Heterocyclic compounds for use in medical therapy
阅读说明：本技术 用于药物治疗的杂环化合物 (Heterocyclic compounds for use in medical therapy ) 是由 C·G·纳斯维舒克 R·诺克罗斯 F·戴伊 A·古尔吉勒尔 E·A·库斯尼尔 于 2020-03-06 设计创作，主要内容包括：本发明提供与泛表达的E3连接酶蛋白cereblon(CRBN)结合的杂环化合物及其用于治疗人或其他宿主中异常细胞增殖的用途。本发明还提供了可用作合成用于靶向蛋白质降解的双功能化合物的合成中间体的化合物。(The present invention provides heterocyclic compounds that bind to the ubiquitously expressed E3 ligase protein cereblon (crbn) and their use for the treatment of abnormal cell proliferation in humans or other hosts. The invention also provides compounds useful as synthetic intermediates for the synthesis of bifunctional compounds for targeted protein degradation.)
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof;
wherein:
A1selected from the group consisting of: -O-, -S-, -CH2-、-CF2-and-NH-, and A2is-CH2-; or
A1Selected from the group consisting of: -O-, -S-, -CH2-and-CF2-, and A2is-NH-;
w is CH or N;
R3independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; by R10Substituted- (CH)2)0-1-an aryl group; - (CH)2)0-1-an aryl group; by R10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-C3-7A cycloalkyl group; by R9Substituted- (CH)2)0-1-a heteroaryl group; - (CH)2)0-1-a heteroaryl group; - (CH)2)0-1-a heterocycloalkyl group; -C (═ O) C1-6An alkyl group; - (CH)2)0-2-C(＝O)-N(R7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; -OH; -NO2；-C1-6alkyl-N (R)11)-C(＝O)-R12(ii) a By R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; -O- (CH)2)0-1-an aryl group; -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -hydroxy-C1-6Alkyl-aryl; -N (R)5,R6)；-NH-C(＝O)C1-6An alkyl group; -NH-C (═ O) OC1-6An alkyl group; and ═ O, where the valence state allows;
m is 0, 1 or 2;
R5and R6Independently at each occurrence selected from H, C1-6Alkyl and phenyl;
or R5And R6Together with the nitrogen to which they are attached form a heterocycloalkyl ring;
R7and R8Independently at each occurrence selected from H and C1-6An alkyl group;
or R7And R8Together with the nitrogen to which they are attached form a heterocycloalkyl ring;
R9independently at each occurrence is selected from C1-6Alkoxy radical, C1-6Alkyl, halogen-C1-6Alkyl, heteroaryl and C1-6Alkyl or C1-6Alkoxy-substituted heteroaryl;
R10independently at each occurrence is selected from C1-6Alkoxy radical, C1-6Alkyl radical, C1-6alkyl-C1-6Alkoxy, halogen and halogen-C1-6An alkyl group;
R11independently at each occurrence selected from H and C1-6An alkyl group; and
R12independently at each occurrence selected from H, C1-6Alkyl and C3-7A cycloalkyl group.
2. A compound selected from one of the following formulas:
or a pharmaceutically acceptable salt thereof;
wherein:
R4independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; by R10Substituted- (CH)2)0-1-an aryl group; - (CH)2)0-1-an aryl group; by R10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-C3-7A cycloalkyl group; by R9Substituted- (CH)2)0-1-a heteroaryl group; - (CH)2)0-1-a heteroaryl group; o, if the valence state allows; -C (═ O) C1-6An alkyl group; -C (═ O) -N (R)7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; by R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -N (R)5,R6) (ii) a and-NH-C (═ O) C1-6An alkyl group;
n is 1 or 2; and
all other variables are as defined in claim 1.
3. A compound of formula III:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1 and claim 2.
4. A compound selected from one of the following formulas:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1 and claim 2.
5. A compound of formula V:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1 and claim 2.
6. A compound of formula VI:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1 and claim 2.
7. A compound selected from one of the following formulas:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1 and claim 2.
8. A compound selected from one of the following formulas:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1 and claim 2.
9. A compound selected from one of the following formulas:
or a pharmaceutically acceptable salt thereof;
wherein:
R2independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; by R10Substituted- (CH)2)0-1-an aryl group; - (CH)2)0-1-an aryl group; by R10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-C3-7A cycloalkyl group; by R9Substituted- (CH)2)0-1-a heteroaryl group; - (CH)2)0-1-a heteroaryl group; -C (═ O) C1-6An alkyl group; -C (═ O) -N (R)7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; by R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; -O- (CH)2)0-1-an aryl group; -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -N (R)5,R6)；-NO2；-NH-C(＝O)C1-6An alkyl group; and-SO2-N(R5,R6) (ii) a And
wherein all other variables are as defined in claim 1 and claim 2.
10. A compound selected from one of the following formulas:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1, claim 2 and claim 9.
11. A compound selected from one of the following formulas:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1, claim 2 and claim 9.
12. A compound of formula XII:
or a pharmaceutically acceptable salt thereof;
wherein:
a is selected from: optionally substituted by one or two R2A group-substituted aryl group; optionally substituted by one or two R3A group-substituted heteroaryl; optionally substituted by one or two R4A group-substituted heterocycloalkyl group; -NH-C (═ O) -C1-6An alkyl group; and a cycloalkyl group; and
wherein the remaining variables are as defined in claim 1, claim 2 and claim 9.
13. A compound selected from one of the following formulas:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1, claim 2 and claim 9.
14. A compound of formula I (1):
or a pharmaceutically acceptable salt thereof;
wherein:
X1selected from the group consisting of a bond, NR34、CH2、CHR34、C(R34)2O and S;
X22is a functional group that can serve as a linking group to a protein-binding moiety; or X22Is a capping valency group and is generally not a linking group;
R34and R34’Independently at each occurrence is selected from: hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C3-C6Heterocyclic, aryl, heteroaryl, - (CO) R36、-(CS)R36、-(C＝NH)R36、-(SO)R36And- (SO)2)R36；
R36Independently at each occurrence is selected from: hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C3-C6Heterocycle, aryl, heteroaryl, hydroxy, C1-C6Alkoxy, thio, C1-C6Thioalkyl, -NH2、-NH(C1-C6Alkyl radical, C3-C7Cycloalkyl radical, C3-C7Heterocycle, aryl or heteroaryl) and-N (independently C)1-C6Alkyl radical, C3-C7Cycloalkyl radical, C3-C7Heterocyclic, aryl or heteroaryl radicals)2；
R20、R21、R22、R23And R24Independently a divalent or polyvalent linking group including, but not limited to, a covalent bond, alkyl, -C (O) -, -C (O) O-, -OC (O) -, -C (O) alkyl, -C (O) Oalkyl, -C (S) -, -SO2-, -S (O) -, -C (S) -, -C (O) NH-, -NHC (O) -, -N (alkyl) C (O) -, -C (O) N (alkyl) -, -O-, -S-, -NH-, -N (alkyl) -, -CH (-O-R)26)-、-CH(-NR34R34')-、-C(-O-R26) Alkyl-, -C (-NR)34R34') alkyl-, -C (R)40R40) -, -alkyl (R)27) -alkyl (R)28)-、-C(R27R28)-、-P(O)(OR26)O-、-P(O)(OR26)-、-NR34C(O)NR34’-, alkenes, haloalkyl, alkoxy, alkynylheteroarylalkyl, aryl, arylalkyl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, carbocycle, - (ethylene glycol)1-6-, - (lactic acid-co-glycolic acid)1-6-, - (propylene glycol)1-6-、-O-(CH2)1-12-O-、-NH-(CH2)1-12-NH-、-NH-(CH2)1-12-O-、-O-(CH2)1-12-NH-、-S-(CH2)1-12-O-、-O-(CH2)1-12-S-、-S-(CH2)1-12-S-、-S-(CH2)1-12-NH-and-NH- (CH)2)1-12-S-；
Wherein each R20、R21、R22、R23And R24Optionally substituted by one or more groups selected from R101Substituted with the substituent(s);
wherein R is20、R21、R22、R23And R24Is not a bond;
R101independently at each occurrence is selected from: hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, hydroxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -COOalkyl, COOH, NO2、F、Cl、Br、I、CF3、NH2NH alkyl, N (alkyl)2Aliphatic and heteroaliphatic;
R26selected from the group consisting of hydrogen, alkyl, silane, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, aliphatic, and heteroaliphatic;
R27and R28Independently selected from hydrogen, alkyl, amine, or together with the carbon atom to which they are attached form C (O), C (S), C ═ CH2、C3-C6Spiro carbocyclic ring or containing 1 or 2A 4-, 5-or 6-membered spiroheterocycle with a heteroatom selected from N and O, or forming a 1-or 2-carbon bridged ring; and
R40in each case selected from: hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azido, amino, cyano, -NH (aliphatic, including alkyl), -N (aliphatic, including alkyl)2、-NHSO2(aliphatic, including alkyl), -N (aliphatic, including alkyl) SO2Alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N (alkyl) SO2(aryl, heteroaryl or heterocycle) -NHSO2Alkenyl, -N (alkyl) SO2Alkenyl, -NHSO2Alkynyl, -N (alkyl) SO2Alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, heterocyclic, and carbocyclic; and
wherein the variables are as defined in claim 1, claim 2 and claim 9.
15. A compound selected from one of the following formulas:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 15.
16. A compound of formula III (1):
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 15.
17. A compound selected from one of the following formulas:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 15.
18. A compound of formula V (1):
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 15.
19. A compound of formula VI (1):
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 15.
20. A compound selected from one of the following formulas:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 15.
21. A compound selected from one of the following formulas:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 15.
22. A compound selected from one of the following formulas:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 15.
23. A compound selected from one of the following formulas:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 15.
24. A compound selected from one of the following formulas:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 15.
25. A compound of formula XII (1):
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 15.
26. A compound selected from one of the following formulas:
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 15.
27. The compound of any one of claims 1-26, wherein a1Is selected from-O-and-NH-, and A2is-CH2-。
28. The compound of any one of claims 1-26, wherein a1Selected from-O-, -S-, -CH2-、-CF2-, and A2is-NH-.
29. The compound of any one of claims 1-28, wherein W is CH.
30. The compound of any one of claims 1-28, wherein W is N.
31. The compound of any one of claims 1-30, wherein R2Independently at each occurrence is selected from: -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -N (R)5,R6)；-NO2；-NH-C(＝O)C1-6An alkyl group; and-SO2-N(R5,R6)。
32. The compound of any one of claims 1-30, wherein R2Independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; quiltR10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-C3-7A cycloalkyl group; -C (═ O) C1-6An alkyl group; -C (═ O) -N (R)7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; by R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; and-O- (CH)2)0-1-an aryl group.
33. The compound of any one of claims 1-32, wherein R3Independently at each occurrence is selected from: -C (═ O) C1-6An alkyl group; - (CH)2)0-2-C(＝O)-N(R7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; -OH; -NO2；-C1-6alkyl-N (R)11)-C(＝O)-R12(ii) a By R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; -O- (CH)2)0-1-an aryl group; -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -hydroxy-C1-6Alkyl-aryl; -N (R)5,R6)；-NH-C(＝O)C1-6An alkyl group; and-NH-C (═ O) OC1-6An alkyl group.
34. The compound of any one of claims 1-32, wherein R3Independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; by R10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-C3-7A cycloalkyl group; by R9Substituted- (CH)2)0-1-a heteroaryl group; and- (CH)2)0-1-heterocycloalkyl.
35. The compound of any one of claims 1-34, wherein R4Independently at each occurrence is selected from: -C (═ O) C1-6An alkyl group; -C (═ O) -N (R)7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; by R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -N (R)5,R6) (ii) a and-NH-C (═ O) C1-6An alkyl group.
36. The compound of any one of claims 1-34, wherein R4Independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; by R10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; and- (CH)2)0-1-C3-7A cycloalkyl group.
37. The compound of any one of claims 1-36, wherein R5And R6Independently at each occurrence selected from H, C1-6Alkyl groups and phenyl groups.
38. The compound of any one of claims 1-36, wherein R5And R6Together with the nitrogen to which they are attached form a heterocycloalkyl ring.
39. The compound of any one of claims 1-38, wherein R7And R8Independently at each occurrence selected from H and C1-6An alkyl group.
40. The compound of any one of claims 1-38, wherein R7And R8Together with the nitrogen to which they are attached form a heterocyclic ringAn alkyl ring.
41. The compound of any one of claims 14-40, wherein X1Selected from the group consisting of a bond or NR34。
42. The compound of any one of claims 14-41, wherein X22Selected from halogen, -NH2、-NHR34、-N(R34)2Hydroxy, thiol, -B (OH)2、-Sn(R36)3、-Si(R36)3、-OS(O)2Alkyl, -OS (O)2Haloalkyl, alkenyl, alkynyl, ethynyl, ethenyl, -C (O) H, -NR34C (O) alkenyl, -NR34C (O) alkynyl, cyano, -SC (O) alkyl, OC (O) alkyl, heterocycle, -C (O) OH, hydrogen, alkyl, aryl, heteroaryl, aliphatic, heteroaliphatic, and carbocyclic.
43. The compound of any one of claims 14-42, wherein R20、R21、R22、R23And R24Independently selected from the group consisting of a bond, alkyl, -C (O) -, -C (O) O-, -OC (O) -, -C (O) alkyl, -C (O) Oalkyl, -C (S) -, -SO2-, -S (O) -, -C (S) -, -C (O) NH-, -NHC (O) -, -N (alkyl) C (O) -, -C (O) N (alkyl) -, -O-, -S-, -NH-, -N (alkyl) -, -CH (-O-R)26)-、-CH(-NR34R34')-、-C(-O-R26) Alkyl-, -C (-NR)34R34') alkyl-, -C (R)40R40) -, -alkyl (R)27) -alkyl (R)28)-、-C(R27R28)-、-P(O)(OR26)O-、-P(O)(OR26)-、-NR34C(O)NR34’-, alkenes, haloalkyl, alkoxy, alkynylheteroarylalkyl, aryl, arylalkyl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, carbocycle, - (ethylene glycol)1-6-, - (lactic acid-co-glycolic acid)1-6-, - (propylene glycol)1-6-、-O-(CH2)1-12-O-、-NH-(CH2)1-12-NH-、-NH-(CH2)1-12-O-、-O-(CH2)1-12-NH-、-S-(CH2)1-12-O-、-O-(CH2)1-12-S-、-S-(CH2)1-12-S-、-S-(CH2)1-12-NH-and-NH- (CH)2)1-12-S-, wherein R20、R21、R22、R23And R24Is not a key.
44. A compound according to claim 43, wherein R20、R21、R22、R23And R24Is not a bond.
45. A compound according to claim 43, wherein R20、R21、R22、R23And R24Is not a bond.
46. A compound according to claim 43, wherein R20、R21、R22、R23And R24Is not a key.
47. A compound according to claim 43, wherein R20、R21、R22、R23And R24None of which are keys.
48. A compound selected from:
or a pharmaceutically acceptable salt thereof.
49. A pharmaceutical composition comprising a compound of any one of claims 1-48 in a pharmaceutically acceptable carrier.
50. A method of treating abnormal cell proliferation in a human subject in need thereof comprising administering an effective amount of a compound of any one of claims 1-48, or a pharmaceutically acceptable salt thereof.
51. A method of treating abnormal proliferation in a human subject comprising administering a compound of formula XIV:
or a pharmaceutically acceptable salt thereof;
wherein:
A1selected from the group consisting of: -O-, -S-, -CH2-、-CF2-and-NH-; and A is2is-CH2-; or
A1Selected from the group consisting of: -O-, -S-, -CH2-and-CF2-, and A2is-NH-;
w is CH or N;
z is selected from: a covalent bond; a carbonyl group; - (CH)2)0-2-NR1-(CH2)0-2-；-(NR1)0-1-C(＝O)-(NR1)0-1-；-(NR1)0-1-C(＝O)-(CH2)1-3-；-O-(CH2)0-2-C(＝O)-NR1-；-(CH2)1-3-；-(CH2)1-3-；-(CH2)0-2-O-(CH2)0-2(ii) a And- (NR)1)0-1-SO0,2-(NR1)0-1-；
Or Z is selected from alkylene, alkenylene, alkynylene, arylene, heteroarylene, heterocyclyl, or carbocyclyl;
a is selected from: optionally substituted by one or two R2A group-substituted aryl group; optionally substituted by one or two R3Radical (I)Substituted heteroaryl; optionally substituted by one or two R4A group-substituted heterocycloalkyl group; -NH-C (═ O) -C1-6An alkyl group; and a cycloalkyl group;
R1independently selected from H or C1-6An alkyl group;
R2independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; by R10Substituted- (CH)2)0-1-an aryl group; - (CH)2)0-1-an aryl group; by R10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-C3-7A cycloalkyl group; by R9Substituted- (CH)2)0-1-a heteroaryl group; - (CH)2)0-1-a heteroaryl group; -C (═ O) C1-6An alkyl group; -C (═ O) -N (R)7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; by R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; -O- (CH)2)0-1-an aryl group; -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -N (R)5,R6)；-NO2；-NH-C(＝O)C1-6An alkyl group; and-SO2-N(R5,R6)；
R3Independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; by R10Substituted- (CH)2)0-1-an aryl group; - (CH)2)0-1-an aryl group; by R10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-C3-7A cycloalkyl group; by R9Substituted- (CH)2)0-1-a heteroaryl group; - (CH)2)0-1-a heteroaryl group; - (CH)2)0-1-heterocyclic ringAn alkyl group; -C (═ O) C1-6An alkyl group; - (CH)2)0-2-C(＝O)-N(R7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; -OH; -NO2；-C1-6alkyl-N (R)11)-C(＝O)-R12(ii) a By R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; -O- (CH)2)0-1-an aryl group; -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -hydroxy-C1-6Alkyl-aryl; -N (R)5,R6)；-NH-C(＝O)C1-6An alkyl group; -NH-C (═ O) OC1-6An alkyl group; and ═ O, where the valence state allows;
R4independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; by R10Substituted- (CH)2)0-1-an aryl group; - (CH)2)0-1-an aryl group; by R10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-C3-7A cycloalkyl group; by R9Substituted- (CH)2)0-1-a heteroaryl group; - (CH)2)0-1-a heteroaryl group; o, if the valence state allows; -C (═ O) C1-6An alkyl group; -C (═ O) -N (R)7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; by R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -N (R)5,R6) (ii) a and-NH-C (═ O) C1-6An alkyl group;
R5and R6Independently at each occurrence selected from H, C1-6Alkyl and phenyl;
or R5And R6Together with the nitrogen to which they are attached form a hetero atomA cycloalkyl ring;
R7and R8Independently at each occurrence selected from H and C1-6An alkyl group;
or R7And R8Together with the nitrogen to which they are attached form a heterocycloalkyl ring;
R9independently at each occurrence is selected from C1-6Alkoxy radical, C1-6Alkyl, halogen-C1-6Alkyl, heteroaryl and C1-6Alkyl or C1-6Alkoxy-substituted heteroaryl;
R10independently at each occurrence is selected from C1-6Alkoxy radical, C1-6Alkyl radical, C1-6alkyl-C1-6Alkoxy, halogen and halogen-C1-6An alkyl group;
R11independently at each occurrence selected from H and C1-6An alkyl group; and
R12independently at each occurrence selected from H, C1-6Alkyl and C3-7A cycloalkyl group.
52. A method of treating abnormal cell proliferation in a human subject comprising administering a compound of one of the following formulae:
or a pharmaceutically acceptable salt thereof.
53. A method of treating abnormal cell proliferation in a human subject comprising administering a compound of formula XIV (1):
or a pharmaceutically acceptable salt thereof;
wherein:
ABselected from optionally substituted by one or two R2Radical-substituted arylene radicals, optionallyOptionally substituted by one or two R3Heteroarylene substituted with radicals, optionally substituted with one or two R4Radical-substituted heterocycloalkylene, -NH-C (═ O) -C1-6Alkylene-and cycloalkylene groups;
the "tail" isAnd is
Wherein the remaining variables are as defined in claim 15.
54. The method of any one of claims 50-53, wherein the abnormal cell proliferation is cancer.
55. The method of any one of claims 50-53, wherein the abnormal cell proliferation is a tumor.
56. The compound of any one of claims 1-48 or the pharmaceutical composition of claim 49, for use in treating abnormal cell proliferation in a human subject.
57. A compound for use in treating abnormal cell proliferation in a human subject, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
58. A compound for use in treating abnormal cell proliferation in a human subject, wherein the compound is selected from formula XIV and formula XIV (1):
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 53.
59. The compound or pharmaceutical composition for use of any one of claims 56-58, wherein the abnormal cell proliferation is cancer.
60. The compound or pharmaceutical composition for use of any one of claims 56-58, wherein the abnormal cell proliferation is a tumor.
61. Use of a compound according to any one of claims 1-48 in the manufacture of a medicament for treating abnormal cell proliferation in a human subject.
62. Use of a compound in the manufacture of a medicament for treating abnormal cell proliferation in a human subject, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
63. Use of a compound according to any one of claims 1-48, wherein the compound is selected from formula XIV and formula XIV (1):
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 15.
Technical Field
The present invention provides compounds that bind to the ubiquitously expressed E3 ligase protein Cereblon (CRBN), which can alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, leading to the breakdown of intrinsic downstream proteins that mediate disease. The invention also provides compounds useful as synthetic intermediates for preparing bifunctional compounds for targeted protein degradation. Thus, the compounds of the present invention are useful for treating or preventing abnormal cell proliferation, including tumors and cancers.
Background
Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. Selective recognition and removal of damaged, misfolded or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). UPP is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, biogenesis of organelles, the cell cycle, DNA transcription and repair, differentiation and development, immune responses and inflammation, neural and muscular degeneration, morphogenesis of neural networks, modulation of cell surface receptors, ion channels and secretory pathways, responses to stress and extracellular regulators, ribosomal biogenesis, and viral infections.
Covalent attachment of multiple ubiquitin molecules to the terminal lysine residue by E3 ubiquitin ligase marks the protein to be degraded by the proteasome, where the protein is digested into small peptides and eventually its constituent amino acids, as building blocks for new proteins. Defective proteasome degradation is associated with a variety of clinical conditions, including alzheimer's disease, parkinson's disease, huntington's disease, muscular dystrophy, cardiovascular disease, and cancer, among others.
Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plant to human, which highlights their physiological importance. Cereblon is part of an E3 ubiquitin ligase protein complex that interacts with damaged DNA binding protein 1(DDB1), forms an E3 ubiquitin ligase complex with Cullin4(CUL4A) and the E2 binding protein ROC1 (also known as RBX1), and functions therein as a substrate receptor to select proteins for ubiquitination. By a mechanism not yet fully elucidated, cereblon ubiquitination of the target protein results in increased levels of fibroblast growth factor 8(FGF8) and fibroblast growth factor 10(FGF 10). FGF8, in turn, regulates many developmental processes, such as limb and auditory vesicle formation. The net result is that this E3 ubiquitin ligase complex is important for embryonic limb growth. In the absence of cereblon, DDB1 forms a complex with DDB2 and DDB2 functions as a DNA damage binding protein.
In an unrelated parallel study, Ito et al (Science 2010,327,1345-1350) entitled "Identification of a Primary Target of Thalidomide Teratogenicity" describes cereblon as a Thalidomide binding protein. Studies have shown that thalidomide-cereblon binding in vivo may be responsible for thalidomide teratogenicity. After Thalidomide was found to cause teratogenicity in The mid 1960 s, although this compound and certain related structures were found to be useful as anti-inflammatory, anti-angiogenic and anti-cancer Agents (see Bartlett et al (nat. rev. cancer 2004,4,314-322) entitled "The Evolution of Thalidomide and its imide Derivatives as anti-cancer Agents"). Thalidomide has been approved for the treatment of certain neoplastic diseases, including multiple myeloma, and is currently being investigated for use with the structural derivatives lenalidomide and Pomalidomide in the treatment of various other types of cancer (see martiniania, r. et al, "Biological activity of lenalidomide and its underlying therapeutic effects in multiple myeloma" Adv hemamol, 2012,2012: 842945; and Terpos, e. et al, "Pomalidomide: a no to t dried multiple and multiple myelomas" (Pomalidomide: a new drug for the treatment of relapsed and refractory multiple myeloma) "anticontages and 2013,6: 531).
The disclosure of thalidomide in combination with cereblon E3 ubiquitin ligase led to studies to incorporate thalidomide and certain derivatives into compounds to target destruction of proteins. Celgene has disclosed imides for similar uses, including U.S. patent 6,045,501; 6,315,720, respectively; 6,395,754; 6,561,976, respectively; 6,561,977, respectively; 6,755,784, respectively; 6,869,399, respectively; 6,908,432, respectively; 7,141,018, respectively; 7,230,012, respectively; 7,820,697, respectively; 7,874,984, respectively; 7,959,566, respectively; 8,204,763, respectively; 8,315,886, respectively; 8,589,188, respectively; 8,626,531, respectively; 8,673,939, respectively; 8,735,428, respectively; 8,741,929, respectively; 8,828,427, respectively; 9,056,120, respectively; 9,101,621, respectively; and 9,101,622.
Patent applications filed by C4 Therapeutics, inc. describing compounds capable of binding to E3 ubiquitin ligase include: WO 2019/236483, entitled "Spirocyclic Compounds"; WO 2019/191112 entitled "Cerebin Binders for the Degradation of Ikaros"; WO 2019/099868 entitled "Degraders and Degrons for Targeted Protein Degradation"; WO 2018/237026 entitled "N/O-Linked Degrons and degronomers for Protein Degradation"; WO 2017/197051 entitled "Amine-Linked C3-glutamide degronomers for Target Protein Degradation"; WO 2017/197055 entitled "heterocyclic 1ic degronomers for Target Protein Degradation"; WO 2017/197036 entitled "Spirocyclic Degromers for Target Protein Degradation"; WO 2017/19704620, entitled "C3-Carbon Linked glutathione degronomers for Target Protein Degradation"; and WO 2017/197056 entitled "Bromodomain Targeting precursors for Target Protein Degradation".
Patent applications filed by C4 Therapeutics, inc. and Hoffmann-La Roche describing compounds capable of binding E3 ubiquitin ligase include: WO 2019/121562 entitled "Bifunctional Inhibitors with EGFR lifting a E3 Ubiquitin ligand Moiety"; WO 2019/149922 entitled "Compound Which mouse Degradation of EGFR, for use Against Cancer"; WO 2018/220149, entitled "Compounds"; and WO 2018/115218 entitled "2-Benzopyrazinyl-N-heteroaryl-2-phenyl-acetic acid Compounds".
Other compound publications include: WO 2011/035124; WO 02/072576; WO 2010/085684; WO 2014/134240; WO 2011/130628; WO 2007/065518; WO 2016/176640; WO 2009/135651; WO 2011/156245; WO 2017/046318; WO 2010/130794; WO 2012/021382; WO 2005/060967; WO 2012/174199; EP 385850; WO 2016/176449; WO 2016/040508; WO 00/20358; EP 125678; WO 2006/058338; WO 2004/108133; WO 2010/108817; WO 2005/113489; WO 2012/061708; WO 2010/023161; WO 2007/041598; WO 2009/050232; WO 2018/93569; terefeck et al, bioorg.Med.chem.Lett.2005,15(15): 3600-03; smolyar et al, Russian Journal of Organic Chemistry 2011,47(8): 119-3; jun Yon Choi et al, J.Med.chem.2012,55(13):852-70.
Novel compounds, compositions and uses thereof are needed that bind to the E3 ligase protein cereblon to treat various medical conditions, particularly abnormal cell proliferation. There is also a need for new compounds that can be used to prepare bifunctional molecules for degrading proteins involved in disease processes.
Disclosure of Invention
In a first aspect, compounds that bind cereblon and modify ubiquitination of proteins by cereblon-containing E3 ubiquitin ligase are provided, as well as uses and preparations thereof. In a second aspect, compounds comprising a chemical moiety capable of binding cereblon are provided which are useful as synthetic intermediates for the preparation of bifunctional compounds which cause degradation of a selected protein via the Ubiquitin Proteosome Pathway (UPP).
The compounds described herein can be administered to a host, e.g., a human, in need thereof in an effective amount, optionally as a pharmaceutically acceptable salt, and optionally in a pharmaceutically acceptable composition. The compounds may be administered for any therapeutic indication that is treated by modulating the function or activity of the cereblon-containing E3 ubiquitin ligase protein complex, including but not limited to the treatment of abnormal cell proliferation such as cancer or tumors, or other known uses of the cereblon binding agents thalidomide, pomalidomide and lenalidomide. In certain embodiments, a compound as described herein may modulate the natural activity of cereblon.
The invention includes novel compounds of formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, and formulae XIII-a to XIII-I. Furthermore, the invention includes the use of a compound of formula XIV for the treatment of a therapeutic condition treatable by modulating the function or activity of a cereblon-containing E3 ubiquitin ligase protein complex. The invention also includes the use of the compounds of formula XIV (1) for the preparation of bifunctional compounds for the degradation of target proteins via the Ubiquitin Proteasome Pathway (UPP). The invention also includes compounds of formula I (1), formula II (1) -a to II (1) -k, formula III (1), formula IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formula VII (1) -a to VII (1) -e, formula VIII (1) -a to VIII (1) -I, formula IX (1) -a to IX (1) -j, formula X (1) -a to X (1) -I, formula XI (1) -a to XII (1) -I, formula XI (1) -a to XIII (1) -I.
In one aspect, there is provided a compound of formula I:
or a pharmaceutically acceptable salt thereof;
wherein:
A1selected from the group consisting of: -O-, -S-, -CH2-、-CF2-and-NH-, and A2is-CH2-; or
A1Selected from the group consisting of: -O-, -S-, -CH2-and-CF2-, and A2is-NH-;
w is CH or N;
R3independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; by R10Substituted- (CH)2)0-1-an aryl group; - (CH)2)0-1-an aryl group; by R10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-C3-7A cycloalkyl group; by R9Substituted- (CH)2)0-1-a heteroaryl group; - (CH)2)0-1-a heteroaryl group; - (CH)2)0-1-a heterocycloalkyl group; -C (═ O) C1-6An alkyl group; - (CH)2)0-2-C(＝O)-N(R7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; -OH; -NO2；-C1-6alkyl-N (R)11)-C(＝O)-R12(ii) a By R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; -O- (CH)2)0-1-an aryl group; -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -hydroxy-C1-6Alkyl-aryl; -N (R)5,R6)；-NH-C(＝O)C1-6An alkyl group; -NH-C (═ O) OC1-6An alkyl group; and ═ O, where the valence state allows;
m is 0, 1 or 2;
R5and R6Independently at each occurrence selected from H, C1-6Alkyl and phenyl;
or R5And R6Together with the nitrogen to which they are attached form a heterocycloalkyl ring;
R7and R8Independently at each occurrence selected from H and C1-6An alkyl group;
or R7And R8Together with the nitrogen to which they are attached form a heterocycloalkyl ring;
R9independently at each occurrence is selected from C1-6Alkoxy radical, C1-6Alkyl, halogen-C1-6Alkyl, heteroaryl and C1-6Alkyl or C1-6Alkoxy-substituted heteroaryl;
R10independently at each occurrence is selected from C1-6Alkoxy radical, C1-6Alkyl radical, C1-6alkyl-C1-6Alkoxy, halogen and halogen-C1-6An alkyl group;
R11independently at each occurrence selected from H and C1-6An alkyl group; and
R12independently at each occurrence selected from H, C1-6Alkyl and C3-7A cycloalkyl group.
In another aspect, there is provided a compound having one of the following formulas:
or a pharmaceutically acceptable salt thereof;
wherein:
R4independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; by R10Substituted- (CH)2)0-1-an aryl group; - (CH)2)0-1-an aryl group; by R10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-C3-7A cycloalkyl group; by R9Substituted- (CH)2)0-1-a heteroaryl group; - (CH)2)0-1-a heteroaryl group; o, if the valence state allows; -C (═ O) C1-6An alkyl group; -C (═ O) -N (R)7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; by R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -N (R)5,R6) (ii) a and-NH-C (═ O) C1-6An alkyl group;
n is 1 or 2; and
all other variables are as defined herein.
In another aspect, there is provided a compound of formula III:
or a pharmaceutically acceptable salt thereof;
wherein all variables are as defined herein.
In another aspect, there is provided a compound having one of the following formulas:
or a pharmaceutically acceptable salt thereof;
wherein all variables are as defined herein.
In another aspect, there is provided a compound of formula V:
or a pharmaceutically acceptable salt thereof;
wherein all variables are as defined herein.
In another aspect, there is provided a compound of formula VI:
or a pharmaceutically acceptable salt thereof;
wherein:
R2independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; by R10Substituted- (CH)2)0-1-an aryl group; - (CH)2)0-1-an aryl group; by R10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-C3-7A cycloalkyl group; by R9Substituted- (CH)2)0-1-a heteroaryl group; - (CH)2)0-1-a heteroaryl group; -C (═ O) C1-6An alkyl group; -C (═ O) -N (R)7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; by R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; -O- (CH)2)0-1-an aryl group; -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -N (R)5,R6)；-NO2；-NH-C(＝O)C1-6An alkyl group; and-SO2-N(R5,R6) (ii) a And
all other variables are as defined herein.
In another aspect, there is provided a compound having one of the following formulas:
or a pharmaceutically acceptable salt thereof;
wherein all variables are as defined herein.
In another aspect, there is provided a compound having one of the following formulas:
or a pharmaceutically acceptable salt thereof;
wherein all variables are as defined herein.
In another aspect, there is provided a compound having one of the following formulas:
or a pharmaceutically acceptable salt thereof;
wherein all variables are as defined herein.
In another aspect, there is provided a compound having one of the following formulas:
or a pharmaceutically acceptable salt thereof;
wherein all variables are as defined herein.
In another aspect, there is provided a compound having one of the following formulas:
or a pharmaceutically acceptable salt thereof;
wherein all variables are as defined herein.
In another aspect, compounds of formula XII are provided:
or a pharmaceutically acceptable salt thereof;
wherein:
a is selected from: optionally substituted by one or two R2A group-substituted aryl group; optionally substituted by one or two R3A group-substituted heteroaryl; optionally substituted by one or two R4A group-substituted heterocycloalkyl group; -NH-C (═ O) -C1-6An alkyl group; and a cycloalkyl group; and
all other variables are as defined herein.
In another aspect, there is provided a compound having one of the following formulas:
or a pharmaceutically acceptable salt thereof;
wherein all variables are as defined herein.
In another aspect, compounds of formula XIV are provided:
or a pharmaceutically acceptable salt thereof, for use in the treatment of a therapeutic disorder treatable by modulating the function or activity of a cereblon-containing E3 ubiquitin ligase protein complex;
wherein Z is selected from: a covalent bond; a carbonyl group; - (CH)2)0-2-NR1-(CH2)0-2-；-(NR1)0-1-C(＝O)-(NR1)0-1-；-(NR1)0-1-C(＝O)-(CH2)1-3-；-O-(CH2)0-2-C(＝O)-NR1-；-(CH2)1-3-；-(CH2)1-3-；-(CH2)0-2-O-(CH2)0-2(ii) a And- (NR)1)0-1-SO0,2-(NR1)0-1-; or
In an alternative embodiment, Z is selected from alkylene, alkenylene, alkynylene, arylene, heteroarylene, heterocyclyl, or carbocyclyl;
each occurrence of R1Independently selected from H or C1-6An alkyl group; and
all other variables are as defined herein.
Compounds of formula I, formula II-a to II-k, formula III, formula IV-a to IV-j, formula V, formula VI, formula VII-a to VII-e, formula VIII-a to VIII-I, formula IX-a to IX-j, formula Xa to Xi, formula XI-a to XI-I, formula XII, formula XHI-a to XIII-I and formula XIV activate, reduce or alter the native activity of cereblon. These compounds of formula I, formula II-a to II-k, formula III, formula IV-a to IV-j, formula V, formula VI, formula VII-a to VII-e, formula VIII-a to VIII-I, formula IX-a to IX-j, formula Xa to Xi, formula XI-a to XI-I, formula XII, formula XHI-a to XIII-I and formula XIV, when administered to a host, typically a human, in an effective amount, are useful as therapeutic agents for the treatment of medical conditions, including but not limited to abnormal cell proliferation, including tumors or cancers; or myeloproliferative or lymphoproliferative disorders such as B cell or T cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome, or post-transplant lymphoproliferative disorder; immune diseases, including autoimmune diseases, such as Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus or type I diabetes; heart dysfunction diseases, including hypercholesterolemia; infectious diseases, including viral or bacterial infections; inflammatory diseases including asthma, chronic peptic ulcer, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, crohn's disease or hepatitis; or any disease that can be treated with thalidomide, pomalidomide or lenalidomide.
In certain embodiments, the invention provides methods of treating a patient, e.g., a human, suffering from an infectious disease by administering an effective amount of a compound of formula I, formula II-a to II-k, formula III, formula IV-a to IV-j, formula V, formula VI, formula VII-a to VII-E, formula VIII-a to VIII-I, formula IX-a to IX-j, formula Xa to Xi, formula XI-a to XI-I, formula XII, formula XHI-a to XIII-I, and formula XIV, wherein the treatment is by acting in conjunction with cereblon or its E3 ubiquitin ligase or by an independent mechanism, optionally in combination with another bioactive agent. The disease state or condition may be caused by a microbial agent or other exogenous agent such as a virus (as non-limiting examples, HIV, HBV, HCV, HSV, HPV, RSV, CMV, ebola virus, flavivirus, pestivirus, rotavirus, influenza, coronavirus, EBV, viral pneumonia, drug resistant virus, avian influenza, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, or hepatitis virus), bacteria (including but not limited to gram negative, gram positive, atypical, staphylococci, streptococcus, escherichia coli, salmonella, helicobacter pylori, meningitis, gonorrhea, chlamydiaceae, mycoplasma, etc.), fungus, protozoa, parasitic helminth (helminth), helminth (work), prion, parasite, or other microorganism.
In another aspect, the disclosed compounds are useful as synthetic intermediates for the preparation of bifunctional compounds that cause degradation of selected proteins via the Ubiquitin Proteasome Pathway (UPP). These compounds contain functional groups that are reactive with a second compound that is capable of binding to the selected protein of interest to produce a bifunctional compound as described above that can cause degradation of the selected protein by UPP.
Accordingly, there is provided a compound of formula XIV (1), or a pharmaceutically acceptable salt thereof, useful for preparing bifunctional compounds which cause degradation of a selected protein by UPP:
wherein:
ABselected from optionally substituted by one or two R2Arylene substituted with radicals, optionally substituted with one or two R3Heteroarylene substituted with radicals, optionally substituted with one or two R4Radical-substituted heterocycloalkylene, -NH-C (═ O) -C1-6Alkylene-and cycloalkylene groups;
"Tail (Tail)" is a chemical moiety comprising a reactive functional group that can be covalently bound to a protein-binding moiety to produce a targeted protein-degrading agent, or
"tail" is a chemical moiety that can be used to alter the properties of a compound, such as hydrophobicity, hydrophilicity, solubility, drug delivery, pharmacokinetics, or other properties, such as charge, polarity, or complexation within an active pocket;
in one embodiment, "tail" is
X1Selected from the group consisting of a bond, NR34、CH2、CHR34、C(R34)2O and S;
X22is a functional group that can serve as a linking group to a protein-binding moiety; or X22Is a capping valency group and is generally not a linking group; x22Representative examples of (A) include, but are not limited to, halogen, -NH2、-NHR34、-N(R34)2Hydroxy, thiol, -B (OH)2、-Sn(R36)3、-Si(R36)3、-OS(O)2Alkyl, -OS (O)2Haloalkyl, alkenyl, alkynyl, ethynyl, ethenyl, -C (O) H, -NR34C (O) olefin, -NR34C (O) alkyne, cyano, -SC (O) alkyl, OC (O) alkyl, heterocycle, -C (O) OH, hydrogen, alkyl, aryl, heteroaryl, aliphatic, heteroaliphatic, and carbocyclic;
R34and R34’Independently at each occurrence is selected from: hydrogen, C1-C6Alkyl (e.g. methyl, ethyl, cyclopropyl or C)1-C3Alkyl group), C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C3-C6Heterocyclic, aryl, heteroaryl, - (CO) R36、-(CS)R36、-(C＝NH)R36、-(SO)R36And- (SO)2)R36；
R36Independently at each occurrence is selected from: hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C3-C6Heterocycle, aryl, heteroaryl, hydroxy, C1-C6Alkoxy, thio, C1-C6Thioalkyl, -NH2、-NH(C1-C6Alkyl radical, C3-C7Cycloalkyl radical, C3-C7Heterocycle, aryl or heteroaryl) and-N (independently C)1-C6Alkyl radical, C3-C7Cycloalkyl radical, C3-C7Heterocyclic, aryl or heteroaryl radicals)2；
R20、R21、R22、R23And R24Independently a divalent or polyvalent linking group including, but not limited to, a covalent bond, alkyl, -C (O) -, -C (O) O-, -OC (O) -, -C (O) alkyl, -C (O) Oalkyl, -C (S) -, -SO2-, -S (O) -, -C (S) -, -C (O) NH-, -NHC (O) -, -N (alkyl) C (O) -, -C (O) N (alkyl) -, -O-, -S-, -NH-, -N (alkyl) -, -CH (-O-R)26)-、-CH(-NR34R34')-、-C(-O-R26) Alkyl-, -C (-NR)34R34') Alkyl-, -C (R)40R40) -, -alkyl (R)27) -alkyl (R)28)-、-C(R27R28)-、-P(O)(OR26)O-、-P(O)(OR26)-、-NR34C(O)NR34’-, alkenes, haloalkyl, alkoxy, alkynylheteroarylalkyl, aryl, arylalkyl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, carbocycle, - (ethylene glycol)1-6-, - (lactic acid-co-glycolic acid)1-6-, - (propylene glycol)1-6-、-O-(CH2)1-12-O-、-NH-(CH2)1-12-NH-、-NH-(CH2)1-12-O-、-O-(CH2)1-12-NH-、-S-(CH2)1-12-O-、-O-(CH2)1-12-S-、-S-(CH2)1-12-S-、-S-(CH2)1-12-NH-and-NH- (CH)2)1-12-S-, wherein 1-6 may independently be 1,2,3,4, 5 or 6, wherein 1-12 may independently be 1,2,3,4, 5, 6,7, 8, 9,10, 11 or 12, wherein one or more CH are2Or the NH group may be substituted by H for methyl, ethyl,Cyclopropyl, F (if on carbon), etc., as described herein, and optionally, a heteroatom, heteroalkyl, aryl, heteroaryl, or cycloaliphatic group interspersed in the chain. Some non-limiting examples include-O-CH (CH)3)-CH(CH3)CH-O-、-O-CH2-CH(CH3)CH-O-、-O-CH(CH3)-CH2CH-O-, and the like.
Wherein each R20、R21、R22、R23And R24Optionally substituted by one or more groups selected from R101Or as defined in the definitions section; wherein R is20、R21、R22、R23And R24Is not a bond;
R101independently at each occurrence is selected from: hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, hydroxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -COOalkyl, COOH, NO2、F、Cl、Br、I、CF3、NH2NH alkyl, N (alkyl)2Aliphatic and heteroaliphatic;
R26selected from the group consisting of hydrogen, alkyl, silane, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, aliphatic, and heteroaliphatic;
R27and R28Independently selected from hydrogen, alkyl, amine, or together with the carbon atom to which they are attached form C (O), C (S), C ═ CH2、C3-C6A spiro carbocyclic ring or a 4-, 5-or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O, or forming a1 or 2 carbon bridged ring;
R40in each case selected from: hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, azido, amino, cyano, -NH (aliphatic, including alkyl), -N (aliphatic, including alkyl)2、-NHSO2(aliphatic, including alkyl), -N (aliphatic, including alkyl) SO2Alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N (alkyl) SO2(aryl, heteroaryl or heterocycle) -NHSO2Alkenyl, -N (alkyl) SO2Alkenyl, -NHSO2Alkynyl, -N (alkyl) SO2Alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, heterocyclic, and carbocyclic; and
all other variables are as defined herein.
In another aspect, there are provided novel compounds comprising compounds of formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae X-a to X-I, formulae XI-a to XI-I, formula XII and formulae XIII-a to XIII-I, wherein one free hydrogen on the molecule has been replaced by a "tail" group as defined herein. Thus, also provided are novel compounds of formula I (1), formula II (1) -a to II (1) -k, formula III (1), formula IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formula VII (1) -a to VII (1) -e, formula VIII (1) -a to VIII (1) -I, formula IX (1) -a to IX (1) -j, formula X (1) -a to X (1) -I, formula XI (1) -a to XI (1) -I, formula XII (1) and formula XIII (1) -a to XIII (1) -I.
In one aspect, there is provided a compound of formula I (1)
Wherein all variables are as defined herein.
In one aspect, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one aspect, compounds of formula III (1) are provided:
wherein all variables are as defined herein.
In one aspect, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one aspect, compounds of formula V (1) are provided:
wherein all variables are as defined herein.
In one aspect, compounds of formula VI (1) are provided:
wherein all variables are as defined herein.
In one aspect, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one aspect, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one aspect, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one aspect, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one aspect, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one aspect, compounds of formula XII (1) are provided:
wherein all variables are as defined herein.
In one aspect, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In a first aspect, the invention provides a compound of formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae I-a to XIII, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae IV-1) -j, formulae X (1) -a to X (1) -I, formula IV-j, formula V-I, formula V-b, Compounds of the formulae XI (1) -a to XI (1) -i, XII (1), XIII (1) -a to XIII (1) -i or XIV (1) are useful as therapeutically active substances.
In another aspect, the invention provides a pharmaceutical composition comprising formula I, formula II-a to II-k, formula III, formula IV-a to IV-j, formula V, formula VI, formula VII-a to VII-e, formula VIII-a to VIII-I, formula IX-a to IX-j, formula Xa to Xi, formula XI-a to XI-I, formula XII, formula XIII-a to XIII-I, formula XIV, formula I (1), formula II (1) -a to II (1) -k, formula III (1), formula IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formula VII (1) -a to VII (1) -e, formula VIII (1) -a to VIII (1) -I, formula IX (1) -a to IX (1) -j, formula IV-j, formula VI-a to VI, formula VI-a to VII (1) -e, formula VIII (1) a to VII (1) -I), and a pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof, as defined herein, A compound of formula X (1) -a to X (1) -i, formula XI (1) -a to XI (1) -i, formula XII (1), formula XIII (1) -a to XIII (1) -i or formula XIV (1) and a therapeutically inert carrier.
In certain embodiments, formula I, formulae II-a through II-k, formula III, formulae IV-a through IV-j, formula V, formula VI, formulae VII-a through VII-e, formulae VIII-a through VIII-I, formulae IX-a through IX-j, formulae Xa through Xi, formulae XI-a through XI-I, formula XII, formulae XIII-a through XIII-I, formula XIV, formula I (1), formulae II (1) -a through II (1) -k, formula III (1), formulae IV (1) -a through IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a through VII (1) -e, formulae VIII (1) -a through VIII (1) -I, formulae IX (1) -a through IX (1) -j, formulae X (1) -a through X (1) -I, formulae IV-j, formulae V (1) -a through X (1) -I, and mixtures thereof, Compounds of formula XI (1) -a to XI (1) -i, formula XII (1), formula XIII (1) -a to XIII (1) -i or formula XIV (1) have at least one desired isotopic substitution of atoms in amounts higher than the natural abundance of that isotope, i.e. enriched. In one embodiment, formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae IV-j, formulae V (1) -a to X (1) -I, Compounds of formula XI (1) -a to XI (1) -i, formula XII (1), formula XIII (1) -a to XIII (1) -i or formula XIV (1) include one or more deuterium atoms.
Other features and advantages of the application will be apparent from the following detailed description and claims.
The invention therefore comprises at least the following features:
a) formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae XI (1) -a to XI (1) -I, formulae VI (1) -a to XI (1) -I, A compound of formula XII (1), formula XIII (1) -a to XIII (1) -i, or a pharmaceutically acceptable salt thereof;
b) formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae XI (1) -a to XI (1) -I, formulae VI (1) -a to XI (1) -I, Use of a compound of formula XII (1), XIII (1) -a to XIII (1) -i or XIV (1), or a pharmaceutically acceptable salt thereof, in an effective amount to treat a patient, typically a human, suffering from a condition responsive to such treatment, comprising modulating cereblon-based ubiquitination of the protein, e.g. abnormal cell proliferation, such as a tumor or cancer; immune or autoimmune or inflammatory diseases, heart diseases, infectious diseases or other diseases responsive to the treatment;
c) formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae XI (1) -a to XI (1) -I, formulae VI (1) -a to XI (1) -I, Use of a compound of formula XII (1), formula XIII (1) -a to XIII (1) -i, or formula XIV (1), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a medical condition, as further described herein;
d) a process for the preparation of a medicament for the therapeutic treatment of a disorder in a host, characterized in that a compound of formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formula IX (1) -j, Compounds of the formulae X (1) -a to X (1) -i, XI (1) -a to XI (1) -i, XII (1), XIII (1) -a to XIII (1) -i or XIV (1) are used for this preparation;
e) formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae XI (1) -a to XI (1) -I, formulae VI (1) -a to XI (1) -I, A compound of formula XII (1), formula XIII (1) -a to XIII (1) -i, or formula XIV (1), or a pharmaceutically acceptable salt thereof, which is useful for treating abnormal cell proliferation, e.g., cancer, in a host, including any cancer described herein;
f) formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae XI (1) -a to XI (1) -I, formulae VI (1) -a to XI (1) -I, Use of a compound of formula XII (1), formula XIII (1) -a to XIII (1) -i, or formula XIV (1), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of abnormal cell proliferation, such as cancer, including any cancer described herein;
g) a method of preparing a medicament for therapeutic use in treating abnormal cell proliferation, e.g. cancer (including any cancer described herein), in a host, characterised by formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formula VIII (1) -a to VIII (1) -I, Compounds of the formulae IX (1) -a to IX (1) -j, X (1) -a to X (1) -i, formulae XI (1) -a to XI (1) -i, formula XII (1), formulae XIII (1) -a to XIII (1) -i or formula XIV (1) are used for this preparation;
h) formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae XI (1) -a to XI (1) -I, formulae VI (1) -a to XI (1) -I, A compound of formula XII (1), XIII (1) -a to XIII (1) -i, or XIV (1), or a pharmaceutically acceptable salt thereof, useful for treating a tumor in a host, including any tumor described herein;
i) formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae XI (1) -a to XI (1) -I, formulae VI (1) -a to XI (1) -I, Use of a compound of formula XII (1), formula XIII (1) -a to XIII (1) -i, or formula XIV (1), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a tumor in a host, including any tumor described herein;
j) a method of preparing a medicament for therapeutic use in the treatment of a tumour in a host, including any tumour described herein, characterised in that formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XIII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formula I, Compounds of the formulae IX (1) -a to IX (1) -j, X (1) -a to X (1) -i, formulae XI (1) -a to XI (1) -i, formula XII (1), formulae XIII (1) -a to XIII (1) -i or formula XIV (1) are used for this preparation;
k) formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae XI (1) -a to XI (1) -I, formulae VI (1) -a to XI (1) -I, A compound of formula XII (1), formula XIII (1) -a to XIII (1) -i, or formula XIV (1), or a pharmaceutically acceptable salt thereof, useful for treating an immune, autoimmune, or inflammatory disease in a host;
l) formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae XI (1) -a to XI (1) -I, Use of a compound of formula XII (1), XIII (1) -a to XIII (1) -i or XIV (1), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an immune, autoimmune or inflammatory disease in a host;
m) A process for the preparation of a medicament for therapeutic use in the treatment of an immune, autoimmune or inflammatory disease in a host, characterized in that formula I, formula II-a to II-k, formula III, formula IV-a to IV-j, formula V, formula VI, formula VII-a to VII-e, formula VIII-a to VIII-I, formula IX-a to IX-j, formula Xa to Xi, formula XI-a to XI-I, formula XII, formula XIII-a to XIII-I, formula XIV, formula I (1), formula II (1) -a to II (1) -k, formula III (1), formula IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formula VII (1) -a to VII (1) -e, formula VIII (1) -a to VIII (1) -I, formula IX (1) -a to IX (1) -j, formula IX (1) -j, Compounds of the formulae X (1) -a to X (1) -i, XI (1) -a to XI (1) -i, XII (1), XIII (1) -a to XIII (1) -i or XIV (1) are used for this preparation;
n) a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formula IV-j, A compound of formula XI (1) -a to XI (1) -i, formula XII (1), formula XIII (1) -a to XIII (1) -i, or formula XIV (1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent;
o) formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formula I, formula IV-j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I), formulae IX (1) -a to IX (1) -j, and, Compounds of formula X (1) -a to X (1) -i, formula XI (1) -a to XI (1) -i, formula XII (1), formula XIII (1) -a to XIII (1) -i, or formula XIV (1), including isolated enantiomers or diastereomers (i.e., greater than 85%, 90%, 95%, 97%, or 99% pure);
p) preparation of a composition comprising an effective amount of a compound of formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formula IV-j, A method of treatment of a compound of formula XI (1) -a to XI (1) -i, formula XII (1), formula XIII (1) -a to XIII (1) -i or formula XIV (1), or a pharmaceutically acceptable salt thereof; and
q) a process for the preparation of a bifunctional compound which causes the degradation of a selected protein by the ubiquitin proteasome pathway, characterized in that a compound of formula I, formula II-a to II-k, formula III, formula IV-a to IV-j, formula V, formula VI, formula VII-a to VII-e, formula VIII-a to VIII-I, formula IX-a to IX-j, formula Xa to Xi, formula XI-a to XI-I, formula XII, formula XIII-a to XIII, formula XIV, formula I (1), formula II (1) -a to II (1) -k, formula III (1), formula IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formula VII (1) -a to VII (1) -e, formula VIII (1) -a to VIII (1) -I, formula IX (1) -a to IX (1) -j, Compounds of formula X (1) -a to X (1) -i, formula XI (1) -a to XI (1) -i, formula XII (1), formula XIII (1) -a to XIII (1) -i or formula XIV (1) are useful for preparing the bifunctional compounds.
Detailed Description
I. Definition of
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In the specification, the singular forms also include the plural forms unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed application. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The compounds of any formula described herein can be in the form of racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides, isomers, such as rotamers, unless specifically described to the exclusion of each by context.
The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" means "and/or". Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are inclusive of the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.
The compounds of the present invention may form solvates with solvents, including water. Thus, in one non-limiting embodiment, the present invention includes solvated forms of the compounds. The term "solvate" refers to a molecular complex of a compound of the invention (including salts thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the present invention and water. Pharmaceutically acceptable solvates according to the invention include those solvates in which the solvent may be isotopically substituted, for example D2O、d6-acetone, d6-DMSO. The solvate may be in liquid or solid form.
A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, - (C ═ O) NH2Attached through the carbon of the carbonyl (C ═ O).
The following definitions of general terms used in this specification apply regardless of whether the terms in question appear alone or in combination with other groups.
Unless otherwise indicated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.
The term "C1-6Alkyl ", alone or in combination with other groups, represents a hydrocarbon group which may be linear or branched, with a single branch or multiple branches, wherein alkyl generally comprises from 1 to 6 carbon atoms, such as methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl (tert-butyl), isopentyl, 2-ethyl-propyl (2-methyl-propyl), 1, 2-dimethyl-propyl, and the like. A specific groupIs methyl.
The term "halogen-C1-6-alkyl ", alone or in combination with other groups, means C as defined herein1-6-alkyl substituted by one or more halogens, in particular from 1 to 5 halogens, more in particular from 1 to 3 halogens. A particular halogen is fluorine. Particular "halogen-C1-6-alkyl "is fluoro-C1-6Alkyl, and in particular "halogen-C1-3-alkyl "is fluoro-C1-3-an alkyl group. Examples are trifluoromethyl, difluoromethyl, fluoromethyl and the like.
In one embodiment, "halogen-C1-6Alkyl "has one carbon.
In one embodiment, "halogen-C1-6Alkyl "has one carbon and one halogen.
In one embodiment, "halogen-C1-6Alkyl "has one carbon and two halogens.
In one embodiment, "halogen-C1-6Alkyl "has one carbon and three halogens.
In one embodiment, "halogen-C1-6Alkyl "has two carbons.
In one embodiment, "halogen-C1-6Alkyl "has three carbons.
In one embodiment, "halogen-C1-6-alkyl "has four carbons.
In one embodiment, "halogen-C1-6Alkyl "has five carbons.
In one embodiment, "halogen-C1-6Alkyl "has six carbons.
"halogen-C1-6Non-limiting examples of-alkyl "include:
"halogen-C1-6Other non-limiting examples of-alkyl "include:
"halogen-C1-6Other non-limiting examples of-alkyl "include:
"halogen-C1-6Other non-limiting examples of-alkyl "include:
the term "hydroxy-C1-6-alkyl ", alone or in combination with other groups, means C as defined herein1-6-alkyl substituted by one or more hydroxyl groups, in particular by 1 hydroxyl group. Examples are-CH2OH、-CH2CH2OH and the like.
The term "cycloalkyl" denotes a monovalent saturated monocyclic or bicyclic hydrocarbon radical of 3 to 10 ring carbon atoms, in particular a monovalent saturated monocyclic hydrocarbon radical of 3 to 8 ring carbon atoms. Bicyclic means consisting of two carbocyclic rings having one or more carbon atoms in common, one of which is saturated and the other may be aromatic. Particular cycloalkyl groups are monocyclic. An example of a monocyclic cycloalkyl group is "C3-7Cycloalkyl radicals ", for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. An example of a saturated bicyclic cycloalkyl is bicyclo [2.2.1 ]]Heptyl or bicyclo [2.2.2]And (4) octyl. Examples of bicyclic cycloalkyl wherein one ring is aromatic are 1H-indenyl or 1,2,3, 4-tetrahydronaphthyl.
The term "hydroxy", alone or in combination with other groups, refers to OH.
The term "Bz" represents benzyl (i.e. phenyl-CH)2-)。
The term "halogen", alone or in combination with other groups, denotes chlorine (Cl), iodine (I), fluorine (F) and bromine (Br). A particular group is F.
The term "heteroaryl" denotes a monovalent heterocyclic monocyclic or bicyclic ring system of 5 to 12 ring atoms, comprising 1,2,3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon, wherein at least one ring is aromatic. Examples of heteroaryl moieties include: pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, aza-phenylRadical diazaA group selected from the group consisting of an isoxazolyl, a benzofuranyl, an isothiazolyl, a benzothiophenyl, an indolinyl, an indolyl, an isoindolyl, an isobenzofuranyl, a benzimidazolyl, a benzoxazolyl, a benzisoxazolyl, a benzothiazolyl, a benzisothiazolyl, a benzooxadiazolyl, a benzothiadiazolyl, a benzotriazolyl, a purinyl, a quinolyl, an isoquinolyl, a quinazolinyl, a quinoxalinyl, and a 2, 3-dihydropyrrolo [2,3-b ]]A pyridyl group. Specific examples include benzimidazolyl, pyridyl, thiazolyl, indolinyl, 1,2,3, 4-tetrahydroquinolinyl, 3, 4-dihydroquinolinyl, benzofuranyl, furanyl, imidazolyl, isoindolyl, and quinolinyl.
In one embodiment, "heteroaryl" is a 5-membered aromatic group containing 1,2,3, or 4 nitrogen atoms.
Non-limiting examples of 5-membered "heteroaryl" include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.
Other non-limiting examples of 5-membered "heteroaryl" groups include:
in one embodiment, "heteroaryl" is a 6-membered aromatic group containing 1,2, or 3 nitrogen atoms (i.e., pyridyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).
Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include:
in one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.
Non-limiting examples of bicyclic "heteroaryl" groups include: indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole and benzothiazole.
Other non-limiting examples of bicyclic "heteroaryl" include:
other non-limiting examples of bicyclic "heteroaryl" groups include:
other non-limiting examples of bicyclic "heteroaryl" include:
in one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.
Non-limiting examples of bicyclic "heteroaryl" include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline and naphthyridine.
Other non-limiting examples of bicyclic "heteroaryl" include:
in another embodiment, "heteroaryl" is optionally substituted with 1,2,3, or 4 substituents.
The term "heterocycloalkyl" denotes a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 9 ring atoms, comprising 1,2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of monocyclic saturated heterocycloalkyl are azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl. Examples of bicyclic saturated heterocycloalkyl are 8-aza-bicyclo [3.2.1] octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo [3.2.1] octyl, 9-aza-bicyclo [3.3.1] nonyl, 3-oxa-9-aza-bicyclo [3.3.1] nonyl or 3-thia-9-aza-bicyclo [3.3.1] nonyl. Examples of partially unsaturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, dihydrooxazolyl, tetrahydropyridinyl or dihydropyranyl. Specific examples include piperazinyl, piperidinyl, pyrrolidinyl and 3, 8-diazabicyclo [3.2.1] octyl.
In one embodiment, "heterocycloalkyl" refers to a ring having one nitrogen and 3,4, 5, 6,7, or 8 carbon atoms.
In one embodiment, "heterocycloalkyl" refers to a ring having one nitrogen and one oxygen and 3,4, 5, 6,7, or 8 carbon atoms.
In one embodiment, "heterocycloalkyl" refers to a ring having two nitrogens and 3,4, 5, 6,7, or 8 carbon atoms.
In one embodiment, "heterocycloalkyl" refers to a ring having one oxygen and 3,4, 5, 6,7, or 8 carbon atoms.
In one embodiment, "heterocycloalkyl" refers to a ring having one sulfur and 3,4, 5, 6,7, or 8 carbon atoms.
Non-limiting examples of "heterocycloalkyl" include aziridine, oxetane, thietane, azetidine, 1, 3-diazetidine, oxetane and thietane.
Other non-limiting examples of "heterocycloalkyl" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.
Other non-limiting examples of "heterocycloalkyl" include tetrahydrofuran, 1, 3-dioxolane, tetrahydrothiophene, 1, 2-oxathiolane, and 1, 3-oxathiolane.
Other non-limiting examples of "heterocycloalkyl" include piperidine, piperazine, tetrahydropyran, 1, 4-dioxane, thiane, 1, 3-dithiane, 1, 4-dithiane, morpholine, and thiomorpholine.
Other non-limiting examples of "heterocycloalkyl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the point of attachment of each group is on the heterocycle.
For example,is a heterocycloalkyl group.
However,is an aryl group.
Non-limiting examples of "heterocycloalkyl" also include:
other non-limiting examples of "heterocycloalkyl" include:
other non-limiting examples of "heterocycloalkyl" include:
non-limiting examples of "heterocycloalkyl" also include:
non-limiting examples of "heterocycloalkyl" also include:
other non-limiting examples of "heterocycloalkyl" include:
other non-limiting examples of "heterocycloalkyl" include:
in another embodiment, "heterocycloalkyl" is optionally substituted with 1,2,3, or 4 substituents.
The term "C1-6-alkoxy ", alone or in combination with other groups, represents-O-C1-6Alkyl, which may be linear or branchedHaving a single branch or multiple branches, wherein the alkyl group typically contains 1 to 6 carbon atoms, such as methoxy (OMe, MeO), ethoxy (OEt), propoxy, isopropoxy (i-propoxy), n-butoxy, i-butoxy (isobutoxy), 2-butoxy (sec-butoxy), t-butoxy (tert-butoxy), isopentyloxy (i-pentyloxy), and the like. In particular "C1-6-alkoxy "is a group having 1 to 4 carbon atoms. A specific group is methoxy.
The term "aryl" denotes a monovalent aromatic carbocyclic mono-or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl (Ph) and naphthyl. A specific "aryl" group is phenyl.
In one embodiment, "aryl" is a 6 carbon aromatic group (phenyl).
In one embodiment, "aryl" is a 10 carbon aromatic group (naphthyl).
In one embodiment, "aryl" is a 6-carbon aromatic group fused to a heterocycle, wherein the point of attachment is an aromatic ring. Non-limiting examples of "aryl" groups include indolines, tetrahydroquinolines, tetrahydroisoquinolines, and dihydrobenzofurans, where the point of attachment of each group is on an aromatic ring.
For example,is an "aryl" group.
However,is a "heterocycloalkyl" group.
In one embodiment, "aryl" is a 6-carbon aromatic group fused to a cycloalkyl group, wherein the point of attachment is an aromatic ring. Non-limiting examples of "aryl" groups include indanes and tetralins, where the point of attachment for each group is on an aromatic ring.
For example,is an "aryl" group.
However,is a "cycloalkyl" group.
In another embodiment, "aryl" is optionally substituted with 1,2,3, or 4 substituents.
The term "optionally substituted" means that the groups herein are included but not limited to C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, C3-C12Cycloalkyl radical, C3-C12Cycloalkenyl radical, C1-C12Heterocycloalkyl radical, C3-C12Heterocycloalkenyl, C1-C10Alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C10Alkylamino radical, C1-C10Dialkylamino, arylamino, diarylamino, C1-C10Alkylsulfonamido, arylsulfonamido, C1-C10Alkylimino, arylimino, C1-C10Alkylsulfonamido, arylsulfonamido, hydroxy, halogen, thio, C1-C10Alkylthio, arylthio, C1-C10Alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminosulfuryl, amidino, guanidino, ureido, cyano, nitro, azido, acyl, sulfuryl, acyloxy, carboxyl and partial substitution of carboxylic esters.
In another embodiment, any suitable group may be present in a "substituted" or "optionally substituted" position and include, but is not limited to, for example, a halogen (which may independently be F, Cl, Br, or I); a cyano group; a hydroxyl group; a nitro group; an azide group; alkanoyl (e.g. C)2-C6Alkanoyl); formamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl groups including those having one or more thioether linkages; an alkylsulfinyl group; alkylsulfonyl including those having one or more sulfonyl linkages; aminoalkyl radicals includingGroups having more than one N atom; aryl (e.g., phenyl, biphenyl, naphthyl, and the like, each ring substituted or unsubstituted); aralkyl groups having, for example, 1 to 3 separate or fused rings and 6 to about 14 or 18 ring carbon atoms, with benzyl being an exemplary aralkyl group; arylalkoxy, e.g., having 1 to 3 separate or fused rings, with benzyloxy being an exemplary arylalkoxy; or a saturated or partially unsaturated heterocyclic ring having 1 to 3 separate or fused rings and one or more N, O or S atoms, or a heteroaryl group having 1 to 3 separate or fused rings and one or more N, O or S atoms, such as coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl. These groups may be further substituted with, for example, hydroxyl, alkyl, alkoxy, halogen, and amino. In certain embodiments, "optionally substituted" includes one or more groups independently selected from halogen, hydroxy, amino, cyano, -CHO, -COOH, -CONH2Comprising C1-C6Alkyl of alkyl, including C2-C6Alkenyl of alkenyl, including C2-C6Alkynyl of alkynyl, -C1-C6Alkoxy radicals, including C2-C6Alkanoyl of alkanoyl, C1-C6Alkyl esters, (mono-and di-C)1-C6Alkylamino) C0-C2Alkyl radical, including C1-C6Haloalkyl of haloalkyl, hydroxy C1-C6Alkyl, ester, carbamate, urea, sulfonamide, -C1-C6Alkyl (heterocyclic), C1-C6Alkyl (heteroaryl), -C1-C6Alkyl radical (C)3-C7Cycloalkyl), O-C1-C6Alkyl radical (C)3-C7Cycloalkyl), B (OH)2Phosphoric acid esters, phosphonic acid esters and compositions comprising C1-C6Haloalkoxy of haloalkoxy. In some embodiments, there is a "substitutionSuitable groups on "or" optionally substituted "are divalent, including but not limited to oxo (═ O), ═ S, ═ CH2And the like. Suitable groups at the "substituted" or "optionally substituted" position can be monovalent, divalent, or trivalent, thereby forming a stable molecule and meeting the desired objectives of the invention.
In one embodiment, a group described herein that may be substituted with 1,2,3, or 4 substituents is substituted with one substituent.
In one embodiment, a group described herein that may be substituted with 1,2,3, or 4 substituents is substituted with two substituents.
In one embodiment, a group described herein that may be substituted with 1,2,3, or 4 substituents is substituted with three substituents.
In one embodiment, a group described herein that may be substituted with 1,2,3, or 4 substituents is substituted with four substituents.
Terms such as "a-b-x substituted with R" refer to the moiety "x" being substituted with R. For example, "by R10Substituted- (CH)2)0-1By aryl is meant that the "aryl" part of the moiety is covered by R10Substitution; ' by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl "means that the" aryl "portion of the moiety is covered by R10Substitution; ' by R9Substituted- (CH)2)0-1By heteroaryl is meant that the "heteroaryl" part of the moiety is covered by R9Substitution; ' by R10substituted-CH2-O-(CH2)0-1By aryl is meant that the "aryl" part of the moiety is covered by R10And (4) substitution.
The term "pharmaceutically acceptable" refers to the properties of a material that can be used to prepare a pharmaceutical composition, which material is generally safe, not unacceptably toxic, and neither biologically nor otherwise undesirable. In one aspect, the material is acceptable for veterinary as well as human pharmaceutical use.
The term "pharmaceutically acceptable salt" refers to salts suitable for use in contact with the tissues of humans and animals. Examples of suitable salts formed with inorganic and organic acids include, but are not limited to, acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, succinic acid, sulfuric acid (sulfuric acid), tartaric acid, trifluoroacetic acid, and the like. Specific acids are formic acid, trifluoroacetic acid and hydrochloric acid. Specific acids are hydrochloric acid, trifluoroacetic acid and fumaric acid.
Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; an alkali metal or organic salt of an acidic residue such as a carboxylic acid. Pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids, for example acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC- (CH) where n is 0 to 42)nCOOH, etc., or use of different acids that yield the same counter ion. Other suitable salt lists can be found, for example, in Remington's Pharmaceutical Sciences, 17 th edition, Mack Publishing Company, Easton, PA, p.1418 (1985).
The term "pharmaceutically acceptable auxiliary substances" refers to carriers and auxiliary substances, such as diluents or excipients, that are compatible with the other ingredients of the formulation.
A "therapeutically effective amount", when administered to a subject to treat a disease state, will vary depending on the compound, the disease state being treated, the severity or disease of the treatment, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.
The terms "as defined herein" and "as described herein" when referring to a variable are incorporated by reference into the broad definition of the variable as well as the specific, more specific and most specific definitions (if any).
The terms "treating," "contacting," and "reacting," when referring to a chemical reaction, refer to the addition or mixing of two or more reagents under suitable conditions to produce a specified and/or desired product. It will be appreciated that the reaction which produces the specified and/or desired product does not necessarily result directly from the combination of the two reagents initially added, i.e., one or more intermediates may be produced in the mixture which ultimately results in the formation of the specified and/or desired product.
The term "aroma" denotes the conventional concept of aromaticity as defined in the literature, in particular in IUPAC-Complex of Chemical technology, 2 nd edition, A.D.McNaught & A.Wilkinson (Eds.). Blackwell Scientific Publications, Oxford (1997).
The term "pharmaceutically acceptable excipient" means any ingredient that is not therapeutically active and is non-toxic, such as disintegrants, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products.
All individual embodiments may be combined.
As used herein, the term "treating" includes: (1) inhibiting a condition, disease, or disorder (e.g., arresting, reducing, or delaying the progression of a disease, or the recurrence of at least one clinical or subclinical symptom in the context of maintenance therapy); and/or (2) relieving the condition (i.e., causing regression of the condition, disease or disorder, or at least one clinical or subclinical symptom thereof). However, it is understood that when a drug is administered to a patient to treat a disease, the results may not always be an effective treatment.
As used herein, the term "preventing" includes: preventing or delaying the onset of clinical symptoms of a condition, disease or disorder that develops in a mammal, particularly a human, who may be suffering from or susceptible to the condition, disease or disorder but does not experience or exhibit clinical or subclinical symptoms of the condition, disease or disorder.
Isotopic substitution
The invention includes formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formula, Compounds of formula XI (1) -a to XI (1) -i, formula XII (1), formula XIII (1) -a to XIII (1) -i or formula XIV (1) having at least one desired isotopic substitution of the atoms in an amount higher than the natural abundance of the isotope, i.e. enriched. Isotopes are atoms of the same atomic number but different mass numbers, i.e. atoms of the same proton number but different neutron numbers.
Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine and iodine, for example2H、3H、11C、13C、14C、15N、17O、18O、18F、35S、36Cl and125I. in one non-limiting embodiment, isotopically labeled compounds can be used for metabolic studies (e.g., with14C) Reaction kinetics study (e.g. with2H or3H) Detection or imaging techniques such as Positron Emission Tomography (PET), or single-photon emission computed tomography (SPECT) include drug or stromal tissue distribution analysis, or for radiotherapy of a patient. In particular, it is possible to use, for example,18f-labelled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
Isotopic substitution, for example deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. In certain embodiments, the isotope is enriched in 90%, 95%, or 99% or more of the isotope at any location of interest. In one non-limiting embodiment, deuterium is enriched at the desired position by 90%, 95%, or 99%.
In one non-limiting embodiment, there may be provided compounds of formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae IV-j, formulae X (1) -a to X (1) -I, Replacement of deuterium atoms is provided in any of the compounds of formula XI (1) -a to XI (1) -i, formula XII (1), formula XIII (1) -a to XIII (1) -i or formula XIV (1). In one non-limiting embodiment, the replacement of a hydrogen atom by a deuterium atom occurs within one or more groups selected from the variables described herein. For example, when any group is or contains, e.g., by substitution, a methyl, ethyl or methoxy group, the alkyl residue may be deuterated (in a non-limiting embodiment, CDH2、CD2H、CD3、CH2CD3、CD2CD3、CHDCH2D、CHDCHD2、OCDH2、OCD2H or OCD3Etc.). In certain other embodiments, when two substitutions are combined to form a ring, the unsubstituted carbon may be deuterated.
Compounds of the invention
The invention provides compounds of formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formula, Compounds of formulae XI (1) -a to XI (1) -i, formula XII (1), formula XIII (1) -a to XIII (1) -i, and pharmaceutically acceptable salts thereof. The invention also provides the use of a compound of formula XIV or formula XIV (1) as further described herein.
Embodiments of formulas I-XIII
In one embodiment, compounds of formula I are provided:
wherein all variables are as defined herein.
In one embodiment, provided compounds of formula I are selected from:
wherein all variables are as defined herein.
In one embodiment, provided compounds of formula I are selected from:
wherein all variables are as defined herein.
In one embodiment of the process of formula I,selected from:
in one embodiment, compounds of formula II-a and formula II-b are provided:
wherein all variables are as defined herein.
In one embodiment, compounds of formula II-c and formula II-d are provided:
wherein all variables are as defined herein.
In one embodiment, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In any of the embodiments of formulas II-a through II-k,selected from:
in one embodiment, compounds having formula III are provided:
wherein all variables are as defined herein.
In one embodiment, the compound of formula III is selected from:
wherein all variables are as defined herein.
In one embodiment, the compound of formula III is selected from:
wherein all variables are as defined herein.
In one embodiment of the process of formula III,selected from:
in one embodiment, compounds of formula IV-a and formula IV-b are provided:
wherein all variables are as defined herein.
In one embodiment, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one embodiment, compounds selected from formulas IV-g and IV-h are provided:
wherein all variables are as defined herein.
In one embodiment, compounds selected from formula IV-i and formula IV-j are provided:
wherein all variables are as defined herein.
In some embodiments of any of formulas IV-a through IV-j, selected from:
in one embodiment, compounds having formula V are provided:
wherein all variables are as defined herein.
In one embodiment, the compound of formula V is selected from:
in one embodiment, the compound of formula V is selected from:
in one embodiment of the process of formula V,selected from:
in one embodiment, compounds having formula VI are provided:
wherein all variables are as defined herein.
In one embodiment, the compound of formula VI is selected from:
wherein all variables are as defined herein.
In one embodiment, the compound of formula VI is selected from:
wherein all variables are as defined herein.
In one embodiment of the process of formula VI,selected from:
in one embodiment, the compound of formula VII-a is selected from:
wherein all variables are as defined herein.
In one embodiment, compounds of formula VII-b, formula VII-c, and formula VII-d are provided:
wherein all variables are as defined herein.
In one embodiment, compounds having the formula VII-e are provided:
wherein all variables are as defined herein.
In one embodiment of any of formulas VII-a through VII-e,selected from:
in one embodiment, compounds are provided having one of the following formulas:
wherein all variables are as defined herein.
In one embodiment, compounds having formula VIII-e) are provided:
wherein all variables are as defined herein.
In one embodiment, compounds having formula VIII-f and formula VIII-g are provided:
wherein all variables are as defined herein.
In one embodiment, compounds of formulas VIII-h and VIII-i are provided:
wherein all variables are as defined herein.
In any of the embodiments of formulas VIII-a through VIII-i,selected from:
in one embodiment, compounds are provided having the formula:
wherein all variables are as defined herein.
In one embodiment, compounds having the formula IX-e are provided:
wherein all variables are as defined herein.
In one embodiment, compounds having the formulas IX-f and IX-g are provided:
wherein all variables are as defined herein.
In one embodiment, compounds of formulas IX-h and IX-i are provided:
wherein all variables are as defined herein.
In one embodiment, compounds having formula IX-j are provided:
wherein all variables are as defined herein.
In one embodiment, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one embodiment, compounds having the formula X-d or X-e are provided:
wherein all variables are as defined herein.
In one embodiment, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one embodiment, compounds of formula X-i are provided:
wherein all variables are as defined herein.
In one embodiment, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one embodiment, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one embodiment, compounds of formula XI-i are provided:
wherein all variables are as defined herein.
In one embodiment, compounds having formula XII are provided:
wherein all variables are as defined herein.
In one embodiment, compounds of formula XII selected from the group consisting of:
in one embodiment, compounds of formula XII selected from the group consisting of:
in one embodiment, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one embodiment, compounds having formula XIII-e are provided:
wherein all variables are as defined herein.
In one embodiment, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one embodiment, compounds having formula XIII-i are provided:
wherein all variables are as defined herein.
In any of the embodiments of formulas IX-a through IX-j, X-a through X-I, XI-a through XI-I, or XHI-a through XIII-I,may be selected from:
embodiments of formula XIV
In a first aspect (A1), the present invention provides a compound of formula XIV
Or a pharmaceutically acceptable salt thereof, wherein:
wherein all variables are as defined herein.
The present invention also provides embodiments (E) listed below:
e1: in one embodiment, the present invention provides a compound of formula XIV according to a1, or a pharmaceutically acceptable salt thereof, wherein Z is selected from the group consisting of:
i) a covalent bond is formed between the first and second substrate,
ii) a carbonyl group, in which,
iii)-NR1-，
iv)-O-CH2-C(＝O)-NR1-，
v)-C(＝O)-NR1-, and
vi)-NR1-C(＝O)-。
e2: in one embodiment, the present invention provides a compound of formula XIV according to any one of a1 or E1, or a pharmaceutically acceptable salt thereof, wherein R1Is hydrogen.
E3: in one embodiment, the present invention provides a compound of formula XIV according to any one of a1 and E1 to E2, or a pharmaceutically acceptable salt thereof, wherein each R is2is-C1-6Alkyl or-N (R)5,R6)。
E4: in one aspect, the present invention provides a compound of formula XIV according to any one of a1 and E1 to E2, or a pharmaceutically acceptable salt thereof, wherein each R is2Is methyl or-N (R)5,R6)。
E5: in one embodiment, the present invention provides a compound of formula XIV according to any one of a1 and E1 to E4, or a pharmaceutically acceptable salt thereof, wherein each R is3Is selected from-C (═ O) -N (R)7,R8)、-C1-6Alkyl, -OH and-NO2Group (d) of (a).
E6: in one embodiment, the present invention provides a compound of formula XIV according to any one of a1 and E1 to E4, or a pharmaceutically acceptable salt thereof, wherein each R is3Is selected from-C (═ O) -N (R)7,R8) Isopropyl, -OH and-NO2Group (d) of (a).
E7: in one embodiment, the present invention provides a compound of formula XIV according to any one of a1 and E1 to E6, or a pharmaceutically acceptable salt thereof, wherein each R is4is-C (═ O) C1-6An alkyl group.
E8: in one aspect, the invention provides a compound of formula XIV according to any one of a1 and E1 to E6Or a pharmaceutically acceptable salt thereof, wherein each R4Is acetyl.
E9: in one embodiment, the present invention provides a compound of formula XIV according to any one of a1 and E1 to E8, or a pharmaceutically acceptable salt thereof, wherein each R is5Is hydrogen.
E10: in one embodiment, the present invention provides a compound of formula XIV according to any one of a1 and E1 to E9, or a pharmaceutically acceptable salt thereof, wherein each R is6Is hydrogen.
E11: in one embodiment, the present invention provides a compound of formula XIV according to any one of a1 and E1 to E10, or a pharmaceutically acceptable salt thereof, wherein each R is7Is C1-6An alkyl group.
E12: in one embodiment, the present invention provides a compound of formula XIV according to any one of a1 and E1 to E10, or a pharmaceutically acceptable salt thereof, wherein each R is7Is methyl.
E13: in one embodiment, the present invention provides a compound of formula XIV according to any one of a1 and E1 to E12, or a pharmaceutically acceptable salt thereof, wherein each R is8Is hydrogen.
E14: in one embodiment, the present invention provides a compound of formula XIV according to any one of a1 and E1 to E13, or a pharmaceutically acceptable salt thereof, wherein a is selected from the group consisting of:
i) by R2A substituted aryl group,
ii) an aryl group, in which the aryl group is substituted,
iii) by one or two R3(ii) a substituted heteroaryl group, wherein,
iv) heteroaryl, and
v) by R4Substituted heterocycloalkyl group.
E15: in one aspect, the present invention provides a compound of formula XIV according to any one of a1 and E1 to E13, or a pharmaceutically acceptable salt thereof, wherein a is selected from the group consisting of:
i) by R2A substituted phenyl group, which is substituted,
ii) a phenyl group, in which the phenyl group,
iii) a tetralin-1-yl group,
iv) by one or two R3A substituted benzimidazol-1-yl group,
v) by R3A substituted isoindolin-2-yl group,
vi) a 2-furyl group,
vii) an indolin-l-yl group,
viii) a benzofuran-3-yl group,
ix)2, 3-dihydropyrrolo [2,3-b ] pyridin-1-yl, and
x) by R4Substituted 4-piperidinyl.
E16: in one embodiment, the present invention provides a compound according to formula XIV of a1, or a pharmaceutically acceptable salt thereof, wherein:
A1selected from the group consisting of: -O-, -S-, -CH2-、-CF2-and-NH-; and A is2is-CH2-; or
A1Selected from the group consisting of: -O-, -S-, -CH2-and-CF2-; and A is2is-NH-;
z is selected from the group consisting of:
i) a covalent bond is formed between the first and second substrate,
ii) a carbonyl group, in which,
iii)-NH-，
iv)-O-CH2-C(＝O)-NH-，
v) -C (═ O) -NH-, and
vi)-NH-C(＝O)-；
w is CH or N;
a is selected from the group consisting of:
i) by R2A substituted aryl group,
ii) an aryl group, in which the aryl group is substituted,
iii) by one or two R3(ii) a substituted heteroaryl group, wherein,
iv) heteroaryl, and
v) by R4Substituted heterocycloalkyl;
R2is-C1-6Alkyl or-NH2；
R3Selected from the group consisting of: -C (═ O) -NH-C1-6Alkyl, -C1-6Alkyl, -OH and-NO2(ii) a And
R4is-C (═ O) C1-6An alkyl group.
E17: in one aspect, the present invention provides a compound of formula XIV according to a1, or a pharmaceutically acceptable salt thereof, wherein:
A1selected from the group consisting of: -O-, -S-, -CH2-、-CF2-and-NH-; and A is2is-CH2-; or
A1Selected from the group consisting of: -O-, -S-, -CH2-and-CF2-; and A is2is-NH-;
z is selected from the group consisting of:
i) a covalent bond is formed between the first and second substrate,
ii) a carbonyl group, in which,
iii)-NH-，
iv)-O-CH2-C(＝O)-NH-，
v) -C (═ O) -NH-, and
vi)-NH-C(＝O)-；
w is CH or N;
a is selected from the group consisting of:
i) by R2A substituted phenyl group, which is substituted,
ii) a phenyl group, in which the phenyl group,
iii) a tetralin-1-yl group,
iv) by one or two R3A substituted benzimidazol-1-yl group,
v) by R3A substituted isoindolin-2-yl group,
vi) a 2-furyl group,
vii) an indolin-l-yl group,
viii) a benzofuran-3-yl group,
ix)2, 3-dihydropyrrolo [2,3-b ] pyridin-1-yl, and
x) by R4Substituted 4-piperidinyl;
R2is methyl or-NH2；
R3Selected from the group consisting of: -C (═ O) -NH-CH3Isopropyl, -OH and-NO2(ii) a And R is4Is an acetyl group.
E18: in one embodiment, the present invention provides a compound according to formula XIV of a1, or a pharmaceutically acceptable salt thereof, wherein:
A1selected from-O-, -S-, -CH2-、-CF2-and-NH-; a. the2is-CH2-; or
A1Selected from-O-, -S-, -CH2-and-CF2-；A2is-NH-; and
w is CH or N.
E19: in one embodiment, the present invention provides a compound according to formula XIV of a1, or a pharmaceutically acceptable salt thereof, wherein:
a is selected from the group consisting of:
i) by R2A substituted aryl group,
ii) an aryl group, in which the aryl group is substituted,
iii) by one or two R3(ii) a substituted heteroaryl group, wherein,
iv) heteroaryl, and
v) by R4Substituted heterocycloalkyl;
R2is-C1-6Alkyl or-NH2；
R3Selected from the group consisting of: -C (═ O) -NH-C1-6Alkyl, -C1-6Alkyl, -OH and-NO2(ii) a And
R4is-C (═ O) C1-6An alkyl group.
E20: in one aspect, the present invention provides a compound of formula XIV according to a1, or a pharmaceutically acceptable salt thereof, wherein:
a is selected from the group consisting of:
i) by R2A substituted phenyl group, which is substituted,
ii) a phenyl group, in which the phenyl group,
iii) a tetralin-1-yl group,
iv) by one or two R3A substituted benzimidazol-1-yl group,
v) by R3A substituted isoindolin-2-yl group,
vi) a 2-furyl group,
vii) an indolin-l-yl group,
viii) a benzofuran-3-yl group,
ix)2, 3-dihydropyrrolo [2,3-b ] pyridin-1-yl, and
x) by R4Substituted 4-piperidinyl;
R2is methyl or-NH2；
R3Selected from the group consisting of: -C (═ O) -NH-CH3Isopropyl, -OH and-NO2(ii) a And R is4Is an acetyl group.
E21: in one embodiment, the present invention provides a compound of formula XIV according to a1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula XIV is selected from the group consisting of:
2-isopropyl-N-methyl-1- (2-oxoindolin-6-yl) benzimidazole-5-carboxamide;
2-isopropyl-N-methyl-1- (2-oxoindolin-5-yl) benzimidazole-5-carboxamide;
6- (2-aminoaniline) -3H-1, 3-benzothiazol-2-one;
6- (2-isopropylbenzimidazol-1-yl) -3H-1, 3-benzothiazol-2-one;
6- (2-aminoaniline) -3H-1, 3-benzoxazol-2-one;
6- (2-isopropylbenzimidazol-1-yl) -3H-1, 3-benzoxazol-2-one;
n- (l-acetyl-4-piperidinyl) -2-oxo-3H-1, 3-benzoxazole-6-carboxamide;
6- (2, 3-dihydropyrrolo [2,3-b ] pyridine-1-carbonyl) -3H-1, 3-benzoxazol-2-one;
6- (indoline-1-carbonyl) -3H-1, 3-benzothiazol-2-one;
5- (indoline-1-carbonyl) indolin-2-one;
2-oxo-N-phenyl-3H-oxazolo [4,5-b ] pyridine-6-carboxamide;
n- (l-acetyl-4-piperidinyl) -2-oxo-3H-oxazolo [4,5-b ] pyridine-6-carboxamide;
5- (indoline-1-carbonyl) -1, 3-dihydropyrrolo [2,3-b ] pyridin-2-one;
3, 3-difluoro-5- (2-isopropylbenzimidazol-1-yl) indolin-2-one;
6- (4-hydroxyisoindoline-2-carbonyl) -3H-1, 3-benzoxazol-2-one;
6- (4-nitroisoindoline-2-carbonyl) -3H-1, 3-benzoxazol-2-one;
n- (3, 3-difluoro-2-oxo-indolin-5-yl) tetralin-1-carboxamide;
n- (3, 3-difluoro-2-oxo-indolin-5-yl) benzofuran-3-carboxamide;
2-isopropyl-N-methyl-1- (2-oxo-1, 3-dihydropyrrolo [2,3-b ] pyridin-5-yl) benzimidazole-5-carboxamide;
5- (2-isopropylbenzimidazol-1-yl) -1, 3-dihydropyrrolo [2,3-b ] pyridin-2-one;
n- (2-oxo-3H-1, 3-benzoxazol-6-yl) benzamide;
n- (2-oxoindolin-5-yl) furan-2-carboxamide;
2- (2-methylphenoxy) -N- (2-oxo-3H-1, 3-benzothiazol-6-yl) acetamide;
2-oxo-N-phenylindoline-5-carboxamide;
2-oxo-N-phenyl-3H-1, 3-benzoxazole-6-carboxamide;
6- (indoline-1-carbonyl) -3H-1, 3-benzoxazol-2-one; and
2-oxo-N-phenyl-3H-1, 3-benzothiazole-6-carboxamide.
E22: in one embodiment, the present invention provides a compound of formula XIV according to a1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula XIV is selected from the group consisting of:
2-isopropyl-N-methyl-1- (2-oxoindolin-6-yl) benzimidazole-5-carboxamide;
2-isopropyl-N-methyl-1- (2-oxoindolin-5-yl) benzimidazole-5-carboxamide;
6- (2-aminoaniline) -3H-1, 3-benzothiazol-2-one;
6- (2-isopropylbenzimidazol-1-yl) -3H-1, 3-benzothiazol-2-one;
6- (2-isopropylbenzimidazol-1-yl) -3H-1, 3-benzoxazol-2-one;
n- (1-acetyl-4-piperidinyl) -2-oxo-3H-1, 3-benzoxazole-6-carboxamide;
6- (2, 3-dihydropyrrolo [2,3-b ] pyridine-1-carbonyl) -3H-1, 3-benzoxazol-2-one;
6- (indoline-1-carbonyl) -3H-1, 3-benzothiazol-2-one;
2-oxo-N-phenyl-3H-oxazolo [4,5-b ] pyridine-6-carboxamide;
n- (1-acetyl-4-piperidinyl) -2-oxo-3H-oxazolo [4,5-b ] pyridine-6-carboxamide;
5- (indoline-1-carbonyl) -1, 3-dihydropyrrolo [2,3-b ] pyridin-2-one;
3, 3-difluoro-5- (2-isopropylbenzimidazol-1-yl) indolin-2-one;
6- (4-hydroxyisoindoline-2-carbonyl) -3H-1, 3-benzoxazol-2-one;
6- (4-nitroisoindoline-2-carbonyl) -3H-1, 3-benzoxazol-2-one;
n- (3, 3-difluoro-2-oxo-indolin-5-yl) tetralin-1-carboxamide;
n- (3, 3-difluoro-2-oxo-indolin-5-yl) benzofuran-3-carboxamide;
2-isopropyl-N-methyl-l- (2-oxo-1, 3-dihydropyrrolo [2,3-b ] pyridin-5-yl) benzimidazole-5-carboxamide; and
5- (2-isopropylbenzimidazol-1-yl) -1, 3-dihydropyrrolo [2,3-b ] pyridin-2-one.
E23: in one embodiment, R3Independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; by R10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-a heterocycloalkyl group; -C (═ O) C1-6An alkyl group; - (CH)2)0-2-C(＝O)-N(R7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; -OH; -NO2；-C1-6alkyl-N (R)11)-C(＝O)-R12(ii) a By R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; -O- (CH)2)0-1-an aryl group; -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -N (R)5,R6)；-NH-C(＝O)C1-6An alkyl group; and-NH-C (═ O) OC1-6An alkyl group.
E24: in one embodiment, R2Independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; by R10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-a heterocycloalkyl group; -C (═ O) C1-6An alkyl group; - (CH)2)0-2-C(＝O)-N(R7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; -OH; -NO2；-C1-6alkyl-N (R)11)-C(＝O)-R12(ii) a By R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; -O- (CH)2)0-1-an aryl group; -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -N (R)5,R6)；-NH-C(＝O)C1-6An alkyl group; and-NH-C (═ O) OC1-6An alkyl group.
E25: a compound of any of the preceding embodiments wherein a1Is selected from the group consisting of-O-and-NH-, and A2is-CH2-。
E26: a compound of any of the preceding embodiments wherein a1Selected from the group consisting of-O-, -S-, -CH2-、-CF2-a group of and A2is-NH-.
E27: a compound of any of the above embodiments wherein W is CH.
E28: a compound of any of the above embodiments wherein W is N.
E29: a compound of any of the above embodiments wherein R2At each timeIndependently at each occurrence, is selected from: -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -N (R)5,R6)；-NO2；-NH-C(＝O)C1-6An alkyl group; and-SO2-N(R5,R6)。
E30: a compound of any of the above embodiments wherein R2Independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; by R10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-C3-7A cycloalkyl group; -C (═ O) C1-6An alkyl group; -C (═ O) -N (R)7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; by R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; and-O- (CH)2)0-1-an aryl group.
E31: a compound of any of the above embodiments wherein R3Independently at each occurrence is selected from: -C (═ O) C1-6An alkyl group; - (CH)2)0-2-C(＝O)-N(R7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; -OH; -NO2；-C1-6alkyl-N (R)11)-C(＝O)-R12(ii) a By R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; -O- (CH)2)0-1-an aryl group; -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -hydroxy-C1-6Alkyl-aryl; -N (R)5,R6)；-NH-C(＝O)C1-6An alkyl group; -NH-C (═ O) OC1-6An alkyl group; and ═ O.
E32: a compound of any of the above embodiments wherein R3Independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; by R10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; - (CH)2)0-1-C3-7A cycloalkyl group; -by R9Substituted (CH)2)0-1-a heteroaryl group; and- (CH)2)0-1-heterocycloalkyl.
E33: a compound of any of the above embodiments wherein R4Independently at each occurrence is selected from: -C (═ O) C1-6An alkyl group; -C (═ O) -N (R)7,R8)；-C(＝O)OC1-6An alkyl group; -C1-6An alkoxy group; -C1-6An alkyl group; by R10substituted-CH2-O-(CH2)0-1-an aryl group; -CH2-O-(CH2)0-1-an aryl group; -a halogen; -halogen-C1-6An alkyl group; -hydroxy-C1-6An alkyl group; -N (R)5,R6) (ii) a and-NH-C (═ O) C1-6An alkyl group.
E34: a compound of any of the above embodiments wherein R4Independently at each occurrence is selected from: by R10Substituted- (CH)2)0-1-(C3-7Cycloalkyl) -aryl; - (CH)2)0-1-(C3-7Cycloalkyl) -aryl; by R10Substituted- (CH)2)0-1-C3-7A cycloalkyl group; and- (CH)2)0-1-C3-7A cycloalkyl group.
E35: a compound of any of the above embodiments wherein R5And R6Independently at each occurrence selected from H, C1-6Alkyl groups and phenyl groups.
E36: a compound of any of the above embodiments wherein R5And R6Together with the nitrogen to which they are attached form a heterocycloalkyl ring.
E37: a compound of any of the above embodiments wherein R7And R8Independently at each occurrence selected from H and C1-6An alkyl group.
E38: in the above embodimentThe compound of any one of the above formulas, wherein R7And R8Together with the nitrogen to which they are attached form a heterocycloalkyl ring.
E39: a compound of any of the above embodiments wherein X1Selected from the group consisting of a bond or NR34。
E40: a compound of any of the above embodiments wherein X22Selected from halogen, -NH2、-NHR34、-N(R34)2Hydroxy, thiol, -B (OH)2、-Sn(R36)3、-Si(R36)3、-OS(O)2Alkyl, -OS (O)2Haloalkyl, alkenyl, alkynyl, ethynyl, ethenyl, -C (O) H, -NR34C (O) olefin, -NR34C (O) alkyne, cyano, -SC (O) alkyl, OC (O) alkyl, heterocycle, -C (O) OH, hydrogen, alkyl, aryl, heteroaryl, aliphatic, heteroaliphatic, and carbocyclic.
E41: a compound of any of the above embodiments wherein R20、R21、R22、R23And R24Independently selected from: a bond, alkyl, -C (O) -, -C (O) O-, -OC (O) -, -C (O) alkyl, -C (O) Oalkyl, -C (S) -, -SO2-, -S (O) -, -C (S) -, -C (O) NH-, -NHC (O) -, -N (alkyl) C (O) -, -C (O) N (alkyl) -, -O-, -S-, -NH-, -N (alkyl) -, -CH (-O-R)26)-、-CH(-NR34R34')-、-C(-O-R26) Alkyl-, -C (-NR)34R34’) Alkyl-, -C (R)40R40) -, -alkyl (R)27) -alkyl (R)28)-、-C(R27R28)-、-P(O)(OR26)O-、-P(O)(OR26)-、-NR34C(O)NR34'-, alkenes, haloalkyl, alkoxy, alkynylheteroarylalkyl, aryl, aralkyl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, carbocycle, - (ethylene glycol)1-6-, - (lactic acid-co-glycolic acid)1-6-, - (propylene glycol)1-6-、-O-(CH2)1-12-O-、-NH-(CH2)1-12-NH-、-NH-(CH2)1-12-O-、-O-(CH2)1-12-NH-、-S-(CH2)1-12-O-、-O-(CH2)1-12-S-、-S-(CH2)1-12-S-、-S-(CH2)1-12-NH-and-NH- (CH)2)1-12-S-, wherein R20、R21、R22、R23And R24Is not a key.
E42: a compound of any of the above embodiments wherein R20、R21、R22、R23And R24Is not a bond.
E43: a compound of any of the above embodiments wherein R20、R21、R22、R23And R24Is not a bond.
E44: a compound of any of the above embodiments wherein R20、R21、R22、R23And R24Is not a key.
In one embodiment, the present invention provides a pharmaceutically acceptable salt or ester of a compound of formula XIV as described herein. In a particular embodiment, the invention provides pharmaceutically acceptable salts, especially the hydrochloride salts, of the compounds of formula XIV as described herein. In another specific embodiment, the present invention provides pharmaceutically acceptable esters of the compounds of formula XIV as described herein. In yet another specific embodiment, the present invention provides a compound of formula XIV as described herein.
Furthermore, the present invention includes all optical isomers, i.e. diastereomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and/or tautomers, as well as solvates of their compounds of formula XIV.
The compounds of formula XIV may contain one or more asymmetric centers and may therefore exist as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Depending on the nature of the various substituents on the molecule, additional asymmetric centers may be present. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomers in mixtures, as well as pure or partially purified compounds, are contemplated to be included in the present invention. The present invention is intended to encompass all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their chromatographic separation can be achieved as known in the art by appropriate modification of the methods disclosed herein. Their absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which may be derivatized, if desired, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds can be separated so that the individual enantiomers are separated. Separation can be carried out by methods well known in the art, such as coupling a racemic mixture of compounds with an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
In embodiments where optically pure enantiomers are provided, optically pure enantiomers means that the compound contains > 90% by weight of the desired isomer, specifically > 95% by weight of the desired isomer, or more specifically > 99% by weight of the desired isomer, said weight percentages being based on the total weight of the isomers of the compound. Chirally pure or chirally enriched compounds may be prepared by chiral selective synthesis or by separation of enantiomers. The separation of the enantiomers can be carried out on the final product or on a suitable intermediate.
In one embodiment of formula XIV, Z is a covalent bond.
In another embodiment of formula XIV, Z is C (═ O).
In another embodiment of formula XIV, Z is selected from:
in another embodiment of formula XIV, Z is selected from:
in another embodiment of formula XIV, Z is selected from:
in another embodiment of formula XIV, Z is selected from:
in another embodiment of formula XIV, Z is selected from:
in another embodiment of formula XIV, Z is selected from:
in another embodiment of formula XIV, Z is selected from:
in one embodiment of the formula XIV,is that
In one embodiment of the formula XIV,is that
In one embodiment of the formula XIV,selected from:
in one embodiment of the formula XIV,selected from:
in one embodiment of the formula XIV,selected from:
in one embodiment of the formula XIV,selected from:
in one embodiment of the formula XIV,selected from:
in one embodiment of the formula XIV,selected from:
in one embodiment of the formula XIV,selected from:
in one embodiment of the formula XIV,selected from:
in one embodiment of the XIV, the first electrode is,selected from:
embodiments of formula XIV (1)
In one aspect, the compound of formula XIV (1) is selected from:
in one aspect, the compound of formula XIV (1) is selected from:
in one aspect, the compound of formula XIV (1) is selected from:
in one aspect, the compound of formula XIV (1) is selected from:
in one aspect, the compound of formula XIV (1) is selected from:
in one aspect, the compound of formula XIV (1) is selected from:
in one aspect, the compound of formula XIV (1) is selected from:
in one aspect, the compound of formula XIV (1) is selected from:
in one aspect, the compound of formula XIV (1) is selected from:
in one aspect, the compound of formula XIV (1) is selected from:
in one aspect, the compound of formula XIV (1) is selected from:
in one aspect, the compound of formula XIV (1) is selected from:
in one aspect, the compound of formula XIV (1) is selected from:
in one aspect, the compound of formula XIV (1) is selected from:
embodiments of the formulae I (1) to XIII (1)
In one aspect, there is provided a compound of formula I (1)
Wherein all variables are as defined herein.
In one embodiment of formula I (1),selected from:
wherein T is
In one aspect, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In any of the embodiments of formulas II (1) a-II (1) k,selected from:
wherein T is
In one aspect, compounds of formula III (1) are provided:
wherein all variables are as defined herein.
In one embodiment of formula III (1),selected from:
wherein T is
In one aspect, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one embodiment of any one of formulas IV (1) -a through IV (1) -J,selected from:
wherein T is
In one aspect, compounds of formula V (1) are provided:
wherein all variables are as defined herein.
In one embodiment of formula V (1),selected from:
wherein T is
In one aspect, compounds of formula VI (1) are provided:
wherein all variables are as defined herein.
In one embodiment of formula VI (1),selected from:
wherein T is
In one aspect, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one embodiment of any of formulas VII (1) a-VII (1) e,selected from:
wherein T is
In one aspect, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one embodiment of any one of formulas VIII (1) -a through VIII (1) -I,selected from:
wherein T is
In one aspect, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one aspect, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one aspect, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one aspect, compounds of formula XII (1) are provided:
wherein all variables are as defined herein.
In one aspect, compounds having one of the following formulas are provided:
wherein all variables are as defined herein.
In one embodiment of any of the compounds of formulae IX (1) -1 to IX (1) -j, X (1) -a to X (1) -i, XI (1) -a to XI (1) -i, and XIII (1) -a to XIII (1) -i,selected from:
wherein T is
Tail embodiments
In one embodiment, the "tail" is a moiety selected from the group consisting of formula T-I, formula T-II, formula T-III, formula T-IV, formula T-V, formula T-VI, and formula T-VII:
wherein all variables are as defined above.
In another embodiment, the "tail" is a moiety selected from the group consisting of formulas T-VIII, T-IX and T-X:
wherein all variables are as defined above. In other embodiments of T-VIII, T-IX and T-X, carbocycles are used instead of heterocycles.
The following are non-limiting examples of "tail" portions that can be used in the present invention. Based on this description, those skilled in the art will understand how to use the full width of the "tail" portion to achieve the objectives of the present invention.
As certain non-limiting examples, formula T-I, formula T-II, formula T-III, formula T-IV, formula T-V, formula T-VI, or formula T-VII include:
in another embodiment, the "tail" is selected from:
in another embodiment, the "tail" is selected from:
R20、R21、R22、R23and R24Non-limiting examples of moieties include:
R20、R21、R22、R23and R24Other non-limiting examples of moieties include:
R20、R21、R22、R23and R24Other non-limiting examples of moieties include:
in further embodiments, the "tail" is an optionally substituted ethylene glycol having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 ethylene glycol units, or an optionally substituted alkyl interspersed with optionally substituted O, N, S, P or Si atoms. In certain embodiments, the "tail" is flanked, substituted or interspersed with aryl, phenyl, benzyl, alkyl, alkylene or heterocyclic groups. In certain embodiments, the "tail" may be asymmetric or symmetric. In some embodiments, a "tail" is a substituted or unsubstituted polyethylene glycol group ranging in size from between about 1 to about 12 ethylene glycol units, 1 to about 10 ethylene glycol units, about 2 to about 6 ethylene glycol units, about 2 to 5 ethylene glycol units, about 2 to 4 ethylene glycol units. In any embodiment of the compounds described herein, a "tail" group can be any suitable moiety described herein.
In further embodiments, the "tail" is selected from:
-NR61(CH2)n1- (lower alkyl) -X22,-NR61(CH2)n1- (lower alkoxy) -X22,
-NR61(CH2)n1- (lower alkoxy) -OCH2-X22,-NR61(CH2)n1- (lower alkoxy) - (lower alkyl) -OCH2-X22,
-NR61(CH2)n1- (cycloalkyl) - (lower alkyl) -OCH2-X22,-NR61(CH2)n1- (heterocycloalkyl) -X22,
-NR61(CH2CH2O)n1- (lower alkyl) -O-CH2-X22,
-NR61(CH2CH2O)n1- (Heterocycloalkyl) -O-CH2-X22,
-NR61(CH2CH2O)n1-aryl-O-CH2-X22,-NR61(CH2CH2O)n1- (heteroaryl) -O-CH2-X22,
-NR61(CH2CH2O)n1- (cycloalkyl) -O- (heteroaryl) -O-CH2-X22,
-NR61(CH2CH2O)n1- (cycloalkyl) -O-aryl-O-CH2-X22,
-NR61(CH2CH2O)n1- (lower alkyl) -NH-aryl-O-CH2-X22,
-NR61(CH2CH2O)n1- (lower alkyl) -O-aryl-CH2-X22,
-NR61(CH2CH2O)n1-cycloalkyl-O-aryl-X22,-NR61(CH2CH2O)n1-cycloalkyl-O-heteroaryl-X22,
-NR61(CH2CH2)n1- (cycloalkyl) -O- (heterocycle) -CH2-X22,
-NR61(CH2CH2)n1- (heterocycle) -CH2-X22and-NR61- (heterocycles) -CH2-X22；
Wherein n1 is 0, 1,2,3,4, 5, 6,7, 8, 9, or 10; and
R61is H, methyl or ethyl.
In further embodiments, the "tail" is selected from:
-N(R61)-(CH2)m1-O(CH2)n2-O(CH2)o1-O(CH2)p1-O(CH2)q1-O(CH2)r1-OCH2-X22,
-O-(CH2)m1-O(CH2)n2-O(CH2)o1-O(CH2)p1-O(CH2)q1-O(CH2)r1-OCH2-X22,
-O-(CH2)m1-O(CH2)n2-O(CH2)o1-O(CH2)p1-O(CH2)q1-O(CH2)r1-OH；
-N(R61)-(CH2)m1-O(CH2)n2-O(CH2)o1-O(CH2)p1-O(CH2)q1-O(CH2)r1-OH；
-(CH2)m1-O(CH2)n2-O(CH2)o1-O(CH2)p1-O(CH2)q1-O(CH2)r1-OH；
-(CH2)m1-O(CH2)n2-O(CH2)o1-O(CH2)p1-O(CH2)q1-O(CH2)r1-OCH2-X22；
-O(CH2)m1O(CH2)n2O(CH2)p1O(CH2)q1OCH2-X22；
-O(CH2)m1O(CH2)n2O(CH2)p1O(CH2)q1OCH2-X22；
wherein m1, n2, o1, p1, q1, and r1 are independently 1,2,3,4, or 5; and is
R61Is H, methyl or ethyl.
In further embodiments, the "tail" is selected from:
m1, n2, o1, p1, q2 and r1 are independently 1,2,3,4 or 5.
In further embodiments, the "tail" is selected from:
in further embodiments, the "tail" is selected from:
in further embodiments, the "tail" is selected from:
wherein R is71is-O-, -NH, N-alkyl, heteroaliphatic, aliphatic or-NMe.
In further embodiments, the "tail" is selected from:
in further embodiments, the "tail" is selected from:
in further embodiments, the "tail" is selected from:
in further embodiments, the "tail" is selected from:
in further embodiments, the "tail" is selected from:
in the above embodiment, X is selected22Such that the compound is sufficiently stable or produces the intended use results.
In further embodiments, the "tail" is selected from:
in certain embodiments, the "tail" is selected from:
in certain embodiments, the "tail" is selected from:
in the above-described structure, the first and second electrodes,represents
In certain embodiments, the "tail" may be a straight chain of 4 to 24 carbon atoms, wherein one or more carbon atoms in the straight chain may be replaced or substituted with oxygen, nitrogen, amide, fluorinated carbon, and the like, such as the following:
in certain embodiments, the "tail" may be nonlinear and may be or include an aliphatic or aromatic or heteroaromatic cyclic moiety.
In certain embodiments, a "tail" may include a continuous, partially continuous, or non-continuous group of ethylene glycol units ranging in size from about 1 to about 12 ethylene glycol units, 1 to about 10 ethylene glycol units, about 2 to about 6 ethylene glycol units, about 2 to 5 ethylene glycol units, about 2 to 4 ethylene glycol units, such as1, 2,3,4, 6,7, 8, 9,10, 11, or 12 ethylene glycol units.
In certain embodiments, the "tail" may have 1,2,3,4, 5, 6,7, 8, 9,10, 11, 12, 13, 14, or 15 fluorine substituents. In another embodiment, the "tail" is perfluorinated. In yet another embodiment, the "tail" is a partially or fully fluorinated polyether. Non-limiting examples of fluorinated "tail" moieties include:
X22representative examples of (a) include:
in certain embodiments, the length can be adjusted as desired or as desired for a desired application.
Methods of treatment
Formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae XI (1) -a to XI (1) -I, formulae VI (1) -a to XI (1) -I, Compounds of formula XII (1), formula XIII (1) -a to XIII (1) -i, or formula XIV (1) may be used in an effective amount to treat a host (including humans) in need thereof, optionally in a pharmaceutically acceptable carrier, to treat any of the conditions described herein.
As used herein, the terms "treatment," "treating," and the like are intended to refer to any action that provides a benefit to a patient to whom a compound of the present invention is administered, including the treatment of any disease state or condition that is modulated by a protein to which a compound of the present invention binds. Exemplary non-limiting disease states or conditions that may be treated using the compounds according to the invention are set forth above, including cancer.
When used with formula I, formulas II-a to II-k, formula III, formulas IV-a to IV-j, formula V, formula VI, formulas VII-a to VII-e, formulas VIII-a to VIII-I, formulas IX-a to IX-j, formulas Xa to Xi, formulas XI-a to XI-I, formula XII, formulas XIII-a to XIII-I, formula XIV, formula I (1), formulas II (1) -a to II (1) -k, formula III (1), formulas IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulas VII (1) -a to VII (1) -e, formulas VIII (1) -a to VIII (1) -I, formulas IX (1) -a to IX (1) -j, formulas X (1) -a to X (1) -I, formulas XI (1) -a to XI (1) -I, The term "disease state or condition" when used in conjunction with a compound of formula XII (1), XIII (1) -a to XIII (1) -i, or XIV (1) refers to any therapeutic indication that may be treated by reducing the activity of cereblon or cereblon-containing E3 ligase, including but not limited to the use of the known cereblon binders thalidomide, pomalidomide, or lenalidomide. Non-limiting examples for cereblon binding agents are multiple myeloma, hematologic diseases such as myelodysplastic syndrome, cancer, tumor, abnormal cell proliferation, HIV/AIDS, HBV, HCV, hepatitis, crohn's disease, sarcoidosis, graft versus host disease, rheumatoid arthritis, behcet's disease, tuberculosis, and myelofibrosis. Other indications include myeloproliferative or lymphoproliferative disorders, such as B-cell or T-cell lymphoma, Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome, or post-transplant lymphoproliferative disorder; immune diseases including autoimmune diseases such as addison's disease, celiac disease, dermatomyositis, graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, arthritis, especially rheumatoid arthritis, lupus or type I diabetes; heart dysfunction diseases, including hypercholesterolemia; infectious diseases, including viral and/or bacterial infections, as generally described herein; inflammatory diseases, including asthma, chronic peptic ulcer, tuberculosis, rheumatoid arthritis, periodontitis and ulcerative colitis.
In certain embodiments, the invention provides a compound of formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formula IV-j, formulae X (1) -a to VII (1) -I, Compounds of formula XI (1) -a to XI (1) -i, formula XII (1), formula XIII (1) -a to XIII (1) -i, or formula XIV (1) are administered to a patient, e.g., a human, suffering from an infectious disease, wherein the protein targeting the infectious agent is treated, optionally in combination with another bioactive agent. The disease state or condition may be a disease caused by a microbial agent or other foreign agent such as a virus (as non-limiting examples, HIV, HBV, HCV, HSV, HPV, RSV, CMV, ebola virus, flavivirus, pestivirus, rotavirus, influenza virus, coronavirus, EBV, viral pneumonia, drug resistant virus, avian influenza, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, or hepatitis virus), bacteria (gram negative, gram positive, fungus, protozoan, parasitic helminth, prion, parasite, or other microorganism, or may be a disease state caused by the overexpression of a protein that causes the disease state and/or condition.
In certain embodiments, the disorder treated with a compound of the present invention is a disorder associated with abnormal cell proliferation. Abnormal cell proliferation, particularly hyperproliferation, can be induced by a variety of factors, including gene mutation, infection, exposure to toxins, autoimmune diseases, and benign or malignant tumors.
There are many skin disorders associated with cellular hyperproliferation. For example, psoriasis is a benign disease of human skin, often characterized by plaques covered by thickened scales. The disease is caused by an increase in epidermal cell proliferation of unknown origin. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma and squamous cell carcinoma.
Other hyperproliferative cellular diseases include vascular proliferative disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancer.
Vascular proliferative disorders include angiogenic disorders and angiogenic disorders. The proliferation of smooth muscle cells during plaque formation in vascular tissue leads to, for example, restenosis, retinopathy and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.
Fibrotic conditions are often due to abnormal formation of extracellular matrix. Examples of fibrotic disorders include cirrhosis of the liver and mesangial proliferative cell disorders. Cirrhosis is characterized by an increase in extracellular matrix components leading to the formation of hepatic scarring. Liver cirrhosis can cause diseases such as liver cirrhosis. An increase in extracellular matrix leading to hepatic scarring may also be caused by viral infections (e.g., hepatitis). Adipocytes appear to play a major role in cirrhosis.
Mesangial diseases are caused by abnormal proliferation of mesangial cells. Mesangial hyperproliferative cell diseases include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection and glomerulopathies.
Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally considered to be an autoimmune disease, is thought to be associated with the activity of autoreactive T cells, and is caused by autoantibodies produced against collagen and IgE.
Other diseases that may include abnormal cell proliferation components include Bechet syndrome, Acute Respiratory Distress Syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipid tissue cell proliferation, septic shock and general inflammation.
Skin contact allergy and asthma are just two examples of immune responses that may be associated with significant morbidity. Others include atopic dermatitis, eczema, sjogren's syndrome including sjogren's syndrome secondary keratoconjunctivitis sicca, alopecia areata, allergic reactions caused by arthropod bite reactions, crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative conjunctivitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may result in any one or more of the following symptoms or signs: itching, swelling, redness, blisters, scabbing, ulceration, pain, desquamation, cracking, hair loss, scarring or exudation of fluids involving the skin, eyes or mucous membranes.
In atopic dermatitis and eczema in general, immune-mediated infiltration of leukocytes (particularly infiltration of monocytes, lymphocytes, neutrophils and eosinophils) into the skin plays an important role in the pathogenesis of these diseases. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Immune-mediated leukocyte infiltration also occurs in sites other than the skin, such as the airways of asthmatic patients and the lacrimal glands of keratoconjunctivitis sicca.
In one non-limiting embodiment, the compounds of the present invention are useful as topical agents for the treatment of contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, sjogren's syndrome including keratoconjunctivitis sicca, alopecia areata, allergic reactions caused by arthropod bite reactions, crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions secondary to sjogren's syndrome. The new method can also be used for reducing skin infiltration of malignant leukocytes in diseases such as mycoses. These compounds are also useful for treating patients suffering from water-deficient dry eye, such as immune-mediated keratoconjunctivitis, by topically applying the compounds to the eye.
Disease states of disorders that can be treated using the compounds according to the invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, fibromatosis, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, ametropia, infertility, Angelman's syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, crohn's syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease 1(PKD1) or 2(PKD2) Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, turner's syndrome.
Other disease states or conditions that may be treated by the compounds of the invention include alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes, type 2 diabetes, epilepsy, guillain-barre syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive compulsive disorders, panic disorders, parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, tourette's syndrome, vasculitis.
Other disease states or conditions that may be treated by the compounds of the present invention include: achalaglobulinemia, chondrogenesis type II, achondroplasia, acromegaly, gaucher type 2, acute intermittent porphyria, Canavan's disease, adenomatous polyposis, ALA dehydratase deficiency, adenylate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, Alkalinemia, Alexandria, Nippon Nile, Alexandria, alpha 1-antitrypsin deficiency, alpha-1 protease inhibitors, emphysema, amyotrophic lateral sclerosis, amyloidosis, Alexandria, enamel development abolish, ALA dehydratase deficiency, Anderson-Fabry disease, androgen-insensitive syndrome, diffuse body keratoma, retinal vascular disease (von Hippel-Lindau disease) Apert syndrome, spider finger (Marfan syndrome), Stickler syndrome, congenital joint relaxation (Ehlers-Danlos syndrome # arthirasia) ataxia telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Beare-Stevenson dermoconvex syndrome, mediterranean fever, familial disease, Benjamin syndrome, beta-thalassemia, bilateral auditory neurofibromatosis (neurofibromatosis type II), factor V Leiden thrombophilia, Bloch-Sulzberger syndrome (pigment incontinence), Blobotch syndrome, X-related iron granulocytic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bonnevivile disease (tuberous sclerosis), prion disease, Birt-Hogg-Dube syndrome, bronze bone disease (osteogenesis imperfecta), big thumb-Hallux syndrome (rubin-Taybi syndrome), diabetes mellitus/hemosclerosis (hemosclerosis), Myelogenous amyotrophic lateral sclerosis (Kennedy's disease), Burger-Grutz syndrome (lipoprotein lipase deficiency), CGD chronic granulomatous disease, Camtomelic dysplasia, biotin enzyme deficiency, cardiomyopathy (Noonan syndrome), Cat-Calf syndrome, CAVD (congenital seminiferous duct deficiency), Caylor cardio-facies syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, chondrodynopathy syndrome (chondrodynoplasia), otomegaepiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, lethal dysplasia, Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous polyposis), congenital erythropoietic porphyria, congenital heart disease, methemoglobinemia, congenital methemoglobinemia, chondrodynoplasia, and chondrodynophagia, X-linked sideroblasts anemia, connective tissue disease, conus-Tokayata syndrome, Kurili anemia (beta thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes disease), hereditary coproporphyrinopathy, Cowden syndrome, craniofacial joint disorder (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Beare-Stevenson skin cyclotron syndrome, primary hyperoxaluria, backbone dysplasia (Strudwick type), muscular dystrophy, Duchenne and BeUser type (DBMD), her syndrome, degenerative neurological diseases including de Grouchy syndrome and Dejerine-Sottas syndrome, developmental disorders, distal spinal muscular atrophy, androgen V-type syndrome, diffuse sclerosis (Carlsberger) sclerosis (Becker disease), diGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitive syndrome, Down syndrome, dwarfism, erythropoietic protoporphyrinopathy, erythropoietic 5-aminolevulinic acid synthase deficiency, erythropoietic porphyria, erythropoietic protoporphyrinopathy, erythropoietic uroporphyria, Friedreich's ataxia familial paroxysmal polythymitis, delayed skin porphyria, familial pressure-sensitive neuropathy, Primary Pulmonary Hypertension (PPH), pancreatic fibrocystic disease, Fragile X syndrome, galactosemia, hereditary brain disease, giant cell hepatitis (neonatal hemochromatosis), Gronblad-Strandberg syndrome (pseudorhabdoma elasticum), Gunther disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren syndrome, sickle cell anemia, hemophilia, and other diseases, Hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, chondrodysplasia, hypopigmented anemia, immune system disorders including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, renal disorders including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia, lacunar dementia, Langer-Saldino chondrogenesis, ataxia telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniest dysplasia, Marfan syndrome, motion disorders, Mowat-Wilson syndrome, Muwaal fibrosis syndrome, Murray fibrosis, neurofibromatosis, and fibrosis, Nance-lnsley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, hypertrophic fibrodysplasia (mcchune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, premature senility syndrome (Hutchinson Gilford early failure syndrome), progressive chorea disease, chronic hereditary (huntingington) (Huntington's disease), progressive muscular atrophy, myelogenous muscular atrophy, propionemia, protoporphyrinopathy, proximal myotonic dystrophy, pulmonary hypertension, PXE (pseudoxanthoma elasticum), retinoblastoma (Rb), Richnella disease (neurofibromatosis type I), recurrent plasmacytoma, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levy syndrome, severe achondroplasia and acanthosis nigricans with developmental delay (SADDAN), Li-Fraumeni syndrome, sarcoma, breast cancer, leukemia and adrenal (SBLA) syndrome, tuberosity sclerosis (tuberous sclerosis), SDAT, congenital SED (congenital spinal epiphyseal dysplasia), SED Strudwick (spondyloepiphyseal dysplasia, Strudwick type), SEDc (congenital spinal epiphyseal dysplasia), SEMD, Strudwick type (spinal dysphylogeny, Strudwick type), Printzen syndrome, cutaneous pigmentation, Smith-Lemli-Reitz syndrome, nongenetic porphyria (porphyria), hereditary plegia, and hereditary paralysis type, Speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitive syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease, Tomaculous neuropathy (hereditary neuropathy with stress palsy), Treacher Collins syndrome, Triplex syndrome (triple X syndrome), trisomy 21 syndrome (Down syndrome), trisomy X syndrome, VHL syndrome (von Hippel-Lindau disease), vision disorders and blindness (Alstrychom syndrome), Vrolik disease, Waardenburg syndrome, Warburg Sjo Fleelius syndrome, Weissenberger-Zweyiille syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disease, Weissensen-Zymidibacter-syndrome, and atopic xeroderma, in addition to chromatosis.
The term "neoplasia" or "cancer" as used throughout the specification refers to a pathological process that results in the formation and growth of a cancerous or malignant tumor, i.e., abnormal tissue that grows by cell proliferation, usually faster than normal tissue, continues to grow after the stimulus that initiates new growth ceases. Malignant tumors show partial or complete lack of structural tissue and functional coordination with normal tissue, most invasion of surrounding tissues, metastasis to multiple sites, and are likely to recur after attempted resection and lead to patient death unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and includes or encompasses pathological processes associated with malignant blood-borne, ascites and solid tumors. Exemplary cancers that may be treated by the compounds of the present invention, alone or in combination with at least one additional anti-cancer agent, include: squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer; leukemia; benign and malignant lymphomas, particularly Burkitfs lymphoma and non-hodgkin lymphoma; benign and malignant melanoma; myeloproliferative diseases; sarcomas, including ewing's sarcoma, angiosarcoma, kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelial tumors, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, astrocytoma, gangliocytoma, medulloblastoma, pineal gland tumor, meningioma, meningiosarcoma, fibroma, and schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinoma. Other cancers that may be treated using compounds according to the invention include, for example, T lineage acute lymphoblastic leukemia (T-ALL), T lineage lymphoblastic lymphoma (T-LL), peripheral T cell lymphoma, adult T cell leukemia, Pre-BALL, Pre-B lymphoma, large B cell lymphoma, Burkitts lymphoma, B cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.
Other cancers that may be treated using compounds disclosed in accordance with the present invention include, for example, acute myeloid leukemia, Acute Lymphocytic Leukemia (ALL), Acute Myelogenous Leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical cancer, anal cancer, anaplastic astrocytoma, angiosarcoma, appendiceal cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, bladder cancer, bone marrow cancer, intestinal cancer, brain stem glioma, breast cancer, triple (estrogen, progestin, and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progestin, and HER-2 are negative), single negative (one of estrogen, progestin, and HER-2 is negative), estrogen receptor positive, HER2 negative breast cancer, estrogen receptor positive breast cancer, and Human Immunodeficiency Virus (HIV), human immunodeficiency virus (human immunodeficiency virus), human immunodeficiency virus (human immunodeficiency) and human immunodeficiency), human immunodeficiency virus (human immunodeficiency) and human immunodeficiency virus (human immunodeficiency) and human immunodeficiency virus (human immunodeficiency) and human immunodeficiency virus (human immunodeficiency) and human immunodeficiency virus (human immunodeficiency), human immunodeficiency virus (human immunodeficiency virus (human immunodeficiency) and human immunodeficiency virus (human immunodeficiency), human immunodeficiency (human immunodeficiency) and human immunodeficiency virus (human immunodeficiency) and human immunodeficiency), human immunodeficiency) and human immunodeficiency virus (human immunodeficiency ) and human immunodeficiency (human immunodeficiency ) and human immunodeficiency virus (human immunodeficiency), human immunodeficiency (human immunodeficiency virus (human immunodeficiency) and human immunodeficiency virus (human immunodeficiency) and human immunodeficiency (human immunodeficiency), human immunodeficiency) and human immunodeficiency virus (human immunodeficiency) and human immunodeficiency), human immunodeficiency (human immunodeficiency), human immunodeficiency virus (human immunodeficiency) and human immunodeficiency virus (human immunodeficiency) and human immunodeficiency), human immunodeficiency virus, Metastatic breast cancer, luminal a breast cancer, luminal B breast cancer, Her2 negative breast cancer, Her2 positive or negative breast cancer, progesterone receptor positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, Ductal Carcinoma In Situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, ewing's sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal tract carcinoid cancer, gastrointestinal stromal tumor (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, Head and neck cancer, endovascular endothelioma, hodgkin's lymphoma, hypopharynx cancer, Invasive Ductal Carcinoma (IDC), Invasive Lobular Carcinoma (ILC), Inflammatory Breast Cancer (IBC), intestinal cancer, intrahepatic bile duct cancer, invasive/invasive breast cancer, islet cell cancer, maxillocarcinoma, kaposi's sarcoma, kidney cancer, larynx cancer, leiomyosarcoma, pia maternally metastatic tumor, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, merkel cell carcinoma, mesenchymal chondrosarcoma, interstitial mass, mesothelioma metastatic breast cancer, metastatic melanoma, metastatic squamous neck cancer, mixed glioma, unilamellar teratoma, oral cancer mucus carcinoma, mucosal melanoma, multiple myeloma, mycosis, melanoma, neuroblastoma, melanoma, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal carcinoma, neck cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell cancer, eye cancer, ocular melanoma, oligodendroglioma, mouth cancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian primary peritoneal cancer, ovarian solitary tumor, Paget's disease, pancreatic cancer, papillary cancer, sinus nasalis cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocystoastrocytoma, pineal region tumor, pineblastoma, pituitary cancer, primary Central Nervous System (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal carcinoma, rhabdomyosarcoma, salivary gland carcinoma, penile carcinoma, prostate cancer, ovarian cancer, prostate cancer, and prostate cancer, Soft tissue sarcoma, osteosarcoma, sarcoma, sinus cancer, skin cancer, Small Cell Lung Cancer (SCLC), small intestine cancer, spine cancer, spinal cord cancer, squamous cell cancer, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma/thymus cancer, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, fallopian tube cancer, tubular cancer, unidentified cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulval cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-BALL, Pre-B lymphoma, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive CML, and Philadelphia chromosome positive CML, Juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, adult T-cell chronic leukemia, diffuse large B-cell lymphoma, follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT), small cell lymphoma, mediastinal large B-cell lymphoma, lymph node marginal zone B-cell lymphoma (NMZL); splenic Marginal Zone Lymphoma (SMZL); large B cell lymphoma in blood vessels; primary effusion lymphoma; or lymphomatoid granulomatosis; b cell prolymphocytic leukemia; splenic lymphoma/leukemia, non-categorical diffuse red myeloid small B cell lymphoma in the spleen; lymphoplasmacytic lymphoma; heavy chain diseases, such as alpha heavy chain disease, gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, bone solitary plasmacytoma; extraosseous plasmacytoma; primary cutaneous follicular central lymphoma, large B-cell lymphoma rich in T cells/histiocytes, DLBCL associated with chronic inflammation; epstein-barr virus (EBV) + DLBCL of the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, legged ALK + large B-cell lymphoma, plasmablast lymphoma; large B-cell lymphoma caused by HHV 8-associated multicenter, Castleman's disease; b-cell lymphoma, an intermediate that cannot be classified and is characterized between diffuse large B-cell lymphomas; or B-cell lymphoma, unclassified and characterized by intermediates between diffuse large B-cell lymphoma and classical hodgkin's lymphoma.
In one embodiment, the cancer is NUT cardia tumor on the midline.
In one embodiment, the cancer is adenoid cystic carcinoma.
The term "biologically active agent" is used to describe agents other than the compounds according to the invention which are used in combination with the compounds of the invention as agents having biological activity to help achieve the intended treatment, inhibition and/or prevention/prophylaxis of using the compounds of the invention. Preferred bioactive agents for use herein include those agents having pharmacological activity similar to that of use or administration of the compounds of the present invention, and include, for example, anti-cancer agents, anti-viral agents, including inter alia anti-HIV and anti-HCV agents, antimicrobial agents, antifungal agents, and the like.
Combination therapy
Formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae XI (1) -a to XI (1) -I, formulae VI (1) -a to XI (1) -I, Compounds of formula XII (1), formula XIII (1) -a to XIII (1) -i, or formula XIV (1) may be used to treat a host, e.g., a human, suffering from a condition described herein, either alone or in combination, in an effective amount.
The compounds disclosed herein can be used alone or in combination with another compound of the invention or another biologically active agent in an effective amount to treat a host, e.g., a human, suffering from a condition described herein.
The term "bioactive agent" is used to describe agents other than the compounds selected according to the present invention that can be used in combination or alternation with the compounds of the present invention to achieve the desired therapeutic result. In one embodiment, the compound of the invention and the biologically active agent are administered in such a way that they are active in vivo over overlapping time periods, e.g., Cmax, Tmax, AUC or other pharmacokinetic parameters with overlapping time periods. In another embodiment, the compound of the invention and the biologically active agent are administered to a host in need thereof that does not have overlapping pharmacokinetic parameters, however, one has a therapeutic effect on the therapeutic efficacy of the other.
In one aspect of this embodiment, the biologically active agent is an immunomodulatory agent, including but not limited to checkpoint inhibitors, including by way of non-limiting example, PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, V-domain Ig suppressor of T cell activation (VISTA) inhibitors, small molecules, peptides, nucleotides, or other inhibitors. In certain aspects, the immunomodulator is an antibody, e.g., a monoclonal antibody.
Pharmaceutical compositions
Formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formula IV-j, formulae V (1) -a to X (1) -I, formula VI-a to VII (1) -e, The compounds of formula XI (1) -a to XI (1) -i, formula XII (1), formula XIII (1) -a to XIII (1) -i, or formula XIV (1) may be administered as pure chemicals, but more typically are administered as pharmaceutical compositions, which include an amount effective for a host, typically a human, in need of such treatment for any of the diseases described herein. Accordingly, the present disclosure provides a pharmaceutical composition for any of the uses described herein, comprising an effective amount of a compound or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier. The pharmaceutical composition may contain the compound or salt as the only active agent, or in an alternative embodiment, the pharmaceutical composition may contain the compound and at least one additional active agent.
In certain embodiments, the dosage form of the pharmaceutical composition comprises from about 0.1mg to about 2000mg, from about 10mg to about 1000mg, from about 100mg to about 800mg, or from about 200mg to about 600mg of the active compound and optionally from about 0.1mg to about 2000mg, from about 10mg to about 1000mg, from about 100mg to about 800mg, or from about 200mg to about 600mg of the additional active agent in a unit dose. Examples are dosage forms having at least 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700 or 750mg of the active compound or a salt thereof. The pharmaceutical composition may also comprise a molar ratio of the active compound and the additional active agent. For example, the pharmaceutical composition may comprise an anti-inflammatory or immunosuppressive agent in a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1, or about 1.5:1 to about 4: 1. The compounds disclosed herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, by implants including ocular implants, transdermally, by buccal administration, rectally, as eye drops, by injection including ophthalmic injection, intravenously, intraaortic, intracranially, subcutaneously, intraperitoneally, subcutaneous tissue layers, nasally, sublingually, or rectally, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers. For ocular delivery, the compounds may be administered in an immediate or controlled release manner or by an ocular device as desired, e.g., via intravitreal, intrastromal, intracameral, sub-tendinous, sub-retinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, retroscleral, peripheral, or lacrimal injection or through a mucus, mucin, or mucosal barrier.
The pharmaceutical composition may be formulated in any pharmaceutically useful form, such as an aerosol, cream, gel, pill, injection or infusion solution, capsule, tablet, syrup, transdermal patch, subcutaneous patch, dry powder, inhalation formulation, medical device, suppository, buccal or sublingual formulation, parenteral formulation or eye drop. Some dosage forms, such as tablets and capsules, are subdivided into unit doses of appropriate size containing appropriate quantities of the active ingredient, e.g., an amount effective to achieve the desired purpose.
The carrier includes excipients and diluents, and must be of sufficiently high purity and low toxicity to render it suitable for administration to a patient undergoing therapy. The carrier may be inert or may have pharmaceutical benefits of its own. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound.
Carrier classes include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one category, for example vegetable oils may be used as lubricants in some formulations and as diluents in other formulations. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, tragacanth powder, malt, gelatin; talc powder and vegetable oil. Optional active agents may be included in the pharmaceutical composition that do not substantially interfere with the activity of the compounds of the present invention.
The pharmaceutical composition/combination may be formulated for oral administration. These compositions may contain any amount of active compound that achieves the desired result, for example 0.1-99 weight percent (wt.%) of the compound and typically at least about 5 wt.% of the compound. Some embodiments comprise from about 25 wt.% to about 50 wt.% or from about 5 wt.% to about 75 wt.% of the compound.
Formulations suitable for rectal administration are generally presented as unit dose suppositories. These can be prepared by mixing the active compound with one or more conventional solid carriers, for example cocoa butter, and then shaping the resulting mixture.
Formulations suitable for topical application to the skin preferably take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Carriers that may be used include petrolatum, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
Formulations suitable for transdermal administration may be in the form of discrete patches adapted to remain in intimate contact with the epidermis of the recipient for an extended period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, e.g., Pharmaceutical Research 3 (6): 318(1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. In one embodiment, a microneedle patch or device is provided for delivering a drug through or into a biological tissue, particularly skin. Microneedle patches or devices allow drug delivery through or into the skin or other tissue barrier at clinically relevant rates with minimal or no irritation to the tissue.
Formulations suitable for pulmonary administration can be delivered by a variety of passive breath-driven and active power-driven single/multi-dose Dry Powder Inhalers (DPIs). The most commonly used devices for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers. There are many types of atomizers available for selection, including jet atomizers, ultrasonic atomizers, and vibrating mesh atomizers. The choice of a suitable pulmonary delivery device depends on parameters such as the nature of the drug and its formulation, site of action and lung pathophysiology.
The compounds and pharmaceutically acceptable salts described herein are useful as therapeutically active substances, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, administration can also be effected rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.
The compounds described herein and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers to prepare pharmaceutical formulations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance, however, no carriers are generally required in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
Furthermore, the pharmaceutical preparations can contain pharmaceutically acceptable auxiliary substances, such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other substances of therapeutic value.
The invention also provides medicaments containing a compound of the invention or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier, as well as processes for their manufacture, which comprise bringing one or more compounds of the formula I and/or pharmaceutically acceptable salts thereof and one or more other therapeutically valuable substances, if desired, into a galenical administration form together with one or more therapeutically inert carriers.
The dosage can vary within wide limits and must, of course, be adjusted to the individual requirements in each particular case. In the case of oral administration, the dosage for an adult may vary from about 0.01mg to about 1000mg of a compound of formula XIV or a corresponding amount of a pharmaceutically acceptable salt thereof per day. The daily dose may be administered in a single dose or divided doses, and in addition, when it is found necessary to exceed the upper limit, the upper limit may also be exceeded.
The following examples illustrate the invention without limiting it, but merely as representative thereof. The pharmaceutical formulation conveniently contains from about 1 to 500mg, especially from 1 to 100mg, of a compound of formula XIV.
Examples of compositions according to the invention are:
example A
Tablets of the following composition were prepared in the usual manner:
table 1: possible tablet compositions
Preparation procedure
1. Ingredients 1,2,3 and 4 were mixed and granulated with purified water.
2. The granules were dried at 50 ℃.
3. The particles are passed through a suitable milling apparatus.
4. Adding the component 5, and stirring for three minutes; compressed on a suitable tablet press.
Example B-1
Capsules of the following composition were prepared:
table 2: possible capsule ingredient composition
Preparation procedure
1. Ingredients 1,2 and 3 were mixed in a suitable mixer for 30 minutes.
2. Add ingredients 4 and 5 and mix for 3 minutes.
3. Filling into suitable capsules.
The compound of formula XIV, lactose and corn starch are first mixed in a mixer and then mixed in a mill. The mixture returns to the mixer; talc was added to it and mixed thoroughly. The mixture is filled by machine into suitable capsules, for example hard gelatin capsules.
Example B-2
Soft gelatin capsules of the following composition were prepared:
composition (I)
mg/capsule
A compound of formula XIV
5
Yellow wax
8
Hydrogenated soybean oil
8
Partially hydrogenated vegetable oils
34
Soybean oil
110
Total of
165
Table 3: possible soft gelatin capsule ingredient compositions
Composition (I)
mg/capsule
Gelatin
75
Glycerin 85%
32
Karion 83
8 (Dry matter)
Titanium dioxide
0.4
Iron oxide yellow
1.1
Total of
116.5
TABLE 4 possible Soft gelatin Capsule compositions
Preparation procedure
The compound of formula XIV is dissolved in the warm molten other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are processed according to conventional procedures.
Example C
Suppositories of the following composition were prepared:
composition (I)
mg/suppository
A compound of formula XIV
15
Suppository block
1285
Total of
1300
TABLE 5 possible suppository compositions
Preparation procedure
The suppository blocks were melted in a glass or steel vessel, mixed thoroughly and cooled to 45 ℃. Subsequently, the finely powdered compound of formula XIV is added thereto and stirred until it is completely dispersed. Pouring the mixture into suppository molds with proper size, standing and cooling; the suppositories are then removed from the moulds and individually packaged in waxed paper or metal foil.
Example D
An injection solution of the following composition was prepared:
composition (I)
mg/injection solution
A compound of formula XIV
3
Polyethylene glycol 400
150
Acetic acid
q.s.ad pH 5.0
Water for injection solution
ad 1.0ml
Table 6: possible injection compositions
Preparation procedure
The compound of formula XIV is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH was adjusted to 5.0 with acetic acid. The volume was adjusted to 1.0ml by adding the remaining amount of water. The solution was filtered, filled into vials with the appropriate excess and sterilized.
Example E
Pouches of the following composition were prepared:
composition (I)
mg/small bag
A compound of formula XIV
50
Lactose, fine powder
1015
Microcrystalline cellulose (AVICEL PH 102)
1400
Sodium carboxymethylcellulose
14
Polyvinylpyrrolidone K30
10
Magnesium stearate
10
Flavoring additive
1
Total of
2500
Table 7: possible sachet composition
Preparation procedure
The compound of formula XIV is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules were mixed with magnesium stearate and flavouring additives and filled into sachets.
Use of compounds
The invention is of formula I, formula II-a to II-k, formula III, formula IV-a to IV-j, formula V, formula VI, formula VII-a to VII-e, formula VIII-a to VIII-I, formula IX-a to IX-j, formula Xa to Xi, formula XI-a to XI-I, formula XII, formula XIII-a to XIII-I, formula XIV, formula I (1), formula II (1) -a to II (1) -k, formula III (1), formula IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formula VII (1) -a to VII (1) -e, formula VIII (1) -a to VIII (1) -I, formula IX (1) -a to IX (1) -j, formula X (1) -a to X (1) -I, formula XI (1) -a to XI (1) -I, Compounds of formula XII (1), XIII (1) -a to XIII (1) -i or XIV (1) bind to the ubiquitously expressed E3 ligase protein Cereblon (CRBN) and alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in the breakdown of endogenous downstream proteins. Thus, the compounds of the present invention are useful for treating or preventing various cancers.
In one aspect, the invention provides a compound of formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae IV-j, formulae X (1) -a to VII (1) -I, and, Compounds of the formulae XI (1) -a to XI (1) -i, XII (1), XIII (1) -a to XIII (1) -i or XIV (1) are used as therapeutically active substances.
In another aspect, the invention provides a compound of formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae IV-j, formulae V (1) -a to X (1) -I, A compound of formula XI (1) -a to XI (1) -i, formula XII (1), formula XIII (1) -a to XIII (1) -i or formula XIV (1), for use in the treatment or prevention of cancer.
In another aspect, the invention provides a compound of formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae IV-j, formulae X (1) -a to VII (1) -I, Use of a compound of formula XI (1) -a to XI (1) -i, formula XII (1), formula XIII (1) -a to XIII (1) -i or formula XIV (1) for the treatment or prevention of cancer.
In another aspect, the invention provides a method of treating or preventing cancer comprising administering a therapeutically effective amount of a compound of formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formula IX (1) -j, as defined herein, A compound of formula X (1) -a to X (1) -i, formula XI (1) -a to XI (1) -i, formula XII (1), formula XIII (1) -a to XIII (1) -i, or formula XIV (1) is administered to a subject.
In another aspect, the invention provides a compound of formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formula IV-j, formulae X (1) -a to VII (1) -I, Use of a compound of formula XI (1) -a to XI (1) -i, formula XII (1), formula XIII (1) -a to XIII (1) -i or formula XIV (1) for the manufacture of a medicament for the treatment or prevention of cancer.
Formula I, formulae II-a to II-k, formula III, formulae IV-a to IV-j, formula V, formula VI, formulae VII-a to VII-e, formulae VIII-a to VIII-I, formulae IX-a to IX-j, formulae Xa to Xi, formulae XI-a to XI-I, formula XII, formulae XIII-a to XIII-I, formula XIV, formula I (1), formulae II (1) -a to II (1) -k, formula III (1), formulae IV (1) -a to IV (1) -j, formula V (1), formula VI (1), formulae VII (1) -a to VII (1) -e, formulae VIII (1) -a to VIII (1) -I, formulae IX (1) -a to IX (1) -j, formulae X (1) -a to X (1) -I, formulae XI (1) -a to XI (1) -I, formulae VI (1) -a to XI (1) -I, Compounds of formula XII (1), XIII (1) -a to XIII (1) -i or XIV (1) can also be used to prepare bifunctional degradant compounds by linking them to a protein targeting moiety that binds to the protein of interest or polypeptide of interest, similar to the bifunctional compounds already described in W02013020557, W02013063560, WO2013106643, WO2015160845, W02016011906, W02016105518, W02017007612, WO2017024318, WO 2017117473.
General Synthesis and preparation Process
The compounds described herein can be prepared by methods known to those skilled in the art. In one non-limiting example, the disclosed compounds can be prepared by the scheme provided below.
The preparation of the compounds of the invention can be carried out in a sequential or convergent synthetic route. The synthesis of the compounds of the invention is illustrated in schemes 1-3 and 27 specific examples below. The skills required to carry out the reaction and purification of the resulting product are known to those skilled in the art. Unless otherwise indicated, the substituents and indices used in the following description of the process have the meanings given herein before.
In more detail, the compounds described herein can be prepared by the methods given below, by the methods given in the examples, or by analogous methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. The reaction sequence is not limited to the sequence shown in schemes 1-3, however, the order of the reaction steps may be freely varied depending on the starting materials and their respective reactivities. The starting materials are commercially available or can be prepared by methods analogous to those given below, by methods described in the references cited in the specification or in the examples, or by methods known in the art.
Scheme 1
Step A: the nitroaminoarene compound 3 may be substituted by aromatic nucleophiles (S) between the 1, 2-fluoro-nitro-arene 1 and the arylamine compound 2NAr) is obtained through reaction.
Examples of suitable 1, 2-fluoro-nitro-arenes 1 include, but are not limited to, 1-fluoro-2-nitrobenzene (CAS1493-27-2), 4-fluoro-N-methyl-3-nitrobenzamide (CAS 475216-25-2), and 4-fluoro-3-nitro-benzoic acid methyl ester (CAS 185629-31-6).
Examples of suitable arylamine compounds 2 include, but are not limited to, 6-amino-3H-1, 3-benzoxazol-2-one (CAS22876-17-1), 6-amino-3H-1, 3-benzothiazol-2-one (CAS56354-98-4), 5-aminoindolin-2-one (CAS 20876-36-2), 5-amino-3, 3-difluoro-indolin-2-one (CAS813424-17-8), 6-aminoindolin-2-one (CAS 150544-04-0) and 5-amino-1, 3-dihydropyrrolo [2,3-b ] pyridin-2-one (CAS 869371-00-6).
SNThe Ar reaction is carried out in the presence of an organic base such as N, N-diisopropylethylamine, triethylamine or N-methylmorpholine in a polar aprotic organic solvent such as N-methyl-2-pyrrolidone or N, N-dimethylformamide at elevated temperature. Preferred conditions are N, N-diisopropylethylamine reacted in N-methyl-2-pyrrolidone at 120 ℃ for 3 hours.
And B: the reduction of the nitro-amino-arene compound 3 to the diamino-arene 4 may be carried out by reacting at atmospheric or elevated pressure in a catalyst such as PtO2Hydrogenation with hydrogen in the presence of Pd-C or raney nickel in a polar solvent such as MeOH, EtOH, dioxane, THF or mixtures thereof.
Preferred conditions are 1 atmosphere of hydrogen at room temperature in a mixture of methanol and THF in the presence of 10% palladium on charcoal for 12 hours.
And C: benzimidazole 7 can be obtained by cyclization of diaminoarene 4 with aldehyde 5 in the presence of sodium metabisulfite. The cyclization reaction is carried out in a polar aprotic organic solvent such as N-methyl-2-pyrrolidone or N, N-dimethylformamide 1 at elevated temperature. Preferred conditions are that N, N-dimethylformamide 1 is reacted at 120 ℃ for 1 hour.
Benzimidazole 7 can also be obtained by cyclization of a diaminoarene 4 with a carboxylic acid 6 in the presence of another acid. Cyclization in strong acids such as HCl or H2SO4In an aqueous solution of (a). Preferred conditions are 6M aqueous HCl at 120 ℃ for 12 hours.
Scheme 2
R, R' ═ H, aryl, heterocycloalkyl, heteroaryl or together with the nitrogen to which they are attached form a heterocycloalkyl or heteroaryl group as defined herein;
W、A1、A2as described herein
Step A: formation of the amide bond can be achieved by conducting the coupling reaction of the appropriate carboxylic acid 8 and primary or secondary amine 9 in the presence of a coupling agent such as DCC, EDC, TBTU or HATU, in the presence of an organic base such as triethylamine, N-diisopropylethylamine or N-methylmorpholine in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ether solvent such as diethyl ether, dioxane, THF, DME or TBME or a polar aprotic organic solvent such as N, N-dimethylacetamide at room temperature or elevated temperature for 2 to 18 hours.
Examples of suitable carboxylic acids 8 include, but are not limited to, 2-oxo-3H-1, 3-benzoxazole-6-carboxylic acid (CAS 54903-16-1), 2-oxo-3H-1, 3-benzothiazole-6-carboxylic acid (CAS99615-68-6), 2-oxoindoline-5-carboxylic acid (CAS102359-00-2), 2-oxo-3H-oxazolo [4,5-b ] pyridine-6-carboxylic acid (CAS1555998-02-1), and 2-oxo-1, 3-dihydropyrrolo [2,3-b ] pyridine-5-carboxylic acid (CAS 1260665-66-4).
Preferred conditions are HATU with N, N-diisopropylethylamine in N, N-dimethylformamide for 4 hours at room temperature.
Scheme 3
R is as defined herein
W，A1，A2As described herein
Step A: formation of the amide bond may be accomplished by conducting the coupling reaction of the appropriate amine 2 and carboxylic acid 11 in the presence of a coupling agent such as DCC, EDC, TBTU or HATU, in the presence of an organic base such as triethylamine, N-diisopropylethylamine or N-methylmorpholine in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ether solvent such as diethyl ether, dioxane, THF, DME or TBME or a polar aprotic organic solvent such as N, N-dimethylformamide at room temperature or elevated temperature for 2 to 18 hours.
Alternatively, amide bond formation can be accomplished by conducting the coupling reaction of the appropriate amine 2 and carboxylic acid 11 in the presence of a coupling agent (e.g., DMTMM) in an alcoholic solvent (e.g., methanol, ethanol, n-propanol, or isopropanol) at room temperature for 1-4 hours.
Examples of suitable arylamine compounds 2 include, but are not limited to, 6-amino-3H-1, 3-benzoxazol-2-one (CAS22876-17-1), 6-amino-3H-1, 3-benzothiazol-2-one (CAS56354-98-4), 5-aminoindolin-2-one (CAS 20876-36-2), 5-amino-3, 3-difluoro-indolin-2-one (CAS813424-17-8), 6-aminoindolin-2-one (CAS 150544-04-0) and 5-amino-1, 3-dihydropyrrolo [2,3-b ] pyridin-2-one (CAS 869371-00-6).
Preferred conditions are DMTMM in methanol at room temperature for 4 hours.
Scheme 4
The compound of formula XIV (1) can be prepared as shown in scheme 4 by reacting intermediate 14 (wherein X is X, wherein X is sodium carbonate or sodium hydride, or an organic base such as triethylamine, DIPEA or DBU) in an organic solvent such as dichloromethane, dimethylformamide or dimethylsulfoxide in the presence of a suitable base such as an inorganic base such as sodium carbonate or sodium hydride, or an organic base such as triethylamine, DIPEA or DBU at room temperature1Is NR34O or S) with intermediate 13 for 1-24 hours, wherein LG1Are suitable leaving groups as will be appreciated by those skilled in the art such as halogen (e.g. Cl, Br or I) or sulfonate (e.g. -O (SO)2)CH3、-O(SO2)CF3or-O (SO)2) (4-methylphenyl)).
Scheme 5
Compounds of formula XIV (1) can be prepared as shown in scheme 5 by reaction over a palladium catalyst (e.g., Pd (PPh)3)4、PdCl2(PPh3)2Or similar catalyst as would be appropriately selected by one skilled in the art), will have CG in an organic solvent at elevated temperature (e.g., reflux of the organic solvent)1Intermediates 16 to radicals having CG2Intermediate 17 of the group was coupled for 1-48 hours. In which X is1Is NR34In some embodiments of O or S, CG1Is H and CG2Can be selected from-B (OH)2-Zn (halogen) or Sn (alkyl)3. In some embodiments, wherein X is1Is CH2、CHR34Or C (R)34)2，CG1Selected from halogen or sulfonate and CG2Can be selected from-B (OH)2-Zn (halogen) or Sn (alkyl)3. In other embodiments, wherein X1Is CH2、CHR34Or C (R)34)2，CG1Can be selected from-B (OH)2-Zn (halogen) or Sn (alkyl)3And CG2Can be selected from halogen or sulfonate.
Scheme 6
Compound 21 of formula XIV (1) can be synthesized by sequential Heck reactions followed by hydrogenation or other suitable reduction as shown in scheme 6. In step A, in the presence of a palladium catalyst (e.g. Pd (dppf) Cl2Or similar catalyst that one of skill in the art would suitably select) and a base (e.g., sodium carbonate) in an organic solvent (e.g., 1, 4-dioxane) at an elevated temperature (e.g., 80 ℃), will contain CG1The radical heterocyclic olefin 18 is reacted with bromide 19 for 1 to 24 hours. In one embodiment of step A, the CG1The group is a pinacol boron group. In step B, the heterocyclic olefin 20 is reacted with the palladium on carbon catalyst in an organic solvent (e.g., ethanol) under a hydrogen atmosphere for 1 to 48 hours. The heterocycloalkenyl group of 18 may be substituted with any cycloalkene or heterocycloalkenyl group as understood by those of ordinary skill in the art to be suitable.
Scheme 7
Compound 24 of formula XIV (1) can be prepared as followsThe synthesis shown in scheme 7 is by Heck reaction followed by hydrogenation or other suitable reduction. In step A, over a palladium catalyst (e.g., Pd (PPh)3)2Cl2Or similar catalyst that one of skill in the art would suitably select) and a base (e.g., triethylamine) in an organic solvent (e.g., DMF) at elevated temperature (e.g., 90 ℃) for 1-24 hours. In step B, the olefin 23 is reacted with the palladium on carbon catalyst in an organic solvent (e.g., ethanol) under a hydrogen atmosphere for 1 to 48 hours.
Scheme 8
Compound 28 of formula XIV (1) can be synthesized by azide-alkyne Huisgen cycloaddition sequence as shown in scheme 8. In step a, alcohol 25 is reacted with propargyl bromide in an organic solvent (e.g., DMF) in the presence of a base (e.g., cesium carbonate) at room temperature for 1-24 hours. In step B, alkyne 27 is reacted with azide 27 in the presence of copper sulfate and sodium ascorbate in an organic solvent (e.g. DMSO).
Scheme 9
Compound 30 of formula XIV (1) can be synthesized as shown in scheme 9 by reaction in the presence of coupling agents (e.g., 2,4, 6-trichlorobenzoyl chloride and 4-dimethylaminopyridine) and a base (e.g., triethylamine) in an organic solvent (e.g., THF) at room temperature for 1-24 hours. In some embodiments, the alcohol group of 25 may be substituted with an amino or sulfur group, as would be readily understood by one of skill in the art.
Scheme 10
Compound 32 of formula XIV (1) can be synthesized as shown in scheme 10 by Mitsunobu reaction of alcohol 31 with second alcohol 25 in the presence of a phosphine (e.g., triphenylphosphine) and an azodicarboxylate (e.g., DEAD or DIAD) in an organic solvent (e.g., THF) at elevated temperature (e.g., reflux) for 1-24 hours.
Scheme 11
Compound 35 of formula XIV (1) can be synthesized as shown in scheme 11 by reductive amination by reacting piperidine 33 with aldehyde 34 in the presence of sodium triacetoxyborohydride and acetic acid, optionally in an organic solvent (e.g., THF) at room temperature for 1-24 hours. In one embodiment, the piperidine group of compound 33 may be substituted with a heterocyclic amine group of different size or substitution, as will be apparent to one of ordinary skill in the art.
Scheme 12
Compound 38 of formula XIV (1) can be synthesized as shown in scheme 12 by reacting carboxylic acid 36 with piperidine 37 in the presence of a coupling agent (e.g., COMU) and a base (e.g., diisopropylethylamine) in an organic solvent (e.g., DMF) at room temperature for 1-24 hours. In one embodiment, the piperidine group of compound 37 may be substituted with a heterocyclic amine group of different size or substitution, as will be apparent to those of ordinary skill in the art.
Scheme 13
Compound 41 of formula XIV (1) can be synthesized as shown in scheme 13 by reacting amine 39 with compound 40 substituted with a Leaving Group (LG), such as bromide, iodide or sulfonate group, in the presence of a base, such as diisopropylethylamine, in an organic solvent, such as DMF, at elevated temperature (e.g., 60 ℃) for 1-24 hours. In some embodiments, the amino group of 39 may be substituted with an alcohol or a thio group, as would be readily understood by one skilled in the art.
Scheme 14
Compounds 44 of formula XIV (1) can be prepared as shown in scheme 14 by reaction between a copper (I) catalyst (e.g., CuI) and a palladium catalyst (e.g., Pd (PPh)3)4) Is synthesized by a Sonagashira reaction of the terminal alkyne 41 with bromide 43 in the presence of a base (e.g. triethylamine) in an organic solvent (e.g. DMF) at elevated temperature (e.g. 80 ℃) for 1-24 hours.
Isolation and purification of Compounds
Isolation and purification of the compounds and intermediates described herein may be carried out by any suitable isolation or purification procedure, if desired, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative low or high pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable isolation and isolation procedures can be had by reference to the preparations and examples below. However, other equivalent isolation or separation procedures may of course be used. Chiral HPLC can be used to separate racemic mixtures of chiral compounds of formula XIV. Racemic mixtures of chiral synthetic intermediates can also be separated using chiral HPLC.
In case the compounds of formula XIV are basic, they may be converted into the corresponding acid addition salts. The conversion is accomplished by treatment with at least a stoichiometric amount of a suitable acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and an organic acid, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Generally, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol, etc., and the acid is added to a similar solvent. The temperature was maintained between 0 ℃ and 50 ℃. The resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.
The compounds of formula XIV as well as all intermediates may be prepared according to analogous methods or according to the methods described herein, as long as their preparation is not described in the embodiments. Starting materials are commercially available, known in the art, or can be prepared by or analogously to methods known in the art.
It will be appreciated that the compounds of formula XIV of the present invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.
Stereochemistry
For convenience, compounds of the present invention having a stereocenter may be drawn without stereochemistry. One skilled in the art will recognize that pure enantiomers and diastereomers may be prepared by methods known in the art. Examples of the method of obtaining the optically active material include at least the following methods.
i) Physical separation of crystals-a technique for manually separating macroscopic crystals of individual enantiomers. This technique can be used if crystals of the individual enantiomers are present, i.e. the material is an aggregate and the crystals are visually distinct;
ii) simultaneous crystallization-a technique whereby the individual enantiomers are crystallized separately from a solution of the racemate, possibly only if the racemate is a solid conglomerate;
iii) enzymatic resolution-a technique by which racemates are partially or completely separated by virtue of the different reaction rates of enantiomers with enzymes;
iv) enzymatic asymmetric synthesis-a synthetic technique whereby at least one synthetic step uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer;
v) chemical asymmetric synthesis-a synthetic technique by which the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries;
vi) diastereomer separation-a technique by which a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) which converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization with the aid of their now more pronounced structural differences, followed by removal of the chiral auxiliary to obtain the desired enantiomer;
vii) first and second order asymmetric transformations-a technique whereby the diastereoisomers from the racemates equilibrate to give advantage in solution of the diastereoisomers from the desired enantiomer, or where the diastereoisomers disturb the equilibrium from preferential crystallization of the desired enantiomer, so that ultimately in principle all material is converted from the desired enantiomer to the crystalline diastereoisomer. The desired enantiomer is then released from the diastereomer;
viii) kinetic resolution-this technique refers to the partial or complete resolution of racemates (or further resolution of partially resolved compounds) by unequal reaction rates of enantiomers with chiral, non-racemic reagents or catalysts under kinetic conditions;
ix) enantiospecific synthesis of non-racemic precursors-a synthetic technique by which the desired enantiomer is obtained from achiral starting materials and the stereochemical integrity is not compromised or only minimally compromised during synthesis;
x) chiral liquid chromatography-a technique by which enantiomers of a racemate are separated in a liquid mobile phase by means of different interactions with a stationary phase, including by chiral HPLC; the stationary phase may be made of chiral material, or the mobile phase may contain additional chiral material to initiate different interactions;
xi) chiral gas chromatography-a technique by which racemates are volatilized and enantiomers are separated from a chromatographic column containing an immobilized non-racemic chiral adsorbent phase by virtue of their different interactions in a gas mobile phase;
xii) extraction with a chiral solvent-a technique by which enantiomers are separated by preferential dissolution of one enantiomer into a particular chiral solvent;
xiii) transport across chiral membranes-a technique by which the racemate is contacted with a thin membrane barrier. Barriers typically separate two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential results in preferential transport across the membrane barrier. Separation occurs because the non-racemic chiral nature of the membrane allows only one enantiomer of the racemate to pass through.
xiv) simulated moving bed chromatography, for use in one embodiment. A variety of chiral stationary phases are commercially available.
Representative examples of the invention
The present invention will be more fully understood with reference to the following examples. However, the claims should not be construed as limited to the scope of the embodiments.
If the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers may be separated or crystallized by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC or chiral HPLC).
All reaction examples and intermediates were prepared under nitrogen atmosphere if not otherwise stated.
Example 1
N- (2-oxo-3H-1, 3-benzoxazol-6-yl) benzamides
The title compound (CAS 932474-64-1) can be purchased from a commercial supplier, for example, in a chemical database such as(American Chemical Society).
Example 2
N- (2-oxoindolin-5-yl) furan-2-carboxamide
The title compound (CAS 921814-32-6) can be purchased from a commercial supplier, for example, in a chemical database such as(American Chemical Society).
Example 3
2- (2-methylphenoxy) -N- (2-oxo-3H-1, 3-benzothiazol-6-yl) acetamide
The title compound (CAS 931736-40-2) can be purchased from a commercial supplier, for example, in a chemical database such as(American national society).
Example 4
2-isopropyl-N-methyl-1- (2-oxoindolin-6-yl) benzimidazole-5-carboxamide
a) N-methyl-3-nitro-4- [ (2-oxoindolin-6-yl) amino]Benzamide derivatives
4-fluoro-N-methyl-3-nitrobenzamide (1264mg, CAS 475216-25-2), 6-aminoindolin-2-one (151mg, CAS 15054)4-04-0) and N, N-diisopropylethylamine (1.59ml) in N-methyl-2-pyrrolidone (20ml) was heated at 120 ℃ for three hours. The reaction mixture was then cooled to room temperature and poured into water and extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and dried in vacuo to give N-methyl-3-nitro-4- [ (2-oxoindolin-6-yl) amino]Benzamide (1800mg, 36%) was used in the next step as a black oil without further purification. MS (ISP) 327.2([ M + H ]]+).
b) 3-amino-N-methyl-4- [ (2-oxoindolin-6-yl) amino]Benzamide derivatives
To N-methyl-3-nitro-4- [ (2-oxoindolin-6-yl) amino]To a stirred suspension of benzamide (1800mg) in methanol (20ml) and THF (20ml) was added 10% palladium on charcoal (200 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. The catalyst was collected by filtration and washed with methanol. The filtrate was then concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, eluent: 0-10% methanol in dichloromethane) to give 3-amino-N-methyl-4- [ (2-oxoindolin-6-yl) amino]Benzamide (800mg, 49%) as a brown solid. MS (ISP) 297.2([ M + H)]+).
c) 2-isopropyl-N-methyl-1- (2-oxoindolin-6-yl) benzimidazole-5-carboxamide
To 3-amino-N-methyl-4- [ (2-oxoindolin-6-yl) amino group at room temperature]To a stirred solution of benzamide (199mg) and isobutyraldehyde (48.5mg, CAS78-84-2) in N, N-dimethylformamide (10ml) was added sodium metabisulfite (153.4 mg). The reaction mixture was then heated at 120 ℃ for 1 hour. Subsequent TLC and LC-MS analysis indicated the reaction was complete. The reaction mixture was poured into water and extracted 3 times with ethyl acetate. The combined organic phases were separated by MgSO4Dried, filtered and concentrated in vacuo. The crude material was purified by preparative reverse phase HPLC to give 2-isopropyl-N-methyl-1- (2-oxoindolin-6-yl) benzimidazole-5-carboxamide as a brown solid (90mg, 35%). Ms (isp): 349.1([ M + H)]+).
Example 5
2-isopropyl-N-methyl-1- (2-oxoindolin-5-yl) benzimidazole-5-carboxamide
The title compound was obtained in analogy to example 4, using 5-aminoindolin-2-one (CAS 20876-36-2) instead of 6-aminoindolin-2-one in step a. White solid ms (isp): 349.1([ M + H)]+).
Example 6
6- (2-Aminoaniline) -3H-1, 3-benzothiazol-2-ones
In analogy to example 4 steps a and b, 1-fluoro-2-nitrobenzene (CAS1493-27-2) was used in step a instead of 4-fluoro-N-methyl-3-nitrobenzamide and 6-aminobenzo [ d]Thiazol-2 (3H) -one (CAS 563254-98-4) instead of 6-aminoindolin-2-one gave the title compound. Brown solid ms (isp): 258.3([ M + H)]+).
Example 7
6- (2-isopropylbenzimidazol-1-yl) -3H-1, 3-benzothiazol-2-one
In analogy to example 4 step c, 6- (2-aminoaniline) -3H-1, 3-benzothiazol-2-one was used instead of 3-amino-N-methyl-4- [ (2-oxoindolin-6-yl) amino]Benzamide the title compound was obtained. White solid ms (isp): 310.2([ M + H)]+).
Example 8
6- (2-aminoaniline) -3H-1, 3-benzoxazol-2-one
Procedure analogous to example 4Steps a and b, step a, use 1-fluoro-2-nitrobenzene (CAS1493-27-2) instead of 4-fluoro-N-methyl-3-nitrobenzamide and 6-aminobenzo [ d ]]Oxazol-2 (3H) -one (CAS22876-17-1) instead of 6-aminoindolin-2-one gave the title compound. Brown solid ms (isp): 242.2([ M + H)]+).
Example 9
6- (2-isopropylbenzimidazol-1-yl) -3H-1, 3-benzoxazol-2-one
In analogy to example 4 step c, 6- (2-aminoanilino) -3H-1, 3-benzoxazol-2-one was used instead of 3-amino-N-methyl-4- [ (2-oxoindolin-6-yl) amino]Benzamide the title compound was obtained. White solid ms (isp): 294.3([ M + H)]+).
Example 10
2-oxo-N-phenylindoline-5-carboxamides
The title compound (CAS1168720-81-7) can be purchased from a commercial supplier, for example, in a chemical database such as(American Chemical Society).
Example 11
2-oxo-N-phenyl-3H-1, 3-benzoxazole-6-carboxamides
The title compound (CAS1791206-26-2) can be purchased from a commercial supplier, for example, at(American ChemicalSocietiy), etc.
Example 12
N- (1-acetyl-4-piperidinyl) -2-oxo-3H-1, 3-benzoxazole-6-carboxamide
To 1- (4-aminopiperidin-1-yl) ethan-1-one (50mg, CAS160357-94-8) and 2-oxo-2, 3-dihydrobenzo [ d]To a mixture of oxazole-6-carboxylic acid (69.3mg, CAS54903-16-1) was added N, N-diisopropylethylamine (181. mu.l) dropwise followed by a solution of HATU in N, N-dimethylformamide (245mg, 1.8ml, 0.358M solution). The reaction mixture was shaken at 25 ℃ for 4 hours. The reaction mixture was directly purified by preparative HPLC and then lyophilized to give N- (1-acetyl-4-piperidinyl) -2-oxo-3H-1, 3-benzoxazole-6-carboxamide as a white solid (45.5mg, 43%). Ms (isp): 304.2([ M + H)]+).
Example 13
6- (indoline-1-carbonyl) -3H-1, 3-benzoxazol-2-one
The title compound (CAS1787518-86-8) can be purchased from a commercial supplier, for example, in a chemical database such as(American Chemical Society).
Example 14
6- (2, 3-dihydropyrrolo [2,3-b ] pyridine-1-carbonyl) -3H-1, 3-benzoxazol-2-one
Analogously to example 12,2, 3-dihydro-1H-pyrrolo [2,3-b ] is used]Pyridine (CAS10592-27-5) instead of 1- (4-aminopiperidin-1-yl) ethan-1-one gave the title compound. White solid ms (isp): 282.1([ M + H)]+).
Example 15
2-oxo-N-phenyl-3H-1, 3-benzothiazole-6-carboxamide
The title compound (CAS503443-01-4) can be purchased from a commercial supplier, for example, in a chemical database such as(American Chemical Society).
Example 16
6- (indoline-1-carbonyl) -3H-1, 3-benzothiazol-2-one
In analogy to example 12, indoline (CAS496-15-1) was used instead of 1- (4-aminopiperidin-1-yl) ethan-1-one and 2-oxo-2, 3-dihydrobenzo [ d ]]Thiazole-6-carboxylic acid (CAS99615-68-6) in place of 2-oxo-2, 3-dihydrobenzo [ d ]]Oxazole-6-carboxylic acid the title compound was obtained. White solid ms (isp):297.2([ M + H)]+).
Example 17
5- (indoline-1-carbonyl) indolin-2-one
In analogy to example 12, indoline (CAS496-15-1) instead of 1- (4-aminopiperidin-1-yl) ethan-1-one and 2-oxoindoline-5-carboxylic acid (CAS102359-00-2) instead of 2-oxo-2, 3-dihydrobenzo [ d ] was used]Oxazole-6-carboxylic acid the title compound was obtained. White solid ms (isp): 279.3([ M + H)]+).
Example 18
2-oxo-N-phenyl-3H-oxazolo [4,5-b ] pyridine-6-carboxamides
In analogy to example 12, aniline was used instead of 1- (4-aminopiperidin-1-yl) ethan-1-one and 2-oxo-2, 3-dihydrooxazolo [4,5-b ]]Pyridine-6-carboxylic acid (CAS1555998-02-1) instead of 2-oxo-2, 3-dihydrobenzo [ d ]]Oxazole-6-carboxylic acid the title compound was obtained. A white solid. Ms (isp): 256.3([ M + H)]+).
Example 19
N- (1-acetyl-4-piperidinyl) -2-oxo-3H-oxazolo [4,5-b ] pyridine-6-carboxamides
Analogously to example 12, 2-oxo-2, 3-dihydrooxazolo [4,5-b ] was used]Pyridine-6-carboxylic acid (CAS1555998-02-1) instead of 2-oxo-2, 3-dihydrobenzo [ d ]]Oxazole-6-carboxylic acid the title compound was obtained. White solid ms (isp): 305.3([ M + H)]+).
Example 20
5- (indoline-1-carbonyl) -1, 3-dihydropyrrolo [2,3-b ] pyridin-2-one
In analogy to example 12, indoline (CAS496-15-1) was used instead of 1- (4-aminopiperidin-1-yl) ethan-1-one and 2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ]]Pyridine-5-carboxylic acid (CAS1260665-66-4) instead of 2-oxo-2, 3-dihydrobenzo [ d ]]Oxazole-6-carboxylic acid the title compound was obtained. White solid ms (isp): 280.2([ M + H)]+).
Example 21
3, 3-difluoro-5- (2-isopropylbenzimidazol-1-yl) indolin-2-one
The title compound was obtained in analogy to example 4, using 1-fluoro-2-nitrobenzene (CAS1493-27-2) instead of 4-fluoro-N-methyl-3-nitrobenzamide and 5-amino-3, 3-difluoroindolin-2-one (CAS813424-17-8) instead of 6-aminoindolin-2-one in step a. White solid ms (isp): 328.1([ M + H)]+).
Example 22
6- (4-Hydroxyisoindoline-2-carbonyl) -3H-1, 3-benzoxazol-2-one
The title compound was obtained in analogy to example 12, using isoindolin-4-ol hydrochloride (CAS72695-20-6) instead of 1- (4-aminopiperidin-1-yl) ethan-1-one. White solid ms (isp): 295.2([ M-H)]-).
Example 23
6- (4-Nitroisoindoline-2-carbonyl) -3H-1, 3-benzoxazol-2-one
The title compound was obtained in analogy to example 12, using 4-nitroisoindoline hydrochloride (CAS1159826-78-4) instead of 1- (4-aminopiperidin-1-yl) ethan-1-one. White solid ms (isp): 326.5([ M + H)]+).
Example 24
N- (3, 3-difluoro-2-oxo-indolin-5-yl) tetralin-1-carboxamide
To 1,2,3, 4-tetrahydronaphthalene-1-carboxylic acid (47.8mg, CAS1914-65-4) and 5-amino-3, 3-difluoroindolin-2-one (50 m) at room temperatureg, CAS813424-17-8) to a stirred solution of methanol (1.67ml) was added DMTMM (90.2mg, CAS 3945-69-5). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then poured into 20ml brine and extracted twice with EtOAc/THF (1: 1). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by preparative HPLC (Gemini NX, 12nm, 5pm, 100X30mm, flow: 40ml/min, eluent: CH3CN/H2O+Et3N) purifying. The product was lyophilized to provide N- (3, 3-difluoro-2-oxo-indolin-5-yl) tetralin-1-carboxamide as a pale orange solid (16mg, 17%). Ms (isp): 343.1([ M + H)]+).
Example 25
N- (3, 3-difluoro-2-oxo-indolin-5-yl) benzofuran-3-carboxamide
The title compound was obtained in analogy to example 24, using benzofuran-3-carboxylic acid (CAS26537-68-8) instead of 1,2,3, 4-tetrahydronaphthalene-1-carboxylic acid. White solid ms (isp): 327.1([ M-H)]-).
Example 26
2-isopropyl-N-methyl-1- (2-oxo-1, 3-dihydropyrrolo [2,3-b ] pyridin-5-yl) benzimidazole-5-carboxamide
a) N-methyl-3-nitro-4- (1H-pyrrolo [ 2.3-b)]Pyridin-5-ylamino) benzamides
In analogy to example 4 step a, 1H-pyrrolo [2,3-b ] was used]Pyridin-5-amine (CAS100960-07-4) instead of the 6-aminoindolin-2-one of step a gave the title compound. A red solid. Ms (isp): 312.0([ M + H)]+).
b)4- [ (3, 3-dibromo-2-oxo-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) amino]-N-methyl-3-nitro Phenyl-carboxamides
To N-methyl-3-nitro-4- (1H-pyrrolo [2, 3-b)]A small amount of pyridinium tribromide (8.32g) was added to a stirred solution of pyridin-5-ylamino) benzamide (3.0g) in t-butanol (100ml) over 7 minutes. The reaction was stirred at 25 ℃ for 12 hours. According to TLC, the reaction was complete. The solvent was removed by concentration in vacuo and the resulting residue was dissolved in a 1:1 mixture of ethyl acetate/water (400 ml). The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (2X 100 ml). The combined organic extracts were washed successively with water and saturated brine, then dried over magnesium sulfate and concentrated in vacuo to give 4- [ (3, 3-dibromo-2-oxo-lH-pyrrolo [2,3-b ]]Pyridin-5-yl) amino]-N-methyl-3-nitro-benzamide (2.2g, 18%). Brown solid ms (isp): 485.9([ M + H)]+)。
c) 3-amino-N-methyl-4- [ (2-oxo-1, 3-dihydropyrrolo [2, 3-b)]Pyridin-5-yl) amino]Benzoyl radical Amines as pesticides
To 4- [ (3, 3-dibromo-2-oxo-lH-pyrrolo [2,3-b ] at room temperature]Pyridin-5-yl) amino]-N-methyl-3-nitro-benzamide (lg) to a 1:1 mixture of methanol/THF (20ml) was added 10% palladium on charcoal (120 mg). The reaction mixture was hydrogenated under hydrogen atmosphere at room temperature. After stirring vigorously for 3 hours, the catalyst was collected by filtration and washed with methanol. The filtrate was then concentrated in vacuo. By column chromatography (SiO)2Petroleum ether/ethyl acetate 1:1) to provide 3-amino-N-methyl-4- [ (2-oxo-1, 3-dihydropyrrolo [2, 3-b)]Pyridin-5-yl) amino]Benzamide (500mg, 89%) as a brown solid. Ms (isp): 298.8([ M + H ]]+)。
d) 2-isopropyl-N-methyl-1- (2-oxo-1, 3-dihydropyrrolo [2, 3-b)]Pyridin-5-yl) benzimidazole- 5-carboxamides
In analogy to example 4 step c, 3-amino-N-methyl-4- [ (2-oxo-1, 3-dihydropyrrolo [2,3-b ] was used]Pyridin-5-yl) amino]Benzamide instead of 3-amino-N-methyl-4- [ (2-oxoindolin-6-yl) amino]Benzamide the title compound was obtained. Palm oil. Ms (isp): 350.3([ M + H)]+)。
Example 27
5- (2-isopropylbenzimidazol-1-yl) -1, 3-dihydropyrrolo [2, 3-bl pyridin-2-one
The title compound was obtained in analogy to example 26, using 1-fluoro-2-nitrobenzene (CAS1493-27-2) instead of 4-fluoro-N-methyl-3-nitrobenzamide in step a. Green solid ms (isp): 293.3([ M + H)]+)。
Example 28
5- (5- (piperidin-4-yl) indoline-1-carbonyl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one
Step 1: the title compound was obtained in analogy to example 12, using 5-bromoindoline (CAS22190-33-6) instead of 1- (4-aminopiperidin-1-yl) ethan-1-one and 2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carboxylic acid (CAS1260665-66-4) instead of 2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-carboxylic acid.
Step 2: 4- (1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carbonyl) indolin-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
Dissolving 5- (5-bromoindoline-1-carbonyl) -1, 3-dihydropyrrolo [2,3-b ] pyridin-2-one in dioxane: to a mixture of water (3: 1) (0.1M) was added 4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (CAS 28696-14-6, 1.3 equiv.), followed by sodium carbonate (2.5 equiv.) and 1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (0.1 equiv.). The solution was degassed with nitrogen and heated at 80 ℃ for 2 hours. The organic supernatant was separated, evaporated under reduced pressure and the residue purified by silica gel column chromatography to give the title compound.
And step 3: 4- (1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carbonyl) indolin-5-yl) piperidine-1-carboxylic acid tert-butyl ester
Tert-butyl 4- (1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carbonyl) indolin-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate was dissolved in ethanol (0.1M) and 10% palladium on charcoal was added to the reaction mixture. The vessel was sealed and placed under a hydrogen atmosphere for 24 hours. The reaction mixture was filtered over celite and the filtrate was evaporated under reduced pressure to give the title compound.
And 4, step 4: 5- (5- (piperidin-4-yl) indoline-1-carbonyl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one
Tert-butyl 4- (1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carbonyl) indolin-5-yl) piperidine-1-carboxylate was dissolved in 1, 4-dioxane: methanol (1: 1) and hydrogen chloride (4M, 1, 4-dioxane solution) was added. The reaction mixture was stirred at 40 ℃ for 2 hours and the reaction mixture was evaporated under reduced pressure to give the title compound.
Example 29
3- (1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carbonyl) indolin-6-yl) propionic acid
Step 1: 5- (6-Bromoindolinyl-1-carbonyl) -1, 3-dihydropyrrolo [2,3-b ] pyridin-2-one the title compound was obtained in analogy to example 12, using 6-bromoindoline (CAS63839-24-7) instead of 1- (4-aminopiperidin-1-yl) ethan-1-one and 2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carboxylic acid (CAS1260665-66-4) instead of 2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-carboxylic acid.
Step 2: (E) -3- (1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carbonyl) indolin-6-yl) acrylic acid tert-butyl ester
5- (6-bromoindoline-1-carbonyl) -1, 3-dihydropyrrolo [2,3-b ] pyridin-2-one is dissolved in N, N-dimethylformamide. Tert-butyl acrylate (1.3 equivalents), triethylamine (2.5 equivalents) and bis (triphenylphosphine) palladium (II) dichloride (0.1 equivalent) were added and the reaction mixture was degassed with nitrogen for 10 min. The reaction mixture was heated at 90 ℃ for 4 hours. The reaction mixture was diluted with ethyl acetate, washed twice with brine and the organic layer was evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography to give tert-butyl (E) -3- (1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carbonyl) indolin-6-yl) acrylate.
And step 3: 3- (1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carbonyl) indolin-6-yl) propionic acid tert-butyl ester
Tert-butyl (E) -3- (1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carbonyl) indolin-6-yl) acrylate was dissolved in ethanol (0.1M) and 10% palladium on charcoal was added to the reaction mixture. The vessel was sealed and placed under a hydrogen atmosphere for 24 hours. The reaction mixture was filtered over celite and the filtrate was evaporated under reduced pressure to give the title compound.
And 4, step 4: 3- (1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carbonyl) indolin-6-yl) propionic acid
Tert-butyl 3- (1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carbonyl) indolin-6-yl) propanoate was dissolved in dichloromethane (0.1M) and trifluoroacetic acid was added. The reaction mixture was stirred at 35 ℃ for 24 hours. The volatiles were evaporated under reduced pressure to give the title compound.
Example 30
5- (4- ((1- (2-hydroxyethyl) -1H-1, 2, 3-triazol-4-yl) methoxy) indoline-1-carbonyl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one
Step 1: 5- (4-hydroxyindoline-1-carbonyl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one
The title compound was obtained in analogy to example 12, using indolin-4-ol (CAS85926-99-4) instead of 1- (4-aminopiperidin-1-yl) ethan-1-one and 2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carboxylic acid (CAS1260665-66-4) instead of 2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-carboxylic acid.
Step 2: 5- (4- (prop-2-yn-1-yloxy) indoline-1-carbonyl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one
5- (4-Hydroxyindoline-1-carbonyl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one was dissolved in N, N-dimethylformamide and cesium carbonate (1.1 eq) and propargyl bromide were added. The reaction mixture was stirred at 25 ℃ for 2 hours. The reaction mixture was partitioned between ethyl acetate and sodium bicarbonate and the organic layer was evaporated under reduced pressure. The crude residue was purified by silica gel chromatography to give 5- (4- (prop-2-yn-1-yloxy) indolin-1-carbonyl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one.
And step 3: 5- (4- ((1- (2-hydroxyethyl) -1H-1, 2, 3-triazol-4-yl) methoxy) indoline-1-carbonyl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one
5- (4- (prop-2-yn-1-yloxy) indoline-1-carbonyl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one was dissolved in DMSO (0.1M), 2-azidoethanol (2.0 equiv., CAS1517-05-1) was added, and the reaction mixture was degassed with nitrogen. An aqueous copper sulfate solution (1M, 1.0 equivalent) and an aqueous sodium ascorbate solution (2M, 2.0 equivalents) were added dropwise to the reaction mixture in that order. The compound was purified by column chromatography to give the title compound.
Example 31
2- (2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-carbonyl) isoindolin-4-ylpiperidine-4-carboxylic acid ester
Step 1: 1- (tert-butyl) 4- (2- (2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-carbonyl) isoindolin-4-yl) piperidine-1, 4-dicarboxylic acid ester
1- (tert-Butoxycarbonyl) piperidine-4-carboxylic acid (CAS84358-13-4, 1 eq.), 2,4, 6-trichlorobenzoyl chloride (CAS4136-95-2, 1 eq.) and 6- (4-hydroxyisoindoline-2-carbonyl) benzo [ d ] oxazol-2 (3H) -one (1 eq.) were dissolved in anhydrous THF (0.1M). Triethylamine (2 equivalents) was added slowly followed by DMAP (25 mol%). The reaction mixture was stirred at room temperature until completion and then quenched with 10% hydrochloric acid solution. The solution was extracted twice with ethyl acetate. The combined organic phases were washed twice with saturated sodium bicarbonate solution, dried and purified by flash column chromatography on silica gel to give the title compound.
Step 2: 2- (2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-carbonyl) isoindolin-4-ylpiperidine-4-carboxylic acid ester
1- (tert-butyl) 4- (2- (2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-carbonyl) isoindolin-4-yl) piperidine-1, 4-dicarboxylate (1 eq) was dissolved in DCM (0.2M) and a solution of 4M HCl in dioxane (0.2M) was added at room temperature. The reaction was stirred at room temperature to completion. The mixture was concentrated and lyophilized to give the title compound.
Example 32
3- ((2- (2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-carbonyl) isoindolin-4-yl) oxy) propanoic acid
Step 1: 3- ((2- (2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-carbonyl) isoindolin-4-yl) oxy) propionic acid tert-butyl ester
A solution of diisopropyl azodicarboxylate (1.3 equivalents) in toluene was added dropwise to 6- (4-hydroxyisoindoline-2-carbonyl) benzo [ d ] at 0 deg.C]Oxazol-2 (3H) -one (1 eq), tert-butyl 3-hydroxypropionate (CAS59854-11-4, 1 eq), and Ph3P (1.3 equiv.) in THF (0.2M). The reaction mixture was heated to reflux until completion. The reaction mixture was cooled and concentrated, and purified by flash chromatography on silica gel to give the title compound.
Step 2: 3- ((2- (2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-carbonyl) isoindolin-4-yl) oxy ] propanoic acid
Tert-butyl 3- ((2- (2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-carbonyl) isoindolin-4-yl) oxy) propanoate (1 eq) was dissolved in DCM (0.2M) and TFA (0.2M) was added at room temperature. The reaction was stirred at room temperature to completion. The mixture was concentrated and lyophilized to give the title compound.
Example 33
6- (4-hydroxy-5- ((4- (hydroxymethyl) piperidin-1-yl) methyl) isoindoline-2-carbonyl) benzo [ d ] oxazol-2 (3H) -one
Step 1: 4-hydroxy-2- (2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-carbonyl) isoindoline-5-carbaldehyde
6- (4-Hydroxyisoindoline-2-carbonyl) benzo [ d ] oxazol-2 (3H) -one (1 eq) and hexamethylenetetramine (CAS100-97-0, 4 eq) were dissolved in TFA (0.5M). The reaction mixture was refluxed using a dean stark system until the reaction was complete. The mixture was then cooled to room temperature. Water was added and the reaction was heated to 80 ℃ for 2 hours. After cooling to room temperature, the mixture was filtered and the precipitate was purified by flash chromatography on silica gel to give the title compound.
Step 2: 6- (4-hydroxy-5- ((4- (hydroxymethyl) piperidin-1-yl) methyl) isoindoline-2-carbonyl) benzo [ d ] oxazol-2 (3H) -one
4-hydroxy-2- (2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-carbonyl) isoindoline-5-carbaldehyde (1 equivalent) and 4-piperidinemethanol (CAS6457-49-4, 1.1 equivalent) were dissolved in THF (0.4M). Acetic acid (drop wise) was added followed by sodium triacetoxyborohydride (1.3 equiv). The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride and the organic layer was evaporated under reduced pressure. The crude residue was purified by silica gel chromatography to give the title compound.
Example 34
5- (5- (1- (5-hydroxypentanoyl) piperidin-4-yl) -2-isopropyl-1H-benzo [ d ] imidazol-1-yl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one
Step 1: 4- (4-fluoro-3-nitrophenyl) piperidine-1-carboxylic acid tert-butyl ester
4- (4-fluorophenyl) piperidine hydrochloride (1 eq) was dissolved in concentrated sulfuric acid (0.5M reaction concentration). The mixture was cooled to 0 ℃ and concentrated nitric acid (1.5 eq) was added slowly dropwise. The solution was slowly warmed to room temperature and then heated to 50 ℃. The solution was stirred for 24 hours. The mixture was then cooled to room temperature, poured into ice water, and treated with 1M NaOH until basic. The product was then extracted from the solution with diethyl ether (3 ×). The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure.
The crude material was then dissolved in THF (0.1M reaction concentration). DMAP (0.1 eq) was added followed by Boc anhydride (1 eq). The mixture was stirred for two hours. Then diluted with ethyl acetate and washed with water. The organic layer was then washed with brine and dried over sodium sulfate, then concentrated under reduced pressure. Column chromatography using an ethyl acetate gradient in hexane afforded 4- (4-fluoro-3-nitrophenyl) piperidine-1-carboxylic acid tert-butyl ester.
Step 2: 4- (3-Nitro-4- ((2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-5-yl) amino) phenyl) piperidine-1-carboxylic acid tert-butyl ester
The title compound was synthesized in analogy to example 4, using tert-butyl 4- (4-fluoro-3-nitrophenyl) piperidine-1-carboxylate instead of 4-fluoro-N-methyl-3-nitrobenzamide.
And step 3: 4- (3-amino-4- ((2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-5-yl) amino) phenyl) piperidine-1-carboxylic acid tert-butyl ester
The title compound was synthesized in analogy to example 4, using tert-butyl 4- (3-nitro-4- ((2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-5-yl) amino) phenyl) piperidine-1-carboxylate instead of N-methyl-3-nitro-4- [ (2-oxoindolin-6-yl) amino ] benzamide.
And 4, step 4: 4- (2-isopropyl-1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-5-yl) -1H-benzo [ d ] imidazol-5-yl) piperidine-1-carboxylic acid tert-butyl ester
The title compound was synthesized in analogy to example 4, using tert-butyl 4- (3-amino-4- ((2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-5-yl) amino) phenyl) piperidine-1-carboxylate instead of 3-amino-N-methyl-4- [ (2-oxoindolin-6-yl) amino ] benzamide.
And 5: 5- (2-isopropyl-5- (piperidin-4-yl) -1H-benzo [ d ] imidazol-1-yl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one trifluoroacetate salt
Tert-butyl 4- (2-isopropyl-1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-5-yl) -1H-benzo [ d ] imidazol-5-yl) piperidine-1-carboxylate (1 eq) was dissolved in dichloromethane (0.2M reaction concentration). Trifluoroacetic acid (10 equivalents) was then added and the mixture was stirred at room temperature for 24 hours. The mixture was then concentrated under reduced pressure to provide the title compound.
Step 6: 5- (5- (1- (5-hydroxypentanoyl) piperidin-4-yl) -2-isopropyl-1H-benzo [ d ] imidazol-1-yl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one
5- (2-isopropyl-5- (piperidin-4-yl) -1H-benzo [ d ] imidazol-1-yl) -1, 3-dihydro-2H-pyrrolo [2, 3b ] pyridin-2-one trifluoroacetate (1 eq) and 5-hydroxypentanoic acid (1 eq) were dissolved in DMF (0.1M reaction concentration). Hunig's base (3 equiv.) was added followed by COMU (1.1 equiv.). The mixture was stirred at room temperature for 2 hours. The mixture was then diluted with ethyl acetate and water. The organic layer was separated and the product was extracted from the aqueous layer with ethyl acetate (3 ×). The combined organic layers were washed with brine and dried over sodium sulfate, then concentrated. The crude material was then purified on silica using a gradient of ethyl acetate/hexane to provide the desired compound.
Example 35
6- (((2-isopropyl-1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-5-yl) -1H-benzo [ d ] imidazol) -4-yl) methyl) amino) hexanoic acid
Step 1: tert-butyl ((3-fluoro-2-nitrobenzyl) oxy) dimethylsilane (3-fluoro-2-nitrophenyl) methanol (1 eq) was dissolved in THF (0.1M reaction concentration). Imidazole (1.2 equiv.) was added followed by TBSCl (1.1 equiv.). The mixture was stirred for 24 hours. Then diluted with ethyl acetate and water. The organic layer was separated and the product was extracted from the aqueous layer using ethyl acetate (3 ×). The combined organic layers were washed with brine and dried over sodium sulfate, then concentrated. The crude material was then purified on silica using a gradient of ethyl acetate/hexane to provide the desired compound.
Step 2: 5- ((3- (((tert-butyldimethylsilyl) oxy) methyl) -2-nitrophenyl) amino) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one
The title compound was synthesized in analogy to example 4, using tert-butyl ((3-fluoro-2-nitrobenzyl) oxy) dimethylsilane instead of 4-fluoro-N-methyl-3-nitrobenzamide.
And step 3: 5- ((2-amino-3- (((tert-butyldimethylsilyl) oxy) methyl) phenyl) amino) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one
The title compound was synthesized in analogy to example 4, using 5- ((3- (((tert-butyldimethylsilyl) oxy) methyl) -2-nitrophenyl) amino) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one instead of N-methyl-3-nitro-4- [ (2-oxoindolin-6-yl) amino ] benzamide.
And 4, step 4: 5- (4- (((tert-butyldimethylsilyl) oxy) methyl) -2-isopropyl-1H-benzo [ d ] imidazol-1-yl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one
The title compound was synthesized in analogy to example 4, using 5- ((2-amino-3- (((tert-butyldimethylsilyl) oxy) methyl) phenyl) amino) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one instead of 3-amino-N-methyl-4- [ (2-oxoindolin-6-yl) amino ] benzamide.
And 5: 5- (4- (hydroxymethyl) -2-isopropyl-1H-benzo [ d ] imidazol-1-yl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one
5- (4- (((tert-butyldimethylsilyl) oxy) methyl) -2-isopropyl-1H-benzo [ d ] imidazol-1-yl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one (1 eq) was dissolved in THF (0.1M reaction concentration) and cooled to 0 ℃. TBAF (1 eq) was added and the mixture was stirred for 2 hours. The mixture was then diluted with water. The product was extracted with ethyl acetate (x 3). The combined organic layers were then washed with brine and dried over sodium sulfate. The crude material was then purified on silica using a gradient of ethyl acetate/hexane.
Step 6: (2-isopropyl-1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-5-yl) -1H-benzo [ d ] imidazol-4-yl) methyl 4-methylbenzenesulfonate
5- (4- (hydroxymethyl) -2-isopropyl-1H-benzo [ d ] imidazol-1-yl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one (1 eq) was dissolved in THF (0.1M reaction concentration). Hunig's base (2 equivalents) was added followed by tosyl chloride. The mixture was stirred for 8 hours. And then diluted with water. The product was extracted with ethyl acetate (x 3). The combined organic layers were then washed with brine and dried over sodium sulfate. The crude material was then purified on silica using a gradient of ethyl acetate/hexane to provide the desired compound.
And 7: 6- (((2-isopropyl-1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-5-yl) -1H-benzo [ d ] imidazol-4-yl) methyl) amino) hexanoic acid tert-butyl ester
(2-isopropyl-1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-5-yl) -1H-benzo [ d ] imidazol-4-yl) methyl 4-methylbenzenesulfonate (1 eq) was dissolved in DMF (0.2M reaction concentration). Hunig's base (3 equiv.) was added followed by tert-butyl 6 aminocaproate (1 equiv.). The mixture was heated to 60 ℃ for 8 hours. The mixture was then cooled to room temperature and diluted with ethyl acetate and 1.0M aqueous HCl. The organic layer was separated and the product was extracted from the aqueous layer using ethyl acetate (3 ×). The combined organic layers were then washed with brine and dried over sodium sulfate. The crude material was then purified on silica using a methanol gradient in dichloromethane to afford the desired compound.
And 8: 6- (((2-isopropyl-1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-5-yl) -1H-benzo [ d ] imidazol-4-yl) methyl) amino) hexanoic acid
Tert-butyl 6- (((2-isopropyl-1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-5-yl) -1H-benzo [ d ] imidazol-4-yl) methyl) amino) hexanoate (1 eq) was dissolved in dichloromethane (0.5M reaction concentration). Trifluoroacetic acid (10 equivalents) was then added and the mixture was allowed to stir at room temperature for 24 hours. The solvent was then removed under reduced pressure and the crude material was purified on silica using a methanol gradient in dichloromethane to obtain the desired product.
Example 36
3- (2-isopropyl-1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-5-yl) -1H-benzo [ d ] imidazol-5-yl) propiolic acid tert-butyl ester
Step 1: 5- ((4-bromo-2-nitrophenyl) amino) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one
The title compound was synthesized in analogy to example 4, using 4-bromo-1-fluoro-2-nitrobenzene instead of 4-fluoro-N-methyl-3-nitrobenzamide.
Step 2: 5- ((2-amino-4-bromophenyl) amino) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one
The title compound was synthesized in analogy to example 4, using 5- ((4-bromo-2-nitrophenyl) amino) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one instead of N-methyl-3-nitro-4- [ (2-oxoindolin-6-yl) amino ] benzamide.
And step 3: 5- (5-bromo-2-isopropyl-1H-benzo [ d ] imidazol-1-yl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one
The title compound was synthesized in analogy to example 4, using 5- ((2-amino-4-bromophenyl) amino) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one instead of 3-amino-N-methyl-4- [ (2-oxoindolin-6-yl) amino ] benzamide.
And 4, step 4: 3- (2-isopropyl-1- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-5-yl) -1H-benzo [ d ] imidazol-5-yl) propiolic acid tert-butyl ester
Reacting 5- (5-bromo-2-isopropyl-1H-benzo [ d ]]Imidazol-1-yl) -1, 3-dihydro-2H-pyrrolo [2,3-b]Pyridin-2-one (1 eq) and tert-butyl propiolate (1.5 eq) were dissolved in DMF (0.2M reaction concentration). Triethylamine (5 equivalents) was added and the mixture was degassedFor 20 minutes. CuI (0.05 eq.) was then added followed by Pd (PPh)3)4(0.1 equiv.). The mixture was degassed for a further 10 minutes and then heated to 80 ℃. The mixture was stirred for 12 hours. Then cooled to room temperature and diluted with ethyl acetate and water. The organic layer was separated and the product was extracted from the aqueous layer using ethyl acetate (3 ×). The combined organic layers were then washed with brine and dried over sodium sulfate. The crude material was then purified on silica using a methanol gradient in dichloromethane to afford the desired compound.
Pharmacological test
The compounds described herein and their pharmaceutically acceptable salts possess valuable pharmacological properties. The compounds were investigated according to the tests given below.
Fluorescent direct binding protocol
Principle of
Determination of the affinity of a compound for a protein containing one or more tryptophans can be measured by monitoring the fluorescence emission in direct mode. The measurement according to the amount of protein available can be performed manually in a cuvette on an ISS-PC1 photon counting spectrofluorometer or automatically in a well plate on a fluorescence plate reading device. Fluorescence titration was performed at 20 ℃ in the selected binding assay buffer using a defined constant protein concentration for changes in anti-ligand concentration. A small aliquot of known ligand concentration dissolved in DMSO was added and fluorescence excited at 280nm was recorded at 340 nm. Fluorescence intensity was corrected for protein dilution and filtration effects (Birdsall et al). Corrected fluorescence intensity is plotted against ligand concentration and the equilibrium dissociation constant, Kd, is calculated using a four parameter sigmoidal function fit using the law of mass action assuming a 1:1 protein-ligand complex (Eftink, 1997).
Method
1) Optimizing measurement parameters to minimize protein consumption and minimize dilution effects and DMSO content;
2) titrating the protein against the ligand through at least 12 titration steps to obtain a good s-curve fit;
3) the same titration measurements were repeated using ligand alone for calibration;
4) the stability of the proteins was checked by titration against DMSO alone;
5) measuring the molar extinction coefficients of the ligands at 280nm and 340nm by means of an ultraviolet spectrophotometer;
6) the measured raw data was corrected using an Excel template.
Quadratic binding fit and KD evaluation were performed using GraphPad Prism software.
Table 8: protein-buffer, reference compound: thalidomide, katakak, thalidomide
Table 9: is provided with
Protein preparation:
volume protein [ mu.L]
Volume buffer [ mu.L]
Protein concentration [ M]
[email protected]/ml
498.2
5.0E-8
Table 10: protein production
Table 11: titration step
Table 12: example affinity for CRBN proteins
All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the invention as defined in the appended claims.