US2021070788A1PendingUtilityA1
Phospholidines that are Bcl Family Antagonists for Use in Clinical Management of Conditions Caused or Mediated by Senescent Cells and for Treating Cancer
Est. expiryApr 30, 2038(~11.8 yrs left)· nominal 20-yr term from priority
A61P 3/10C07F 9/65844A61P 19/02C07F 9/65846A61P 35/00
59
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Claims
Abstract
This disclosure provides compounds with Bcl inhibitory activity based on a new chemical scaffold. The phospholidine compounds can include a P-phenyl phospholidine moiety which is substituted with an N-aryl or N-heteroaryl group. The P-phenyl phospholidine moiety can be optionally substituted at phosphorus with thio (═S) instead of oxo (═O). A second heteroatom attached to phosphorus can be cyclically linked to the N-substituted nitrogen atom of the phospholidine that is attached to the phosphorus to provide, together with the phosphorus atom through which they are connected, a heterocyclic ring. By incorporating such a cyclic constraint between two phosphorus substituents of the core linking moiety a favorable binding conformation can be promoted in the compounds. Selected compounds promote apoptosis in senescent cells, and can be developed for treating senescent-related conditions, such as osteoarthritis, ophthalmic disease, pulmonary disease, and atherosclerosis. Selected compounds promote apoptosis in cancer cells, and can be developed as chemotherapeutic agents.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1 . A compound of Formula (I):
wherein:
X 1 is O or S;
R 1 and R 3 together with the N and P atoms through which they are connected form a 5-, 6- or 7-membered heterocyclic ring, optionally substituted with one or more R 23 ;
R 4 is selected from hydrogen, alkyl, substituted alkyl, nitro, alkylsulfonyl (e.g., CH 3 SO 2 —), substituted alkylsulfonyl (e.g., CF 3 SO 2 —), alkylsulfinyl, substituted alkylsulfinyl, cyano, C(O)OH, C(O)NH 2 , halogen, SO 2 NH 2 , alkylaminosulfonyl, substituted alkylaminosulfonyl, alkylsulfonylamino and substituted alkylsulfonylami no, alkanoyl, substituted alkanoyl, alkylaminocarbonyl, substituted alkylaminocarbonyl, alkyloxycarbonyl and substituted alkyloxycarbonyl;
R 22 is selected from hydrogen, alkyl and substituted alkyl;
each R 23 is independently selected from alkyl, substituted alkyl, —CONH 2 , COOH, CONHR 22 , hydroxyl, halogen, alkoxy and substituted alkoxy;
Z 2 is selected from —NR 5 R 6 , hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkylsulfanyl, substituted alkylsulfanyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, carbocycle, substituted carbocycle, heterocycle, substituted heterocycle, arylalkoxy, substituted arylalkoxy, aryloxy, substituted aryloxy, aryloxyalkoxy, substituted aryloxyalkoxy, arylsulfanyl, substituted arylsulfanyl, arylsulfanylalkoxy, substituted arylsulfanylalkoxy, cycloalkylalkoxy, substituted cycloalkylalkoxy, cycloalkyloxy, substituted cycloalkyloxy, halogen, carbonyloxy, haloalkoxy, haloalkyl, hydroxy and nitro;
Z 3 is selected from heterocycle, substituted heterocycle, —NR 5 R 6 , aryl, substituted aryl, heteroaryl, substituted heteroaryl, carbocycle and substituted carbocycle;
R 5 and R 6 are independently selected from hydrogen, alkyl and substituted alkyl;
R 11 and R 12 are each one or more optional substituents each independently selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, halogen, cyano, nitro, carboxy, C(O)NH 2 , SO 2 NH 2 , sulfonate, hydroxyl, alkylsulfonyl, substituted alkylsulfon24yl, alkylaminosulfonyl, substituted alkylaminosulfonyl, alkylsulfonylamino, substituted alkylsulfonylamino, alkyloxycarbonyl, substituted alkyloxycarbonyl and —NR 5 R 6 ; and
R 31 is selected from H, R 12 and L 3 -Y 3 wherein L 3 is a linker and Y 3 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl.
2 . The compound of claim 1 , which has the structure shown in Formula (IVa) or Formula (IVb):
wherein:
Z 4 is selected from CH, CR 13 and N;
L 2 , L 3 , L 4 and L 5 are each independently a linker;
Y 2 is selected from alkyl, substituted alkyl, hydroxyl, alkoxy, substituted alkoxy, —NR 7 R 8 , aryl, substituted aryl, heteroaryl, substituted heteroaryl, carbocycle, substituted carbocycle, heterocycle and substituted heterocycle;
Y 3 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;
Y 4 , Y 5 and Y 6 are independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, carbocycle, substituted carbocycle, heterocycle, and substituted heterocycle;
R 7 and R 8 are independently selected from hydrogen, alkyl and substituted alkyl, or R 7 and R 8 together with the nitrogen to which they are attached form a 5-, 6- or 7-membered heterocyclic ring or substituted 5-, 6- or 7-membered heterocyclic ring; and
R 13 is one or more optional substituents selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, halogen, cyano, nitro, carboxy, C(O)NH 2 , SO 2 NH 2 , sulfonate, hydroxyl, alkylsulfonyl, substituted alkylsulfonyl, alkylaminosulfonyl, substituted alkylaminosulfonyl, alkylsulfonylamino, substituted alkylsulfonylamino, alkyloxycarbonyl, substituted alkyloxycarbonyl, alkylamino, dialkylamino, substituted alkylamino and substituted dialkylamino.
3 . The compound of claim 2 , which has the structure shown in Formula (IVa).
4 . The compound of claim 2 , which has the structure shown in Formula (IVb).
5 . The compound of claim 2 , wherein the compound is selected from:
i) a compound of Formula (IVa), wherein Y 3 is a substituted or unsubstituted fused bicyclic heteroaryl (e.g., a pyrrolo-pyridine); and ii) a compound of Formula (IVb), wherein Y 3 is a substituted or unsubstituted phenyl.
6 . The compound of claim 2 , which has the structure shown in Formula (V):
wherein:
Y 2 is selected from OR″, OP(═O)(OR″) 2 and NR 7 R 8 ;
Z 5 is selected from NR 19 , NH, O and S;
Z 7 is selected from S and O;
L 6 and L 7 are independently a covalent bond, C 1-6 alkyl linker or substituted C 1-6 alkyl linker;
R 13 and R 14 and each R 15 are independently one or more optional substituents selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, halogen, cyano, nitro, carboxy, C(O)NH 2 , SO 2 NH 2 , sulfonate, hydroxyl, alkylsulfonyl, substituted alkylsulfonyl, alkylaminosulfonyl, substituted alkylaminosulfonyl, alkylsulfonylamino, substituted alkylsulfonylamino, alkyloxycarbonyl, substituted alkyloxycarbonyl, alkylamino, dialkylamino, substituted alkylamino and substituted dialkylamino;
R 16 is selected from hydrogen, halogen and R 15 ;
R 17 and R 18 are independently selected from hydrogen, cyano, nitro, halogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, OR, SR, NRR′, COR, OCOR, CO 2 R, CONRR′, CONRSO 2 R′, —C 1-3 alkyleneCH(OH)CH 2 OH, SO 2 R and SO 2 NRR′; and
R 19 is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, OR, SR, NRR′, COR, OCOR, CO 2 R, CONRR′, CONRSO 2 R′, NRCOR, NRCONRR′, NRC(═S)NRR′, NRSO 2 R and SO 2 NRR′;
each R″ is independently H, alkyl or substituted alkyl; and
R and R′ are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, heterocycle-alkyl- and substituted heterocycle-alkyl-.
7 . The compound of claim 6 , which has the structure shown in Formula (VIa):
wherein:
Z 6 is selected from O, NR 40 *, CHR 40 , C(R 40 ) 2 and CH 2 ;
R 40 * is selected from alkyl, substituted alkyl, —(CH 2 ) m1 OR and —(CH 2 ) m2 OP(═O)(OR) 2 , wherein m1 and m2 are independently an integer from 1 to 6 and each R is independently H, alkyl or substituted alkyl;
each R 40 is independently selected from —OR, —N(R) 2 , —C(O)OR, —(CH 2 ) m1 OR, —(CH 2 ) m3 N(R) 2 , —(CH 2 ) m2 OP(═O)(OR) 2 , —OP(═O)(OH) 2 , and —OP(═O)(OR) 2 wherein m1, m2 and m3 are each independently an integer from 1 to 6 and each R is independently H, alkyl or substituted alkyl; and
q 1 and q 2 are independently an integer from 1 to 6.
8 . The compound of claim 6 , which has the structure shown in Formula (VIb):
wherein Y 2 is selected from OH, OR, NH 2 , NHR, NR 2 , —OP(═O)(OR) 2 and —OP(═O)(OH) 2 wherein each R is independently C 1-6 alkyl or substituted C 1-6 alkyl; and
q 1 and q 2 are independently an integer from 1 to 6.
9 . The compound of claim 7 , which has the structure shown in Formula (VIIa):
wherein:
X 2 is selected from Z 12 , S, O and NR 22 ;
Z 11 is selected from C(═O), —C(═O)X 3 — and Z 12 ;
each Z 12 is independently CR 24 R 25 ;
X 3 is O or S;
n is 0, 1, 2 or 3;
each R 24 and each R 25 are independently selected from hydrogen, alkyl and substituted alkyl;
R 4 is selected from NO 2 , SO 2 CH 3 , SO 2 CF 3 and COR 51 ;
Z 4 is selected from CH and N;
Z 6 is selected from O, CHC(O)R 18 , and CH(CH 2 ) p R 18 wherein p is 0-6 and each R 18 is independently —OR, —N(R) 2 , —OP(═O)(OH) 2 , and —OP(═O)(OR) 2 wherein each R is independently H, alkyl or substituted alkyl (e.g., a C 1-4 alkyl such as ethyl or tert-butyl);
R 14 and R 16 are independently hydrogen or halogen; and
R 17 is selected from SO 2 R 52 , COR 52 , CO 2 R 52 , CONR 51 R 52 , CONR 52 SO 2 R 51 and SO 2 NR 51 R 52 ;
R 18 and R 19 are independently selected from hydrogen, alkyl and substituted alkyl;
R 51 is selected from C 1-6 alkyl and substituted C 1-6 alkyl; and
R 52 is selected from hydrogen, C 1-6 alkyl and substituted C 1-6 alkyl.
10 . The compound of claim 9 , selected from the following table:
Compound
X 2
Z 11 -(Z 12 ) n
R 4
R 14
R 16
R 17
R 18
R 19
Z 4
Z 6
1
O
CH 2 CH 2
SO 2 CF 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
CHOH
2
O
CH 2 CH 2
SO 2 CF 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
CHOPO(OH) 2
3
O
CH 2 CH 2
SO 2 CF 3
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
CHOH
4
O
CH 2 CH 2
SO 2 CF 3
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
CHOPO(OH) 2
5
O
CH 2 CH 2 CH 2
SO 2 CF 3
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
CHOH
6
O
CH 2 CH 2 CH 2
SO 2 CF 3
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
CHOPO(OH) 2
7
O
CH 2 CH 2 CH 2
SO 2 CH 3
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
CHOH
8
O
CH 2 CH 2 CH 2
SO 2 CH 3
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
CHOPO(OH) 2
9
O
CH 2 CH 2
SO 2 CH 3
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
CHOH
10
O
CH 2 CH 2
SO 2 CH 3
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
CHOPO(OH) 2
11
O
CH 2 CH 2
SO 2 CH 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
CHOH
12
O
CH 2 CH 2
SO 2 CH 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
CHOPO(OH) 2
13
O
CH 2 CH 2
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
CHOH
14
O
CH 2 CH 2
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
CHOPO(OH) 2
15
O
CH 2 CH 2
NO 2
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
CHOH
16
O
CH 2 CH 2
NO 2
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
CHOPO(OH) 2
17
O
CH 2 CH 2 CH 2
NO 2
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
CHOH
18
O
CH 2 CH 2 CH 2
NO 2
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
CHOPO(OH) 2
11 . The compound of claim 8 , which has the structure shown in Formula (VIIb):
wherein:
X 2 is selected from Z 12 , S, O, and NR 22 ;
Z 11 is selected from —C(═O)—, —C(═O)X 3 — and Z 12 ;
each Z 12 is independently CR 24 R 25 ;
X 3 is O or S;
n is 0, 1, 2 or 3;
each R 24 and each R 25 are independently selected from hydrogen, alkyl and substituted alkyl;
Y 2 is selected from —OR 52 , —N(R 52 ) 2 , and —OP(═O)(OR 52 ) 2 ;
R 4 is selected from NO 2 , SO 2 CH 3 , SO 2 CF 3 and COR 51 ;
Z 4 is selected from CH and N;
R 14 and R 16 are independently hydrogen or halogen; and
R 17 is selected from SO 2 R 52 , COR 52 , 002R 52 , CONR 51 R 52 , CONR 52 SO 2 R 51 and SO 2 NR 51 R 52 ;
R 18 and R 19 are independently selected from hydrogen, alkyl and substituted alkyl;
R 51 is selected from C 1-6 alkyl and substituted C 1-6 alkyl; and
R 52 is selected from hydrogen, C 1-6 alkyl and substituted C 1-6 alkyl.
12 . The compound of claim 11 , selected from the following table:
Compound
X 2
Z 11 -(Z 12 ) n
R 4
R 14
R 16
R 17
R 18
R 19
Z 4
Y 2
19
O
CH 2 CH 2
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
20
O
CH 2 CH 2
SO 2 CF 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
21
O
CH 2 CH 2
SO 2 CF 3
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
22
O
CH 2 CH 2
SO 2 CF 3
H
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
23
O
CH 2 CH 2
SO 2 CH 3
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
24
O
CH 2 CH 2
SO 2 CH 3
H
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
25
O
CH 2 CH 2
SO 2 CH 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
26
O
CH 2 CH 2
NO 2
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
27
O
CH 2 CH 2
NO 2
H
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
28
O
CH 2 CH 2
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
OH
29
O
CH 2 CH 2
SO 2 CF 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
OH
30
O
CH 2 CH 2
SO 2 CF 3
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
OH
31
O
CH 2 CH 2
SO 2 CF 3
H
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
OH
32
O
CH 2 CH 2
SO 2 CH 3
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
OH
33
O
CH 2 CH 2
SO 2 CH 3
H
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
OH
34
O
CH 2 CH 2
SO 2 CH 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
OH
35
O
CH 2 CH 2
NO 2
F
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
OH
36
O
CH 2 CH 2
NO 2
H
Cl
CO 2 H
CH 3
CH(CH 3 ) 2
N
OH
13 . The compound of claim 1 , wherein X 1 is O.
14 . The compound of claim 1 , wherein X 1 is S.
15 . The compound of claim 9 , which has the structure shown in Formula (VIIIIa):
where:
R 4 is selected from NO 2 , SO 2 CH 3 , SO 2 CF 3 and COR 51 ;
n is 1 or 2;
Z 6 is selected from O, CHC(O)R 18 , and CH(CH 2 ) p R 18 wherein p is 0-6 and each R 18 is independently —OR, —N(R) 2 , —OP(═O)(OH) 2 , and —OP(═O)(OR) 2 wherein each R is independently H, alkyl or substituted alkyl (e.g., a C 1-4 alkyl such as ethyl or tert-butyl);
R 14 and R 16 are independently hydrogen or halogen; and
R 17 is selected from SO 2 R 52 , COR 52 , CO 2 R 52 , CONR 51 R 52 , CONR 52 SO 2 R 51 and SO 2 NR 51 R 52 ;
R 51 is selected from C 1-6 alkyl and substituted C 1-6 alkyl; and
R 52 is selected from hydrogen, C 1-6 alkyl and substituted C 1-6 alkyl.
16 . The compound of claim 11 , which has the structure shown in Formula (VIIIb):
where:
Y 2 is selected from —OR 52 , —N(R 52 ) 2 , and —OP(═O)(OR 52 ) 2 ;
R 4 is selected from NO 2 , SO 2 CH 3 , SO 2 CF 3 and COR 51 ;
n is 1 or 2;
R 14 and R 16 are independently hydrogen or halogen; and
R 17 is selected from SO 2 R 52 , COR 52 , CO 2 R 52 ,CONR 51 R 52 , CONR 52 SO 2 R 51 and SO 2 NR 51 R 52 ;
R 51 is selected from C 1-6 alkyl and substituted C 1-6 alkyl; and
R 52 is selected from hydrogen, C 1-6 alkyl and substituted C 1-6 alkyl.
17 . The compound according to claim 1 , selected from the following:
18 . A phosphorylated form of a compound according to claim 1 .
19 . The compound of claim 1 , which has an E 050 for irradiated IMR90 cells of less than 0.1 μM.
20 . A method of selectively removing senescent cells and/or cancer cells from a mixed cell population or tissue, comprising contacting the cell population or the tissue with a compound according to claim 1 .Cited by (0)
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