US2021363148A1PendingUtilityA1
Compound having bruton's tyrosine kinase (btk)-inhibition and degradation activity
Assignee: SHANGHAI MEIZER PHARMACEUTICALS CO LTDPriority: Sep 3, 2017Filed: Aug 6, 2021Published: Nov 25, 2021
Est. expirySep 3, 2037(~11.1 yrs left)· nominal 20-yr term from priority
Inventors:Yongzhi Shu
A61P 17/06A61P 37/02C07D 487/04A61P 35/02A61P 19/02A61P 35/00
53
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Claims
Abstract
A compound for inhibiting and degrading Bruton's tyrosine kinase (Btk) is disclosed. The compound is a substituted glutarimide represented by Formula I′. The compound can be used in the preparation of drugs for treating Btk activity-related diseases.
Claims
exact text as granted — not AI-modified1 - 10 . (canceled)
11 . A compound represented by formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
each is independently a single or double bond;
A is absent or selected from C(═O), C(═O)X 1 ; SOX 1 , SO 2 X 1 , C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, and C 1-8 heterocyclic hydrocarbyl; wherein X 1 is absent or selected from (CR 12 R 13 ) j O, (CR 12 R 13 ) j S, 3- to 8-membered heteroaromatic ring, 3- to 8-membered aromatic ring and NR 14 ; wherein R 12 , R 13 , R 14 is each independently H, C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, or C 1-8 heterocyclic hydrocarbyl; j is an integer between 0 and 3; wherein each C 1-8 heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, and C 1-8 heterocyclic hydrocarbyl is optionally and independently substituted;
W is absent or selected from O, NR 17 , and X 2 C(═O)X 3 ; wherein R 17 is H, C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, or C 1-8 heterocyclic hydrocarbyl; wherein X 2 , X 3 is each independently absent or selected from O, S and NR 18 ; wherein R 18 is H, C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, or C 1-8 heterocyclic hydrocarbyl; wherein each C 1-8 heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and further wherein each C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, and C 1-8 heterocyclic hydrocarbyl is optionally and independently substituted;
Y is (CR 22 R 23 ) h , CHX 4 (CR 22 R 23 ) h , CX 4 ═CH(CR 22 R 23 ) h , or C(═CH 2 )(CR 22 R 23 ) h ; wherein h is an integer between 0 and 30; wherein R 22 , R 23 is each independently selected from H, cyano, hydroxyl, amino, C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, C 1-8 heterocyclic hydrocarbyl, and C 1-8 hydrocarbyloxy; wherein X 4 is H, halogen, cyano, nitro, hydroxyl, C 1-8 hydrocarbyloxy, C 1-8 hydrocarbyloxycarbonyl, C 1-8 amino, C 1-8 ester, C 1-8 aminocarbonyl, C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, or C 1-8 heterocyclic hydrocarbyl; wherein each C 1-8 heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and further wherein each C 1-8 hydrocarbyloxy, C 1-8 hydrocarbyloxycarbonyl, C 1-8 amino, C 1-8 ester, C 1-8 aminocarbonyl, C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, and C 1-8 heterocyclic hydrocarbyl is optionally and independently substituted;
Z is (CR 24 R 25 ) i , CHX 5 (CR 24 R 25 ) i , CX 5 ═CH(CR 24 R 25 ) i or C≡C(CR 24 R 25 ) i ; wherein i is an integer between 0 and 30; wherein R 24 , R 25 is each independently selected from H, cyano, hydroxyl, amino, C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, C 1-8 heterocyclic hydrocarbyl, and C 1-8 hydrocarbyloxy; wherein X 5 is H, halogen, cyano, nitro, hydroxyl, C 1-8 hydrocarbyloxy, C 1-8 hydrocarbyloxycarbonyl, C 1-8 amino, C 1-8 ester, C 1-8 aminocarbonyl, C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, or C 1-8 heterocyclic hydrocarbyl; wherein each C 1-8 heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and further wherein each C 1-8 hydrocarbyloxy, C 1-8 hydrocarbyloxycarbonyl, C 1-8 amino, C 1-8 ester, C 1-8 aminocarbonyl, C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, and C 1-8 heterocyclic hydrocarbyl is optionally and independently substituted;
B is absent or selected from O, C═O, S, NR 15 , NR 15 C(═O), C(═O)NR 15 , C(═O)O, OC(═O)O, NR 15 C(═O)O, OC(═O)NR 15 , NR 15 C(═O)NR 16 ; wherein R 15 , R 16 is each independently selected from H, C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, and C 1-8 heterocyclic hydrocarbyl; wherein each C 1-8 heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and further wherein each C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, and C 1-8 heterocyclic hydrocarbyl is optionally and independently substituted;
X is selected from CR 19 R 20 , C(═O), S(═O), SO 2 , NR 21 ; wherein R 19 , R 20 is each independently selected from H, cyano, hydroxyl, amino, C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, C 1-8 heterocyclic hydrocarbyl, and C 1-8 hydrocarbyloxy; wherein R 21 is selected from H, C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, and C 1-8 heterocyclic hydrocarbyl; wherein each C 1-8 heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and further wherein each C 1-8 hydrocarbyl, C 1-8 cyclic hydrocarbyl, and C 1-8 heterocyclic hydrocarbyl is optionally and independently substituted;
R 1 is H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C(O)H, C(O)C 1-6 hydrocarbyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, heterocyclic hydrocarbyl, or phenyl, wherein the heterocyclic hydrocarbyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C(O)C 1-6 hydrocarbyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, heterocyclic hydrocarbyl, or phenyl is optionally substituted;
each R 2 is independently H, F, Cl, Br, I, CN, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C(O)H, C(O)C 1-6 hydrocarbyl, C(O)NH 2 , C(O)NHC 1-6 hydrocarbyl, C(O)N(C 1-6 hydrocarbyl) 2 , NR 34 R 35 , OR 33 , cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein the heterocyclic hydrocarbyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C(O)C 1-6 hydrocarbyl, C(O)NHC 1-6 hydrocarbyl, C(O)N(C 1-6 hydrocarbyl) 2 , cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionally and independently substituted;
each R 3 is independently H, F, Cl, Br, I, CN, NO 2 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, NR 28 R 29 , OR 27 , X 6 C(O)R 31 , X 6 S(O) k R 30 , cyclic hydrocarbyl, or heterocyclic hydrocarbyl; wherein k is 0, 1, or 2; each X 6 is independently absent, NR 32 , or S; wherein each heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionally and independently substituted;
each R 4 is independently H, CN, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C(O)OH, or C(O)O(hydrocarbyl), wherein each C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C(O)O(hydrocarbyl) is optionally and independently substituted;
each R 5 is independently H, F, Cl, Br, I, CN, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C(O)H, C(O)C 1-6 hydrocarbyl, C(O)NH 2 , C(O)NHC 1-6 hydrocarbyl, C(O)N(C 1-6 hydrocarbyl) 2 , NR 34 R 35 , OR 33 , cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein the heterocyclic hydrocarbyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C(O)C 1-6 hydrocarbyl, C(O)NHC 1-6 hydrocarbyl, C(O)N(C 1-6 hydrocarbyl) 2 , cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionally and independently substituted;
R 6 is independently H, F, Cl, Br, I, CN, NO 2 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, NR 28 R 29 , OR 27 , X 6 C(O)R 31 , X 6 S(O) k R 30 , cyclic hydrocarbyl, or heterocyclic hydrocarbyl; each X 6 is independently absent, NR 32 , or S; wherein each heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionally and independently substituted;
R 7 is independently H, F, Cl, Br, I, CN, NO 2 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, NR 28 R 29 , OR 27 , X 6 C(O)R 31 , X 6 S(O) k R 30 , cyclic hydrocarbyl, or heterocyclic hydrocarbyl; each X 6 is independently absent, NR 32 , or S; wherein each heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionally and independently substituted;
each R 8 is independently H;
each R 9 is independently H;
R 10 is H;
each R 11 is independently H;
each R 33 is independently H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein the heterocyclic hydrocarbyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionally and independently substituted;
each R 34 is independently H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein the heterocyclic hydrocarbyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionally and independently substituted;
each R 35 is independently H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein the heterocyclic hydrocarbyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionally and independently substituted;
each R 27 is independently H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein each heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionally and independently substituted;
each R 28 is independently H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein each heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionally and independently substituted;
each R 29 is independently H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein each heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionally and independently substituted;
each R 3 O is independently H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein each heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionally and independently substituted;
each R 31 is independently H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein each heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionally and independently substituted;
each R 32 is independently H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein each heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionally and independently substituted;
a is 0, 1, 2, 3, 4, or 5;
b is 0, 1, 2, or 3;
c is an integer between 0 and 30;
d is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
e is 2;
f is 2; and
g is 4;
wherein the optional substituents are independently selected from the group consisting of F, Cl, Br, I, CN, C 1-6 halohydrocarbyl, C(O)H, C(O)C 1-6 hydrocarbyl, NH 2 , NH(C 1-6 hydrocarbyl), N(C 1-6 hydrocarbyl) 2 , OH, O (C 1-6 hydrocarbyl), and S(O) 2 C 1-6 hydrocarbyl.
12 . The compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein,
(i) A is absent; W is X 2 C(═O)X 3 , wherein X 2 is NR 18 and X 3 is absent; Y is (CR 22 R 23 ) h , wherein R 22 , R 23 is each independently selected from H, hydroxyl, and C 1-4 hydrocarbyl, h is an integer between 1 and 6; Z is (CR 24 R 25 ) i , wherein R 24 , R 25 is each independently selected from H, hydroxy, C 1-4 hydrocarbyl, i is an integer between 1 and 6; c is 0; and further wherein each C 1-4 hydrocarbyl is optionally and independently substituted; (ii) A is absent; W is absent or O; Y is (CR 22 R 23 ) h , wherein R 22 , R 23 is each independently selected from H, hydroxyl, and C 1-4 hydrocarbyl, h is an integer between 0 and 3; B is O; Z is (CR 24 R 25 ) i , wherein R 24 , R 25 is each independently selected from H, hydroxy, C 1-4 hydrocarbyl, i is an integer between 1 and 3; c is an integer between 1 and 6; and further wherein each C 1-4 hydrocarbyl is optionally and independently substituted; (iii) A is absent; W is NR 17 ; wherein R 17 is H, or C 1-4 hydrocarbyl; Y is (CR 22 R 23 ) h , wherein R 22 , R 23 is each independently selected from H, hydroxyl, and C 1-4 hydrocarbyl, h is an integer between 0 and 3; Z is (CR 24 R 25 ) i , wherein R 24 , R 25 is each independently selected from H, hydroxy, and C 1-4 hydrocarbyl, i is an integer between 1 and 4; B is O; c is an integer between 1 and 6; and further wherein each C 1-4 hydrocarbyl is optionally and independently substituted; or (iv) A is absent; W is absent; Y is (CR 22 R 23 ) h , wherein R 22 , R 23 is each independently selected from H, hydroxyl, and C 1-4 hydrocarbyl, h is an integer between 0 and 3; Z is (CR 24 R 25 ) i , wherein R 24 , R 25 is each independently selected from H, hydroxy, and C 1-4 hydrocarbyl, i is an integer between 0 and 3; B is O; c is an integer between 1 and 10; and further wherein each C 1-4 hydrocarbyl is optionally and independently substituted.
13 . The compound according to claim 11 , wherein, in formula I, X is C(═O).
14 . The compound according to claim 11 , wherein, R 1 is selected from H, and C 1-4 alkyl; and further wherein the C 1-4 alkyl is optionally and independently substituted.
15 . The compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein, R 4 is selected from H, cyano, and C 1-6 alkyl; and further wherein the C 1-6 alkyl is optionally and independently substituted.
16 . The compound according to claim 11 , wherein the compound is selected from the group consisting of:
Compound
No.
Structure
3
10
13
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
39
40
41
43
and
44
or a pharmaceutically acceptable salt thereof.
17 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to claim 11 .
18 . A medicament for treatment of a disease related to activity or expression level of Bruton's tyrosine protein kinase (Btk), comprising the compound according to claim 11 .
19 . A method for modulating Bruton's tyrosine kinase activity in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of the compound according to claim 11 .
20 . The method according to claim 19 , wherein the subject has an autoimmune disease or a tumor.
21 . The method according to claim 20 , wherein the autoimmune disease is selected from the group consisting of psoriasis and rheumatoid arthritis.
22 . The method according to claim 20 , wherein the tumor is related to a disease selected from the group consisting of B-cell lymphoma, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma.
23 . A method for inhibiting tumor cell proliferation in vitro, comprising contacting the tumor cell with the compound according to claim 11 .
24 . The method according to claim 23 , wherein the tumor cell is related to a disease selected from the group consisting of B-cell lymphoma, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma.Join the waitlist — get patent alerts
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