JPWO2020038415A5

JPWO2020038415A5 -

Info

Publication number: JPWO2020038415A5
Application number: JP2021509151A
Authority: JP
Publication date: 2022-08-29
Anticipated expiration: 2039-08-21

Claims

A bivalent compound, or a pharmaceutically acceptable salt thereof, comprising a tropomyosin receptor kinase (TRK) ligand conjugated to a degradation tag via a linker moiety , wherein
said TRK ligand comprises a moiety of Formula 1;

During the ceremony,
X is CR'R",
R′ and R″ are independently selected from hydrogen, halogen, OH, and C ₁ -C ₈ alkyl;
R is optionally substituted aryl;
R ¹ , R ² , and R ³ are independently hydrogen;
R ⁴ is attached to the linker moiety of said divalent compound and is selected from a single bond, optionally substituted C3 _- C8 cycloalkyl, and optionally substituted 3-8 membered heterocyclyl _;
Ar is one or more independently selected from hydrogen, halogen, CN, NO ₂ , OR ¹² , NR ¹³ R ¹⁴ , NR ¹³ COR ¹⁴ , C ₃ -C ₈ cycloalkyl, and 3-8 membered heterocyclyl; aryl optionally substituted with the substituents of
R ¹² , R ¹³ and R ¹⁴ are independently selected from hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkoxy and 3-8 membered heterocyclyl; or,
R ¹³ and R ¹⁴ together with the atoms to which they are connected form a 4- to 8-membered cycloalkyl or heterocyclyl ring,
wherein said linker moiety is of Formula 9;

During the ceremony,
A, W, and B are independently on each occurrence null or R′—R″, R′COR″, R′CO ₂ R″, R′C(O)N(R ¹ ) R'', R'OR'', R'OC(O)R'', R'OC(O)OR'', R'OCON(R ¹ )R'', R'N(R ¹ ) a divalent moiety selected from R'', R'NR ¹ COR'', R'NR ¹ C(O)OR'', and R'NR ¹ CON(R ² )R'';
R′ and R″ are independently null, R ^r —(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkylene, C ₂ -C ₈ alkenylene, C ₂ -C ₈ alkynylene, C ₁ -C ₈ hydroxyalkylene, C ₁ -C ₈ haloalkylene, 3-10 membered carbocyclyl, and 4-10 membered heterocyclyl;
R ^r is selected from 3-10 membered carbocyclyl and 4-10 membered heterocyclyl;
R ¹ and R ² are independently selected from hydrogen and C ₁ -C ₈ alkyl, and
m is 0-15, and
the resolution tag is part of Formula 5B;

During the ceremony,
V, W, and X ^are independently CR2 ;
Y is selected from ^CO and ^CR3R4 ;
Z is null, CO, CR ⁵ R ⁶ , NR ⁵ , O, optionally substituted C ₁ -C ₁₀ alkylene, optionally substituted C ₁ -C ₁₀ alkenylene, optionally substituted C ₁ -C _10alkynylene , optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;
R ¹ and R ² are hydrogen;
R ³ and R ⁴ are hydrogen, and
A divalent compound, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 ^are ^hydrogen .

R ⁴ -Ar is part of formula A1;

During the ceremony ,
^* indicates the connection to the linker moiety of the divalent compound,
R ^a is selected from NR ¹³ R ¹⁴ and NR ¹³ COR ¹⁴ ;
R ¹³ and R ¹⁴ are independently selected from hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkoxy and 3-8 membered heterocyclyl, or
2. The divalent compound of claim 1, wherein R ¹³ and R ¹⁴ together with the atoms to which they are attached form a 4- to 8-membered cycloalkyl or heterocyclyl ring, or a pharmaceutically acceptable compound thereof. salt.

3. The divalent compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein said degradation tag is selected from the group consisting of:

4. The bivalent compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein said linker moiety comprises a ring of formula C1.

R. ^ｒr teeth

or a pharmaceutically acceptable salt thereof, according to any one of claims 1-3, wherein

The linker is -(CO)-(CH _２2 ) _１－８1-8 -, -(CH _２2 ) _１－９1-9 -, -(CH _２2 ) _１－２1-2 -(CO)-NH-(CH _２2 ) _２－９2-9 -, -(CH _２2 ) _１－２1-2 -(CO)-NH-(CH _２2 ) _１－３1-3 -(OCH _２2 CH _２2 ) _１－７1-7 -, -(CH _２2 ) _０－１0-1 -(CO)-(CH _２2 ) _１－３1-3 -(OCH _２2 CH _２2 ) _１－７1-7 -, -(CO)-(CH _２2 ) _０－３0-3 -(alkenylene)-(CH _２2 ) _０－３0-3 -, -(CO)-(CH _２2 ) _０－３0-3 -(alkynylene)-(CH _２2 ) _０－３0-3 -, -(CO)-(CH _２2 ) _０－３0-3 -(3- to 8-membered carbocyclyl)-(CH _２2 ) _０－３0-3 -, -(CO)-(CH _２2 ) _０－３0-3 -(3- to 8-membered heterocarbocyclyl)-(CH _２2 ) _０－３0-3 -, -(CH _２2 ) _０－３0-3 -(alkenylene)-(CH _２2 ) _０－３0-3 -, -(CH _２2 ) _０－３0-3 -(alkynylene)-(CH _２2 ) _０－３0-3 -, -(CH _２2 ) _０－３0-3 -(3- to 8-membered carbocyclyl)-(CH _２2 ) _０－３0-3 -, -(CH _２2 ) _０－３0-3 -(3- to 8-membered heterocarbocyclyl)-(CH _２2 ) _０－３0-3 -, R ^ｒr -(CO)-(CH _２2 ) _１－８1-8 -, R ^ｒr -(CH _２2 ) _１－９1-9 -, R ^ｒr -(CH _２2 ) _１－２1-2 -(CO)-NH-(CH _２2 ) _２－９2-9 -, R ^ｒr -(CH _２2 ) _１－２1-2 -(CO)-NH-(CH _２2 ) _１－３1-3 -(OCH _２2 CH _２2 ) _１－７1-7 -, R ^ｒr -(CH _２2 ) _０－１0-1 -(CO)-(CH _２2 ) _１－３1-3 -(OCH _２2 CH _２2 ) _１－７1-7 -, R ^ｒr -(CO)-(CH _２2 ) _０－３0-3 -(alkenylene)-(CH _２2 ) _０－３0-3 -, R ^ｒr -(CO)-(CH _２2 ) _０－３0-3 -(alkynylene)-(CH _２2 ) _０－３0-3 -, R ^ｒr -(CO)-(CH _２2 ) _０－３0-3 -(3- to 8-membered carbocyclyl)-(CH _２2 ) _０－３0-3 -, R ^ｒr -(CO)-(CH _２2 ) _０－３0-3 -(3- to 8-membered heterocarbocyclyl)-(CH _２2 ) _０－３0-3 -, R ^ｒr -(CH _２2 ) _０－３0-3 -(alkenylene)-(CH _２2 ) _０－３0-3 -, R ^ｒr -(CH _２2 ) _０－３0-3 -(alkynylene)-(CH _２2 ) _０－３0-3 -, R ^ｒr -(CH _２2 ) _０－３0-3 -(3- to 8-membered carbocyclyl)-(CH _２2 ) _０－３0-3 -, and R ^ｒr -(CH _２2 ) _０－３0-3 -(3- to 8-membered heterocarbocyclyl)-(CH _２2 ) _０－３0-3 or a pharmaceutically acceptable salt thereof, according to any one of claims 1-3, selected from the group consisting of:

The divalent compound is
2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl) imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione (TR-123),
2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo) [1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)isoindoline-1,3-dione (TR-172),
2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo) [1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)isoindoline-1,3-dione (TR-173),
2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl) imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)isoindoline-1,3-dione (TR-181),
3-(6-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl) pyridin-2-yl)piperazin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-185),
3-(5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl) pyridin-2-yl)piperazin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-186),
3-(5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl) )pyridin-2-yl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-191),
3-(6-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl) )pyridin-2-yl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-196),
2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl) imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione (TR-198),
3-(6-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl) Pyridin-2-yl)piperazin-1-yl)-3-oxoprop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-202)
3-(5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl) Pyridin-2-yl)piperazin-1-yl)-3-oxoprop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (TR-203)
2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo) [1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)isoindoline-1,3-dione (TR-204)
2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo) [1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-carbonyl)azetidin-1-yl)isoindoline-1,3-dione (TR-211)
2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl) imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)isoindoline-1,3-dione (TR-225)
N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[[1-[2-(2,6-dioxo-3-piperidyl)- 1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]methyl]piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamide (TR-231)
N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[[2-(2,6-dioxo-3-piperidyl)- 1,3-dioxo-isoindolin-5-yl]amino]ethyl]piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamide (TR-232)
N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-(4-(6-(6-((R)-2 -(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-233), or its pharmaceutical 2. The divalent compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of salts acceptable for:

The divalent compound is N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[[1-[2-(2,6-dioxo -3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]methyl]piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamide (TR-231) or a pharmaceutically acceptable salt thereof.

The divalent compound is N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-[4-[2-[[2-(2,6-dioxo -3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]ethyl]piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamide (TR-232) or its pharmaceutical 8. A divalent compound according to claim 7, or a pharmaceutically acceptable salt thereof, which is a pharmaceutically acceptable salt.

The divalent compound is N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-(4-(6-(6- ((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-233 ), or a pharmaceutically acceptable salt thereof, according to claim 7, or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition comprising a bivalent compound according to any of claims 1-10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

12. The pharmaceutical composition of claim 11 for use in a method of treating a tropomyosin receptor kinase (TRK)-mediated disease, said method comprising treating a subject with a TRK-mediated disease by administering said pharmaceutical composition 12. The pharmaceutical composition of claim 11, comprising the step of administering

13. The pharmaceutical composition of claim 12, wherein the TRK-mediated disease results from TRK expression, TRK overexpression, TRK mutation, or TRK condensation.

The TRK-mediated diseases consist of cancer, inflammatory diseases, acute or chronic pain, pruritus, bone-related diseases, neurodegenerative diseases, infectious diseases, cachexia, anorexia, demyelination, and dysmyelination. 13. A pharmaceutical composition according to claim 12, selected from the group.

15. The pharmaceutical composition of claim 14, wherein said TRK-mediated disease is cancer.