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US 2026/0199323 A1Published application
Ligand compounds for e3 ubiquitin ligase, protein degraders developed on basis of ligand compounds, and uses thereof
AssigneeGluetacs Therapeutics (Shanghai) Co., Ltd.
InventorsXiaobao Yang, Renhong Sun, Yan Li, Baoyin Zhao, Ruiyan Zhang
Life of this patent
Estimating the term…
Abstract
The present disclosure provides compounds of Formula (I) and (II) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof, and uses thereof. The present disclosure also provides pharmaceutical compositions comprising, as an active ingredient, the compounds of Formula (I) and (II) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof, and uses thereof.
Claims46
A compound of Formula (I)
- or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof,
- wherein A represents CO, CH2 or CD2;
- R1, R2, R3 and R4 are the same or different and independently represent hydrogen, deuterium, halogen, optionally deuterated C1-6 alkyl, optionally deuterated C1-6 alkoxy, or halogenated C1-6 alkyl;
- (Ra)m indicates that benzene ring is substituted with m Ra substituents, with each Ra being the same or different and independently representing the structure of the following formula:
- wherein R represents chlorine, bromine, iodine, hydroxy, leaving group, NR7R8 or a group W1,
- wherein R7 and R8 are the same or different and independently represent hydrogen, C1-6 alkyl, C2-6 alkynyl-C1-6 alkylene-, C2-6 alkenyl-C1-6 alkylene-, optionally substituted 4- to 15-membered nitrogen-containing heterocyclyl, or R2a—R1a—, where R1a is optionally substituted C1-6 alkylene or optionally substituted C2-6 alkenylene, R2a represents halogen, amino, hydroxy, carboxyl, CHO, C2-6 alkynyl, C2-6 alkenyl or a leaving group;
- and
- W1 represents the structure of the following formula:
- wherein ring W2 represents optionally substituted nitrogen-containing heterocyclyl, each ring W3 is the same or different and independently represents optionally substituted nitrogen-containing heterocyclylene, t represents an integer of 1 or 2, and ring W4 represents optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;
- R5 and R6 are the same or different and independently represent hydrogen, fluorine, chlorine, bromine, iodine, optionally substituted methyl, or optionally substituted linear or branched C2-30 alkyl, wherein one or more groups Rc and/or one or more groups Rd and/or any combination of one or more groups Rc and Rd are optionally inserted into the backbone carbon chain of the linear or branched C2-30 alkyl group, wherein carbon-carbon bond between one or more pairs of adjacent carbon atoms in the backbone carbon chain is interrupted by the group Rc, Rd, or a combination of Rc and Rd;
- wherein each Rc is selected from the group consisting of O, N(Re), C(O), C(O)O, S(O), S(O)2, S(O)2NH, NHS(O)2, OC(O), C(O)N(Re), N(Re)C(O), or N(Re)C(O)N(Re), where each Re independently represents H or C1-6 alkyl, and in case that two or more groups Rc are inserted into the backbone carbon chain of the linear or branched C2-30 alkyl group, the two or more groups Rc are not directly connected to each other;
- and wherein each Rd is selected from the group consisting of cycloalkylene, arylene, heterocyclylene, heteroarylene, alkynylene, alkenylene, or any combination thereof, wherein the cycloalkylene, arylene, heterocyclylene, and heteroarylene are independently optionally substituted with a substituent selected from the group consisting of deuterium, optionally deuterated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, hydroxy, amino, mercapto, halogen, cyano, optionally deuterated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH—, halogenated C1-6 alkyl, NH2—C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)—, optionally deuterated C1-6 alkyl-C(O)NH—, or any combination thereof;
- or
- R and R5, together with the carbon atom to which they are connected, form carbonyl group, R6 represents hydrogen, optionally substituted methyl, or optionally substituted linear or branched C2-30 alkyl, wherein one or more groups Rc and/or one or more groups Rd and/or any combination of one or more groups Rc and Rd are optionally inserted into the backbone carbon chain of the linear or branched C2-30 alkyl group, wherein carbon-carbon bond between one or more pairs of adjacent carbon atoms in the backbone carbon chain is interrupted by the group Rc, Rd, or a combination of Rc and Rd;
- wherein each Rc is selected from the group consisting of O, N(Re), C(O), C(O)O, S(O), S(O)2, S(O)2NH, NHS(O)2, OC(O), C(O)N(Re), N(Re)C(O), or N(Re)C(O)N(Re), where each Re independently represents H or C1-6 alkyl, and in case that two or more groups Rc are inserted into the backbone carbon chain of the linear or branched C2-30 alkyl group, the two or more groups Rc are not directly connected to each other;
- and wherein each Rd is selected from the group consisting of cycloalkylene, arylene, heterocyclylene, heteroarylene, alkynylene, alkenylene, or any combination thereof, wherein the cycloalkylene, arylene, heterocyclylene, and heteroarylene are independently optionally substituted with a substituent selected from the group consisting of deuterium, optionally deuterated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, hydroxy, amino, mercapto, halogen, optionally deuterated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH—, halogenated C1-6 alkyl, NH2—C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)—, optionally deuterated C1-6 alkyl-C(O)NH—, cyano, or any combination thereof;
- (Rb)n indicates that the benzene ring is substituted with n Rb substituents, with each Rb being the same or different and independently representing deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, optionally deuterated C1-6 alkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkyl, optionally substituted C3-6 cycloalkyl, C2-6 alkenyl or C2-6 alkynyl;
- and
- m represents an integer of 1, 2, 3, or 4, n represents an integer of 0, 1, 2, or 3, and the sum of m and n is an integer of 1, 2, 3, or 4;
- wherein when R and R5 together with the carbon atom to which they are connected form a carbonyl group and R6 represents hydrogen, m represents an integer of 1, 2, or 3, n represents an integer of 1, 2, or 3, and
- the sum of m and n is an integer of 2, 3, or 4;
- with the proviso that the following compounds and compounds of Formula (I′) are excluded:
- and
- when A represents CH2 or C(O) and R represents unsubstituted piperazinyl, m represents an integer of 1 and n represents an integer of 0;
- when A represents CH2 or C(O) and Ra represents H2N—CH2—, m represents an integer of 1 and n represents an integer of 0;
- when A represents C(O) and R represents bromine, m represents an integer of 1 and n represents an integer of 0;
- and
- the compounds of Formula (I′):
- wherein in Formula (I′), A represents CH2 or C(O), and R represents unsubstituted piperidinyl or methylamino substituted piperidinyl.
26 more elements
A compound of Formula (II)
- or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs thereof,
- wherein PBM-Rf— represents a targeting moiety capable of binding protein, ULM represents a E3 ubiquitin ligase ligand moiety, LIN is a linker moiety, and PBM-Rf— is covalently bonded to ULM through LIN;
- ULM represents the structure of Formula (ULM):
- wherein A represents CO, CH2 or CD2;
- R1, R2, R3 and R4 are the same or different and each independently represent hydrogen, deuterium, halogen, optionally deuterated C1-6 alkyl, optionally deuterated C1-6 alkoxy, or halogenated C1-6 alkyl;
- (Rb)n indicates that the benzene ring is optionally substituted with n Rb substituents, with each Rb being the same or different and independently representing deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, optionally deuterated C1-6 alkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkyl, optionally substituted C3-6 cycloalkyl, C2-6 alkenyl or C2-6 alkynyl;
- n represents an integer of 0, 1, 2 or 3;
- LIN represents the structure of the following formula:
- wherein R5 and R6 are the same or different and each independently represent hydrogen, fluorine, chlorine, bromine, iodine, optionally substituted methyl, or optionally substituted linear or branched C2-30 alkyl, wherein one or more groups Rc and/or one or more groups Rd and/or any combination of one or more groups Rc and Rd are optionally inserted into the backbone carbon chain of the linear or branched C2-30 alkyl group, wherein carbon-carbon bond between one or more pairs of adjacent carbon atoms in the backbone carbon chain is interrupted by the group Rc, Rd, or a combination of Rc and Rd;
- wherein each Rc is selected from the group consisting of 0, N(Re), C(O), C(O)O, S(O), S(O)2, S(O)2NH, NHS(O)2, OC(O), C(O)N(Re), N(Re)C(O), or N(Re)C(O)N(Re), where each Re independently represents H or C1-6 alkyl, and in case that two or more groups Rc are inserted into the backbone carbon chain of the linear or branched C2-30 alkyl group, the two or more groups Rc are not directly connected to each other;
- and wherein each Rd is selected from the group consisting of cycloalkylene, arylene, heterocyclylene, heteroarylene, alkynylene, alkenylene, or any combination thereof, wherein the cycloalkylene, arylene, heterocyclylene, and heteroarylene are each independently optionally substituted with a substituent selected from the group consisting of deuterium, optionally deuterated C1-6 alkyl, optionally deuterated C3-6 cycloalkyl, hydroxy, amino, mercapto, halogen, cyano, optionally deuterated C1-6 alkoxy, optionally deuterated C1-6 alkyl-NH—, halogenated C1-6 alkyl, NH2—C1-6 alkylene, optionally deuterated C1-6 alkyl-NHC(O)—, optionally deuterated C1-6 alkyl-C(O)NH—, or any combination thereof;
- Rf represents a bond, —O—, —N(Rg)—, —NHC(O)—Rh—W5—*, —C(O)NH—Rh—W5—*, —NHC(O)—W5—*, —C(O)NH—W5—*, —NHC(O)—*, —C(O)NH—*, —O—Rh—W5—*, —O—W5—*, —O—Rh—N(Ri)—*, —N(Rg)—Rh—N(Ri)—*, —W5—, —W5—N(Rg)—*, —N(Rg)—W5—*, —N(Rg)—W5—N(Ri)—*, —Rh—W5—*, —Rh—C(O)—W5—*, —C(O)—W5—*, —Rh—C(O)NH—Rj—W5*, —Rh—NHC(O)—Rj—W5—*, —Rh—C(O)NH—*, —Rh—NHC(O)—*, —Rh—, —Rh—N(Ri)—*, or
- wherein W5 represents the structure of the following formula:
- wherein each ring W6 is the same or different and each independently represents nitrogen-containing heterocyclylene, t1 represents an integer of 1 or 2, (Ra2)m2 indicates that each ring W6 is optionally substituted with m2 Ra2 substituents, with each Ra2 independently representing deuterium, optionally deuterated C1-6 alkyl, optionally halogenated C1-6 alkyl, C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C2-6 alkynyl, C2-6 alkenyl, optionally deuterated C3-6 cycloalkyl, or R12a—R1a—, where R11a is optionally substituted C1-6 alkylene or optionally substituted C2-6 alkenylene, and R12a represents halogen, R13aR14aN—, hydroxy, carboxyl, ethynyl, or vinyl, wherein R13a and R14a are the same or different and each independently represent hydrogen or C1-3 alkyl, and m2 represents an integer of 0-20;
- each ring W7 is the same or different and each independently represents nitrogen-containing heterocyclylene, arylene, or heteroarylene, t2 represents an integer of 0 or 1, (Ra3)m3 indicates that each ring W7 is independently optionally substituted with m3 Ra3 substituents, with each Ra3 independently representing deuterium, optionally deuterated C1-6 alkyl, C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C2-6 alkynyl, C2-6 alkenyl, optionally deuterated C3-6 cycloalkyl, or R16a—R15a—, where R15a is optionally substituted C1-6 alkylene or optionally substituted C2-6 alkenylene, and R16a represents halogen, R17aR18aN—, hydroxy, carboxyl, ethynyl, or vinyl, wherein R17a and R18a are the same or different and each independently represent hydrogen or C1-3 alkyl, and m3 represents an integer of 0-20;
- and
- Rg and Ri each independently represent hydrogen or C1-6 alkyl, Rh and Rj each independently represent optionally substituted C1-6 alkylene or optionally substituted C2-6 alkenylene, and symbol * indicates the point of attachment to LIN;
- wherein when PBM represents the structure of the following formula:
- and simultaneously —Rf-LIN- represents
- where symbol ** indicates the point of attachment to ULM, (Rb)n indicates that benzene ring of Formula (ULM) is substituted with 1, 2, or 3 Rb, with each Rb being the same or different and each independently representing deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, optionally deuterated C1-6 alkyl, optionally deuterated C1-6 alkoxy, halogenated C1-6 alkyl, optionally substituted C3-6 cycloalkyl, C2-6 alkenyl, or C2-6 alkynyl;
- with the proviso that the following compounds are excluded:
- 3-(4-((3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
- N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;
- N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;
- N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)piperidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;
- N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;
- N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)pyrrolidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;
- N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;
- N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)azetidin-3-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide;
- 2-(2,6-dioxopiperidin-3-yl)-5-((4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)isoindoline-1,3-dione;
- and
- 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)methyl)isoindoline-1,3-dione.
29 more elements
(canceled)
(canceled)
37-46. (canceled)
Dependencies are inferred from the claim text.