;
R is H, C 1 -C 3 alkyl or haloalkyl, cycloalkyl, cycloalkyl containing one or more heteroatoms selected from N, O, or S, -(alkylene) m -C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m m-NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 , -(alkylene) m -O—R 5 , -(alkylene)m-S(O) n -R 5 , or -(alkylene) m -S(O) n -NR 3 R 4 ;
each R 1 is independently aryl, alkyl, cycloalkyl, or haloalkyl, wherein each of said alkyl, cycloalkyl, and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and two R 1 s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle;
y is 0, 1, 2, 3, or 4;
R 2 is
R 2* is a bond, alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m -, -(alkylene) m -S(O) 2 -(alkylene) m -, or -(alkylene) m -NH-(alkylene) m -,
P is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group;
each R x1 is independently alkyl, —(C(O))—O-alkyl, -(alkylene)m-cycloalkyl, or -(alkylene) m -heterocyclyl;
t is 0, 1, or 2;
R 3 and R 4 at each occurrence are independently:
(i) hydrogen or
(ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl; or R 3 and R 4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring;
R 5 is:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl;
n is 0, 1, or 2;
m is 0, 1, or 2;
R 6 is H, lower alkyl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 , -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n -R 5 , or -(alkylene) m -S(O)n-NR 3 R 4 ;
each R 14 is independently H, C 1 -C 3 alkyl or haloalkyl, cycloalkyl, cycloalkyl containing one or more heteroatoms selected from N, O, or S, -(alkylene) m - C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 , -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n -R 5 , or -(alkylene) m -S(O) n -NR 3 R 4 ;
or two R 14 groups bonded to the same carbon form an exocyclic double bond;
or two R 14 groups bonded to the same carbon form a carbonyl group; and
when the compound of Formula VI has a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, two R 14 groups are present as allowed for in Formula VI above; or
when the compound of Formula VI does not include a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, four R 14 groups are present as allowed for in Formula VI above;
or a pharmaceutically acceptable salt thereof.
59. The compound of claim 58 , wherein
is
60. The compound of claim 58 , wherein
is