2,4-DIOXOTETRAHYDROPYRIMIDINYL DERATIVES AS DEGRONS IN PROTACS
The present invention provides a series of 2,4-dioxotetrahydropyrimidinyl derivatives that bind cereblon, and their application as degrons in PROTACs. Androgen receptor PROTACs containing the 2,4-dioxotetrahydropyrimidinyl containing degrons and medical uses of these PROTACS are also disclosed.
1 - 46 . (canceled)
47 . A compound of formula (I), or a tautomer of a compound of formula (I), or a salt thereof:
wherein:
X 1 is N or C—R 2 wherein R 2 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, —CONR 5 R 6 and —(CONR 3 R 4 )m(L)p(TBM)q;
X 4 is C—R 7 or N wherein R 7 is selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy;
X 2 and X 3 are independently selected from N or CH;
X 15 and X 22 are independently selected from N or C;
either R 3 and R 4 together with the nitrogen atom to which they are attached, join together to form a monocyclic or spiro nitrogen containing heterocyclic ring, or R 3 is H or C 1-4 alkyl and R 4 is —(CH 2 ) n R 28 , wherein R 28 is a monocyclic or spiro nitrogen containing heterocyclic ring;
n is 0 or 1;
R 5 and R 6 are independently selected from hydrogen or C 1-4 alkyl;
R 1 is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or a group of formula (II), wherein * represents the position of attachment to the compound of formula (I):
a and b are independently 0 or 1;
X 16 is N or CH;
X 17 is CR 34 R 35 wherein either R 34 and R 35 together with the carbon atom to which they are attached, join together to form a cyclobutyl ring, or wherein R 34 is —(CHR 36 )r-, or a bond to the compound of formula (I) and R 35 is hydrogen or halogen;
X 25 is CR 12 R 13 or O;
r is 0, 1 or 2;
a is 0, 1 or 2 and b and j are independently 0 or 1 with the proviso that b and j cannot both be 0;
R 36 is hydrogen or methyl;
R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from hydrogen or halogen;
L is a chemical linker;
TBM is a target binding moiety;
m, p and q are independently 0 and 1;
wherein when X 15 is N, then X 22 is C; and
wherein when X 1 is —(CONR 3 R 4 )m(L)p(TBM)q, then R 1 is C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy.
48 . A compound of formula (I), or a tautomer or a salt thereof, according to claim 47 , which has formula (Ia):
wherein:
X 1 is N or C—R 2 wherein R 2 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and —CONR 5 R 6 ;
X 4 is C—R 7 or N wherein R 7 is selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy;
X 2 and X 3 are independently selected from N or CH;
X 15 and X 22 are independently selected from N or C;
r is 0, 1 or 2;
a is 0, 1 or 2 and b and j are independently 0 or 1 with the proviso that b and j cannot both be 0;
X 16 is N or CH;
X 18 is CR 35 , wherein R 35 is hydrogen or halogen;
X 25 is CR 12 R 13 or O;
R 5 and R 6 are independently selected from hydrogen or C 1-4 alkyl;
R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 35 are independently selected from hydrogen or halogen;
R 36 is hydrogen or methyl;
L is a chemical linker;
TBM is a target binding moiety;
p and q are independently 0 and 1; and
wherein when X 15 is N, then X 22 is CH.
49 . A compound of formula (Ia), or a tautomer or a salt, thereof according to claim 48 , wherein X 1 is N or CH.
50 . A compound of formula (Ia), a tautomer or a salt thereof, according to claim 48 , wherein X 4 is C—R7.
51 . A compound of formula (Ia), or a tautomer or a salt thereof, according to claim 48 , wherein X 4 is N.
52 . A compound of formula (Ia), or a tautomer or a salt thereof, according to claim 48 , wherein X 2 is CH.
53 . A compound of formula (Ia), or a tautomer or a salt thereof, according to claim 48 , wherein X 3 is CH.
54 . A compound of formula (Ia), or a tautomer or a salt thereof, according to claim 48 , wherein X 15 is C.
55 . A compound of formula (Ia), or a tautomer or a salt thereof, according to claim 48 , wherein X 22 is N.
56 . A compound of formula (Ia), or a tautomer or a salt thereof, according to claim 48 , wherein X 16 is N, X 25 is CR 12 R 13 , j is 1 and a and b are independently 0 or 1.
57 . A compound of formula (Ia), or a tautomer or a salt thereof, according to claim 48 , wherein r is 0.
58 . A compound of formula (Ia), or a tautomer or a salt thereof, according to claim 48 , wherein:
R 8 , R 9 and R 35 are independently selected from hydrogen or halogen; and
R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each hydrogen.
59 . A compound of formula (Ia), or a tautomer or a salt thereof, according to claim 48 , wherein q is 1.
60 . A pharmaceutical composition comprising the compound, or a tautomer or a pharmaceutically acceptable salt thereof, according to claim 59 and a pharmaceutically acceptable excipient.
61 . A compound of formula (Ia), or a tautomer or a salt thereof, according to claim 48 , which has the formula (Iaaaa):
62 . A compound of formula (Iaaaa), or a tautomer or a salt thereof, according to claim 61 , wherein q is 1.
63 . A pharmaceutical composition comprising the compound, tautomer or a pharmaceutically acceptable salt thereof, according to claim 62 and a pharmaceutically acceptable excipient.
64 . A compound of formula (I), or a tautomer or a salt thereof, according to claim 47 , which has formula (Ib)
wherein:
R 1 is C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy, wherein said C 1-4 alkyl group is optionally substituted by one C 1-4 alkoxy group;
X 2 and X 3 are independently selected from N or CH;
X 15 and X 22 are independently selected from N or C;
X 4 is C—R 7 or N wherein R 7 is selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy;
either R 3 and R 4 together with the nitrogen atom to which they are attached, join together to form a monocyclic or spiro nitrogen containing heterocyclic ring, or R 3 is H or C 1-4 alkyl and R 4 is —(CH 2 ) n R 28 , wherein R 28 is a monocyclic or spiro nitrogen containing heterocyclic ring;
m is 0 or 1;
n is 0 or 1;
L is a chemical linker;
TBM is a target binding moiety; and
p and q are independently 0 and 1; and
wherein when X 15 is N, then X 22 is CH.
65 . A compound of formula (Ib), or a tautomer or a salt thereof, according to claim 64 , wherein X 4 is N or CH.
66 . A compound of formula (Ib), or a tautomer or a salt thereof, according to claim 65 , wherein X 4 is CH.
67 . A compound of formula (Ib), or a tautomer or a salt thereof, according to claim 64 , wherein X 2 is CH.
68 . A compound of formula (Ib), or a tautomer or a salt thereof, according to claim 64 , wherein X 3 is CH.
69 . A compound of formula (Ib), or a tautomer or a salt thereof, according to claim 64 , wherein X 15 is C.
70 . A compound of formula (Ib), or a tautomer or a salt thereof, according to claim 64 , wherein X 22 is N.
71 . A compound of formula (Ib), or a tautomer or a salt thereof, according to claim 64 , wherein m is 1.
72 . A compound of formula (Ib), or a tautomer or a salt thereof, according to claim 64 , wherein R 3 is H or C 1 -4alkyl and R 4 is —(CH2)nR28, wherein R 28 is a monocyclic nitrogen containing heterocyclic ring.
73 . A compound of formula (Ib), or a tautomer or a salt thereof, according to claim 64 , wherein the group NR 3 R 4 , has a structure selected from the following:
wherein the asterisk represents the position of attachment to the carbonyl group and the # represents the point of attachment to L.
74 . A compound of formula (Ib), or a tautomer or salt thereof, according to claim 64 , wherein R1 is C1-4alkyl.
75 . A compound of formula (Ib), or a tautomer or salt thereof, according to claim 74 , wherein R1 is isopropyl.
76 . A compound of formula (Ib), or a tautomer or salt thereof, according to claim 64 , wherein q is 1.
77 . A pharmaceutical composition comprising the compound, a tautomer or a pharmaceutically acceptable salt thereof, according to claim 76 and a pharmaceutically acceptable excipient.
78 . A compound of formula (Ib), or a tautomer or salt thereof, according to claim 64 , which has the formula (Ibbbb):
79 . A compound of formula (Ibbbb), or a tautomer or salt thereof, according to claim 68 , wherein q is 1.
80 . A pharmaceutical composition comprising the compound, a tautomer or pharmaceutically acceptable salt thereof, according to claim 79 and a pharmaceutically acceptable excipient.
81 . A compound of formula (Iaaaa), or a tautomer or salt thereof, according to claim 62 , wherein the TBM is an androgen receptor binding moiety.
82 . A pharmaceutical composition comprising the compound, tautomer or a pharmaceutically acceptable salt thereof, according to claim 81 and a pharmaceutically acceptable excipient.
83 . A method of treating a disorder selected from the group consisting of cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome and Kennedy's Disease, comprising administering to a human in need thereof, a therapeutically effective amount of the compound, tautomer or a pharmaceutically acceptable salt thereof, as defined in claim 81 or the pharmaceutical composition according to claim 82 .