Tricyclic Lactams for Use in the Protection of Hematopoietic Stem and Progenitor Cells Against Ionizing Radiation
This invention is in the area of tricyclic lactam compounds and methods for protecting healthy cells, and in particular hematopoietic stem and progenitor cells (HSPC), from the damage associated with ionizing radiation (IR) exposure using selective radioprotectants.
1 . A method for reducing the effect of ionizing radiation exposure on cyclin-dependent kinase 4 (CDK4) replication-dependent hematopoietic stem cells and/or progenitor cells (HSPCs) in a subject exposed to ionizing radiation, the method comprising administering to the subject an effective amount of a compound of Formula I, II, III, IV, or V:
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;
each X′ is independently, CH or N;
X″ is independently CH 2 , S or NH, arranged such that the moiety is a stable 5-membered ring;
R, R 8 , and R 11 are independently H, C 1 -C 3 alkyl or haloalkyl, cycloalkyl or 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 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring;
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, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0, 1 or 2 and n 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 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring; or R 3 and R 4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring;
R 5 and R 5 * at each occurrence is:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance;
R x at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene) m -OR 5 , -(alkylene) m -O-alkylene-OR 5 , -(alkylene) m -S(O) n —R 5 , -(alkylene) m -NR 3 R 4 , -(alkylene) m -CN, -(alkylene) m -C(O)—R 5 , -(alkylene) m -C(S)—R 5 , -(alkylene) m -C(O)—OR 5 , -(alkylene) m -O—C(O)—R 5 , -(alkylene) m -C(S)—OR 5 , -(alkylene) m -C(O)-(alkylene) m -NR 3 R 4 , -(alkylene) m -C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—R 5 , -(alkylene) m -N(R 3 )—C(S)—R 5 , -(alkylene) m -O—C(O)—NR 3 R 4 , -(alkylene) m -O—C(S)—NR 3 R 4 , -(alkylene) m -SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—SO 2 —R 5 , -(alkylene) m -N(R 3 )—SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—OR 5 ) -(alkylene) m -N(R 3 )—C(S)—OR 5 , or -(alkylene) m -N(R 3 )—SO 2 —R 5 ; wherein:
said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene) m -CN, -(alkylene) m -OR 5 *, -(alkylene) m -S(O) n —R 5 *, -(alkylene) m -NR 3 *R 4 *, -(alkylene) m -C(O)—R 5 *, -(alkylene) m -C(═S)R 5 *, -(alkylene) m -C(═O)OR 5 *, -(alkylene) m -OC(═O)R 5 *, -(alkylene) m -C(S)—OR 5 *, -(alkylene) m -C(O)—NR 3 *R 4 *, -(alkylene) m -C(S)—NR 3 *R 4 *,
-(alkylene) m -N(R 3 *)—C(O)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—R 5 *, -(alkylene) m -N(R 3 *)—C(S)—R 5 *, -(alkylene) m -O—C(O)—NR 3 *R 4 *, -(alkylene) m -O—C(S)—NR 3 *R 4 *, -(alkylene) m -SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—SO 2 —R 5 *, -(alkylene) m -N(R 3 *)—SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—OR 5 *, -(alkylene) m -N(R 3 *)—C(S)—OR 5 *, or -(alkylene) m -N(R 3 *)—SO 2 —R 5 *,
n is 0, 1 or 2, and
m is 0, 1 or 2;
R 3 * and R 4 * at each occurrence are independently:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance; or R 3 * and R 4 * together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance; and
R 6 is H or 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 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring; and
R 10 is (i) NHR A , wherein R A is unsubstituted or substituted C 1 -C 8 alkyl, cycloalkylalkyl, or -TT-RR, C 1 -C 8 cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O, and S; TT is an unsubstituted or substituted C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl linker; and RR is a hydroxyl, unsubstituted or substituted C 1 -C 6 alkoxy, amino, unsubstituted or substituted C 1 -C 6 alkylamino, unsubstituted or substituted di-C 1 -C 6 alkylamino, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or (ii) —C(O)—R 12 or —C(O)O—R 13 , wherein R 12 is NHR A or R A and R 13 is R A ;
when compounds comprise a double bond in the 6-membered ring fused to the pyrimidine ring, two R 8 groups are present and are as defined above;
when compounds do not comprise a double bond in the 6-membered ring fused to the pyrimidine ring, four R 8 groups are present and are as defined above;
or a pharmaceutically acceptable salt thereof.
2 . The method of claim 1 , wherein each R 8 is independently hydrogen or C 1 -C 3 alkyl.
3 . The method of claim 1 , wherein the compound has the formula:
4 . The method of claim 1 , wherein the compound has the formula:
5 . The method of claim 1 , wherein the compound has the formula:
6 . The method of claim 1 , wherein the compound has the formula:
7 . The method of claim 1 , wherein the compound has the formula:
8 . The method of claim 1 , wherein the compound has the formula:
9 . The method of claim 1 , wherein the compound has the formula:
10 . The method of claim 1 , wherein the compound has the formula:
11 . The method of claim 1 , wherein the compound has the formula:
12 . The method of claim 1 , wherein the compound has the formula:
13 . The method of claim 1 , wherein the compound has the formula:
14 . The method of claim 1 , wherein the compound has the formula:
15 . The method of claim 1 , wherein the compound has the formula:
16 . The method of claim 1 , wherein the compound has the formula:
17 . The method of claim 1 , wherein the compound has the formula:
18 . The method of claim 1 , wherein the compound has the formula:
19 . The method of claim 1 , wherein the compound is selected from the group consisting of:
Structure
Reference
Structure
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
U
V
W
X
Y
Z
AA
BB
CC
DD
EE
FF
GG
HH
II
JJ
KK
LL
MM
NN
OO
PP
RR
SS
TT
UU
VV
WW
XX
YY
ZZ
AAA
BBB
CCC
DDD
EEE
FFF
GGG
HHH
III
JJJ
KKK
LLL
MMM
NNN
OOO
PPP
QQQ
RRR
SSS
TTT
UUU
VVV
WWW
XXX
20 . The method of claim 1 , wherein the subject is a human.
21 . The method of claim 1 , wherein the subject's HSPCs return to approximately pre-treatment baseline cell cycle activity prior to the exposure to IR.
22 . The method of claim 1 , wherein the compound is administered to the subject prior to the exposure to IR.
23 . The method of claim 1 , wherein the subject is undergoing radio-therapy to treat a disease.
24 . The method of claim 1 , wherein the subject is being treated for a proliferative disorder.
25 . The method of claim 1 , wherein the subject is being treated for a CDK4/6 replication independent cancer.
26 . The method of claim 1 , wherein the subject is being treated for an ionizing radiation exposure associated with an environmental or occupational condition.
27 . The method of claim 1 , wherein administration of the compound does not affect growth of diseased cells.
28 . The method of claim 1 , wherein the subject is further treated with a hematopoietic growth factor upon dissipation of the CDK4/6 inhibitor's inhibitory effect.
29 . The method of claim 28 , wherein the hematopoietic growth factor is selected form the group consisting of granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), thrombopoietin, interleukin (IL)-12, steel factor, and erythropoietin (EPO).
30 . The method of claim 1 , wherein the compound is administered to the subject prior to exposure to the ionizing radiation, during exposure to the ionizing radiation, after exposure to the ionizing radiation, or a combination thereof.
31 . The method of claim 1 , wherein the compound is administered to the subject less than about 24 hours prior to exposure to the ionizing radiation.
32 . The method of claim 1 , wherein the compound is administered to the subject prior to exposure to the ionizing radiation such that the compound reaches peak serum levels during exposure to the ionizing radiation.
33 . The method of claim 1 , wherein the compound is administered to the subject less than about 4 hours prior to exposure to the ionizing radiation.
34 . The method of claim 1 , wherein the compound is administered to the subject after exposure to the ionizing radiation.
35 . The method of claim 1 , wherein the compound is administered to the subject about 12 hours or more after exposure to the ionizing radiation.
36 . A method for reducing the effect of ionizing radiation exposure on cyclin-dependent kinase 4 (CDK4) replication-dependent hematopoietic stem cells and/or progenitor cells (HSPCs) in a subject exposed to ionizing radiation, the method comprising administering to the subject an effective amount of 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 (including methyl) or haloalkyl, cycloalkyl or 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 any of which may be optionally independently substituted with one or more R x groups as allowed by valence, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring;
or two R 14 groups bonded to the same carbon can form an exocyclic double bond;
or two R 14 groups bonded to the same carbon can 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.
37 . The method of claim 1 , wherein the compound is selected from the group consisting of:
38 . The method of claim 36 , wherein the compound is selected from the group consisting of:
39 . A method for reducing the effect of ionizing radiation exposure on cyclin-dependent kinase 4 (CDK4) replication-dependent hematopoietic stem cells and/or progenitor cells (HSPCs) in a subject exposed to ionizing radiation, the method comprising administering to the subject an effective amount of a compound of Formula I, II, III, IV, or V:
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;
each X′ is independently CH or N;
X″ is independently CH 2 , S or NH, arranged such that the moiety is a stable 5-membered ring;
R, R 8 , and R 11 are independently H, C 1 -C 3 alkyl (including methyl) or haloalkyl, cycloalkyl or 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 any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valence, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring;
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, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0, 1, or 2 and n is 0, 1 or 2;
wherein heterocyclo may be optionally independently substituted with 1 to 3 R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring;
R 3 and R 4 at each occurrence are independently:
(i) hydrogen or
(ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring; or R 3 and R 4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring;
R 5 and R 5 * at each occurrence is:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valance;
R x at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene) m -OR 5 , -(alkylene) m -O-alkylene-OR 5 , -(alkylene) m -S(O) n —R 5 , -(alkylene) m -NR 3 R 4 , -(alkylene) m -CN, -(alkylene) m -C(O)—R 5 , -(alkylene) m -C(S)—R 5 , -(alkylene) m -C(O)—OR 5 , -(alkylene) m -O—C(O)—R 5 , -(alkylene) m -C(S)—OR 5 , -(alkylene) m -C(O)-(alkylene) m -NR 3 R 4 , -(alkylene) m -C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—R 5 , -(alkylene) m -N(R 3 )—C(S)—R 5 , -(alkylene) m -O—C(O)—NR 3 R 4 , -(alkylene) m -O—C(S)—NR 3 R 4 , -(alkylene) m -SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—SO 2 —R 5 , -(alkylene) m -N(R 3 )—SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—OR 5 , -(alkylene) m -N(R 3 )—C(S)—OR 5 , or -(alkylene) m -N(R 3 )—SO 2 —R 5 ; wherein:
said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups, any of which, other than heterocyclo, may be further independently substituted with one or more
-(alkylene) m -CN, -(alkylene) m -OR 5 *, -(alkylene) m -S(O) n —R 5 *, -(alkylene) m -NR 3 *R 4 *, -(alkylene) m -C(O)—R 5 *, -(alkylene) m -C(═S)R 5 *, -(alkylene) m -C(═O)OR 5 *, -(alkylene) m -OC(═O)R 5 *, -(alkylene) m -C(S)—OR 5 *, -(alkylene) m -C(O)—NR 3 *R 4 *, -(alkylene) m -C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—R 5 *, -(alkylene) m -N(R 3 *)—C(S)—R 5 *, -(alkylene) m -O—C(O)—NR 3 *R 4 *, -(alkylene) m -O—C(S)—NR 3 *R 4 *, -(alkylene) m -SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—SO 2 —R 5 *, -(alkylene) m -N(R 3 *)—SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—OR 5 *, -(alkylene) m -N(R 3 *)—C(S)—OR 5 *, or -(alkylene) m -N(R 3 *)—SO 2 —R 5 *, and
wherein heterocycle may be further independently substituted with one to three substitutions selected from
-(alkylene) m -CN, -(alkylene) m -OR 5 *, -(alkylene) m -S(O) n —R 5 *, -(alkylene) m -NR 3 *R 4 *, -(alkylene) m -C(O)—R 5 *, -(alkylene) m -C(═S)R 5 *, -(alkylene) m -C(═O)OR 5 *, -(alkylene) m -OC(═O)R 5 *, -(alkylene) m -C(S)—OR 5 *, -(alkylene) m -C(O)—NR 3 *R 4 *, -(alkylene) m -C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—R 5 *, -(alkylene) m -N(R 3 *)—C(S)—R 5 *, -(alkylene) m -O—C(O)—NR 3 *R 4 *, -(alkylene) m -O—C(S)—NR 3 *R 4 *, -(alkylene) m -SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—SO 2 —R 5 *, -(alkylene) m -N(R 3 *)—SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—OR 5 *, -(alkylene) m -N(R 3 *)—C(S)—OR 5 *, or -(alkylene) m -N(R 3 *)—SO 2 —R 5 *;
n is 0, 1 or 2, and
m is 0, 1; or 2 and
R 3 * and R 4 * at each occurrence are independently:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valance; or R 3 * and R 4 * together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance;
R 6 is H, absent, or 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 any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valence, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring; and
R 10 is 1 (i) NHR A , wherein R A is unsubstituted or substituted C 1 -C 8 alkyl, cycloalkylalkyl, or -TT-RR, C 1 -C 8 cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O, and S; TT is an unsubstituted or substituted C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl linker; and RR is a hydroxyl, unsubstituted or substituted C 1 -C 6 alkoxy, amino, unsubstituted or substituted C 1 -C 6 alkylamino, unsubstituted or substituted di-C 1 -C 6 alkylamino, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or (ii) —C(O)—R 12 or —C(O)O—R 13 , wherein R 12 is NHR A or R A and R 13 is R A ;
when the compound of Formula I, II, III, IV, or V has a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, two R 8 groups are present as allowed for in Formula I, II, III, IV, or V above; or
when the compound of Formula I, II, III, IV, or V does not include a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, four R 8 groups are present as allowed for in Formula I, II, III, IV, or V 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 substituents;
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.
40 . A method for reducing the effect of ionizing radiation exposure on cyclin-dependent kinase 4 (CDK4) replication-dependent hematopoietic stem cells and/or progenitor cells (HSPCs) in a subject exposed to ionizing radiation, the method comprising administering to the subject an effective amount of 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 39 ;
each R 14 is independently H, C 1 -C 3 alkyl (including methyl) or haloalkyl, cycloalkyl or 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 any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valence, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring;
or two R 14 groups bonded to the same carbon can form an exocyclic double bond;
or two R 14 groups bonded to the same carbon can 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;
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 substituents;
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.