Antibody-drug complex containing toll-like receptor 7/8 dual agonist compound

Patent metadata

Field	Value
Publication number	US-2025312471-A1
Application number	US-202519208726-A
Country	US
Kind code	A1
Filing date	May 15, 2025
Priority date	Oct 31, 2022
Publication date	Oct 9, 2025
Grant date	—

Abstract

A compound of formula (II), of a salt thereof:wherein X is S or NH, R1 is a lower alkyl or —CH2-isoxazoldiyl-CH3, when R1 is —CH2-isoxazoldiyl-CH3, then X is S, R2 is halogen or H, R3 is CH3 or H, and R40 is a group of formula (a1), (b1), or (c1).

First claim

1 . A compound of formula (II), of a salt thereof:

wherein
X is S or NH,
R 1 is a lower alkyl or —CH 2 -isoxazoldiyl-CH 3 , when R 1 is —CH 2 -isoxazoldiyl-CH 3 , then X is S,
R 2 is halogen or H,
R 3 is CH 3 or H, and
R 40 is a group of formula (a1), (b1), or (c1):

wherein ring A is a 4- to 6-membered cyclic amine comprising a plurality of C and single N atom,
ring B is a 4- to 6-membered cyclic amine comprising a plurality of C, single N and single G,
G is N or CH,
R A is —CH 2 O—, —C(CH 3 ) 2 O—, —O—, or —CH 2 NH—, when R A is —O— or —CH 2 NH—, then X is S, R 2 is halogen, or R 3 is CH 3 ;
R B is a haloalkyl, CH 2 OH, C(CH 3 ) 2 OH, OH, CH 2 NH 2 or H, when R B is OH, CH 2 NH 2 or H, then G is CH, X is S, R 2 is halogen, or R 3 is CH 3 ;
R C is a C 3-6 cycloalkyl or a —CH 2 —C 3-6 cycloalkyl,
M is H or a group of formula (d):

wherein
L D is -lower alkylene-, —C(═O) lower alkylene-, —C(═O)NH lower alkylene-, —C(═O) lower alkylene-(OCH 2 CH 2 ) m —NH—C(═O) lower alkylene-, —(CH 2 CH 2 O) m —C(═O) lower alkylene-, or —C(═O)-cyclohexandiyl-lower alkylene-, and
m is an integer in an range of from 1 to 10.

2 . The compound or salt of claim 1 , wherein
ring A is a 5-membered cyclic amine comprising four C and single N, and ring B is a 6-membered cyclic amine comprising two C, single N, two C, and single G.

3 . The compound or salt of 2 , wherein
R A is —CH 2 O— or —C(CH 3 ) 2 O—, and R B is a haloalkyl, CH 2 OH, or C(CH 3 ) 2 OH.

4 . The compound or salt of claim 3 , wherein
L D is -lower alkylene-, —C(═O) lower alkylene-, —C(═O)NH lower alkylene-, or —C(═O) lower alkylene-(OCH 2 CH 2 ) m —NH—C(═O) lower alkylene-, and m is an integer of 4 to 8.

5 . The compound or salt of claim 4 , wherein
X is NH, R 1 is a lower alkyl, R 2 is halogen or H, and R 3 is H.

6 . The compound or salt of to claim 1 , wherein
X is NH, R 1 is a lower alkyl, R 2 is Cl or H, R 3 is H, R 40 has formula (a1), formula (b1), or formula (c1), ring A is a 5-membered cyclic amine comprising four C and single N, ring B is a 6-membered cyclic amine comprising two C, single N, two C, and single G, G is N, R A is —CH 2 O—, R B is a haloalkyl, R C is a C 3-6 cycloalkyl, M is a group of formula (d), and L D is —C(═O)CH 2 CH 2 — or —C(═O)NHCH 2 CH 2 —.

7 . The compound or salt of claim 1 , wherein
X is NH, R 1 is a lower alkyl, R 2 is H, R 3 is H, R 40 has formula (b1), ring B is a 6-membered cyclic amine comprising two C, single N, two C, and single G, G is N, R B is a haloalkyl, and L D is —C(═O)CH 2 CH 2 —.

8 . The compound or salt of claim 1 , which is
5-[(4-{[(2S)-2-(fluoromethyl)piperazin-1-yl]methyl}-2-methoxyphenyl)methyl]-N 4 -pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine or a salt thereof, 5-[(4-{[(3R)-3-(fluoromethyl)piperazin-1-yl]methyl}-2-methoxyphenyl)methyl]-N 4 -pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine or a salt thereof, 5-({4-[(cyclopropylamino)methyl]-2-methoxyphenyl}methyl)-N 4 -pentyl-5H-pyrrolo [3,2-d]pyrimidine-2,4-diamine or a salt thereof {(2S)-1-[(4-{[2-amino-7-chloro-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]pyrrolidin-2-yl}methanol or a salt thereof, 5-({2-methoxy-4-[(piperidin-4-yl)methyl]phenyl}methyl)-N 4 -pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine or a salt thereof, 5-[(4-{[(2R)-2-(fluoromethyl)piperazin-1-yl]methyl}-2-methoxyphenyl)methyl]-N 4 -pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine or a salt thereof, 5-[(4-{[(cyclobutylmethyl)amino]methyl}-2-methoxyphenyl)methyl]-N 4 -pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine or salt thereof, 1-{3-[(3S)-4-[(4-{[2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]meth yl}-3-methoxyphenyl)methyl]-3-(fluoromethyl)piperazin-1-yl]-3-oxopropyl}-1H-pyrrole-2,5-dione or a salt thereof, {(2S)-1-[(4-{[2-amino-7-chloro-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]pyrrolidin-2-yl}methyl [2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl]carbamate or salt thereof, N-[(4-{[2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]-N-cyclopropyl-3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamide or a salt thereof, or 1-{3-[(3R)-4-[(4-{[2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]meth yl}-3-methoxyphenyl)methyl]-3-(fluoromethyl)piperazin-1-yl]-3-oxopropyl}-1H-pyrrole-2,5-dione or salt thereof.

9 . The compound or salt of claim 1 , which is 5-[(4-{[(2S)-2-(fluoromethyl)piperazin-1-yl]methyl}-2-methoxyphenyl)methyl]-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine or a salt thereof.

10 . The compound or salt of claim 1 , which is 5-[(4-{[(2S)-2-(fluoromethyl)piperazin-1-yl]methyl}-2-methoxyphenyl)methyl]-N 4 -pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine or a salt thereof.

11 . The compound or salt of claim 1 , which is 5-[(4-{[(3R)-3-(fluoromethyl)piperazin-1-yl]methyl}-2-methoxyphenyl)methyl]-N 4 -pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine or a salt thereof.

12 . The compound or salt of claim 1 , which is 5-({4-[(cyclopropylamino)methyl]-2-methoxyphenyl}methyl)-N 4 -pentyl-5H-pyrrolo[3,2-d]p yrimidine-2,4-diamine or a salt thereof.

13 . The compound or salt of claim 1 , which is {(2S)-1-[(4-{[2-amino-7-chloro-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]pyrrolidin-2-yl}methanol or a salt thereof.

14 . The compound or salt of claim 1 , which is 5-({2-methoxy-4-[(piperidin-4-yl)methyl]phenyl}methyl)-N 4 -pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine or a salt thereof.

15 . The compound or salt of claim 1 , which is 5-[(4-{[(2R)-2-(fluoromethyl)piperazin-1-yl]methyl}-2-methoxyphenyl)methyl]-N 4 -pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine or a salt thereof.

16 . The compound or salt of claim 1 , which is 5-[(4-{[(cyclobutylmethyl)amino]methyl}-2-methoxyphenyl)methyl]-N 4 -pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine or salt thereof.

17 . The compound or salt of claim 1 , which is 1-{3-[(3S)-4-[(4-{[2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]-3-(fluoromethyl)piperazin-1-yl]-3-oxopropyl}-1H-pyrrole-2,5-dione or a salt thereof.

18 . The compound or salt of claim 1 , which is {(2S)-1-[(4-{[2-amino-7-chloro-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]pyrrolidin-2-yl}methyl [2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl]carbamate or salt thereof.

19 . The compound or salt of claim 1 , which is N-[(4-{[2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphen yl)methyl]-N-cyclopropyl-3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamide or a salt thereof.

20 . The compound or salt of claim 1 , which is 1-{3-[(3R)-4-[(4-{[2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]-3-(fluoromethyl)piperazin-1-yl]-3-oxopropyl}-1H-pyrrole-2,5-dione or salt thereof.

Assignees

• Astellas Pharma Inc

Inventors

• Akaiwa Michinori
• Seki Yohei
• Wang Yinghua
• Miguelez Javier Ramos
• Ohnuki Kei
• Kamikubo Takashi
• Asano Toru
• Kamikawa Akio
• Chaen Takashi
• Hoshi Rika
• Soga Shinji
• Kwon Chulwon

Classifications

• A61K47/6849 Primary

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• A61K47/6889

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title

• C07K16/28

  against receptors, cell surface antigens or cell surface determinants · CPC title

• C07K16/18

  against material from animals or humans · CPC title

• C07K16/00

  Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies · CPC title