5H-pyrrolo[3,2-d]pyrimidine-2,4-diamino compounds and antibody conjugates thereof

Patent metadata

Field	Value
Publication number	US-12534465-B2
Application number	US-202017617573-A
Country	US
Kind code	B2
Filing date	Jun 10, 2020
Priority date	Jun 10, 2019
Publication date	Jan 27, 2026
Grant date	Jan 27, 2026

Abstract

The present disclosure relates to 5H-Pyrrolo[3,2-d]pyrimidine-2,4-diamino compounds, and/or antibody conjugates thereof; and pharmaceutical compositions thereof, methods of producing the conjugates, and methods of using the conjugates and compositions for therapy.

First claim

What is claimed is:

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt, solvate or N-oxide thereof;
wherein
R 1a , R 1b , R 2a , and R 2b are independently, at each occurrence, selected from hydrogen, and C 1-6 alkyl;
ring A is cycloalkyl, heterocycloalkyl, monocyclic aryl, monocyclic heteroaryl, fused bicyclic aryl, or fused bicyclic heteroaryl, where heterocycloalkyl and each heteroaryl comprise 1, 2, 3 or 4 heteroatoms independently selected from N, S, and O;
ring B is a 4-membered N-linked heterocycloalkyl, which is substituted with 1-2 R 3 ; wherein the heterocycloalkyl includes 1 or 2 heteroatoms independently selected from N, S, and O;
and wherein R 3 is, independently, at each occurrence, —N(R 3a ) 2 , —OR 3b , —C(R 3c ) 2 NH 2 , C 1-6 alkyl, heterocycloalkyl, heteroaryl, or partially saturated heteroaryl, or two R 3 attached to the same carbon, together with the carbon atom to which they are attached, form a spiro-heterocycloalkyl; wherein heterocycloalkyl, spiro-heterocycloalkyl, heteroaryl, and partially saturated heteroaryl in R 3 include 1, 2, 3 or 4 heteroatoms independently selected from N, S, and O, and are optionally substituted with 1-2 C 1-3 alkyl; or
ring B is a 5-6 membered N-linked heterocycloalkyl, which is substituted with 1-3 R 3 , or a 5-6 membered N-linked heteroaryl, which is substituted with 1-3 R 3 ; wherein the heterocycloalkyl includes 1 or 2 heteroatoms independently selected from N, S, and O; and wherein R 3 is, independently, at each occurrence, —N(R 3a ) 2 , —OR 3b , —C(R 3c ) 2 NH 2 heterocycloalkyl, heteroaryl, or partially saturated heteroaryl, or two R 3 attached to the same carbon, together with the carbon atom to which they are attached, form a spiro-heterocycloalkyl; wherein heterocycloalkyl, spiro-heterocycloalkyl, heteroaryl, and partially saturated heteroaryl in R 3 include 1, 2, 3 or 4 heteroatoms independently selected from N, S, and O, and are optionally substituted with 1-2 C 1-3 alkyl;
or
ring B is a 7-10 membered N-linked heterocycloalkyl, which is substituted with 1-3 R 3 , or a 5-10 membered N-linked heteroaryl which is substituted with 1-3 R 3 ; wherein R 3 is, independently, at each occurrence, —N(R 3a ) 2 , —OR 3b , —C(R 3c ) 2 NH 2 , C 1-6 alkyl, heterocycloalkyl, heteroaryl, or partially saturated heteroaryl, or two R 3 attached to the same carbon, together with the carbon atom to which they are attached, form a spiro-heterocycloalkyl; wherein heterocycloalkyl, spiro-heterocycloalkyl, heteroaryl, and partially saturated heteroaryl in R 3 include 1, 2, 3 or 4 heteroatoms independently selected from N, S, and O, and are optionally substituted with 1-2 C 1-3 alkyl;
or
ring B is unsubstituted 2,5-diazabicyclo[2.2.2]octanyl or 3,9-diazabicyclo[3.3.2]decanyl;
R 3a is independently, at each occurrence, selected from hydrogen, C 1-6 alkyl, —C(═O)—CH 2 NH 2 , and cycloalkyl;
R 3b is independently, at each occurrence, selected from hydrogen,

 where q1 is 1, 2, or 3, and —CH 2 -aryl-CH 2 NH 2 ;
R 3c is independently, at each occurrence, selected from hydrogen, and C 1-6 alkyl, or two R 3c , together with the carbon atom to which they are attached, form a cycloalkyl;
R 4 is C 1-6 alkyl; and
R 5 is C 3-6 cycloalkyl, or C 1-6 alkyl, each of which is optionally substituted with 1, 2, or 3 R 5a groups independently selected from halo, hydroxy, alkoxy, amino, C 1-6 alkylamino, C 1-6 dialkylamino, C 3-6 cycloalkyl, aryl, and heteroaryl, wherein heteroaryl includes 1, 2, 3 or 4 heteroatoms independently selected from N, S, and O, and wherein any of the R 5a C 3-6 cycloalkyl, aryl, and heteroaryl groups are optionally further substituted with 1, 2, or 3 groups independently selected from halo, hydroxy, alkyl, and haloalkyl.

2 . The compound of claim 1 , wherein
ring A is cycloalkyl, heterocycloalkyl, monocyclic aryl, monocyclic heteroaryl, fused bicyclic aryl, or fused bicyclic heteroaryl, where heterocycloalkyl and each heteroaryl comprise 1, 2, 3 or 4 heteroatoms selected from N, S, and O; ring B is a 4-membered N-linked heterocycloalkyl, which is further substituted with 1-2 R 3 ; wherein R 3 is, independently, at each occurrence, —N(R 3a ) 2 , —OR 3b , —C(R 3c ) 2 NH 2 , C 1-6 alkyl, heterocycloalkyl, heteroaryl, or partially saturated heteroaryl, or two R 3 attached to the same carbon, together with the carbon atom to which they are attached, form a spiro-heterocycloalkyl; wherein heterocycloalkyl, spiro-heterocycloalkyl, heteroaryl, and partially saturated heteroaryl include 1, 2, 3 or 4 heteroatoms selected from N, S, and O, and are optionally further substituted with 1-2 C 1-3 alkyl; or ring B is a 5-6 membered N-linked heterocycloalkyl, which is further substituted with 1-3 R 3 ; wherein R 3 is, independently, at each occurrence, —N(R 3a ) 2 , —OR 3b , —C(R 3c ) 2 NH 2 heterocycloalkyl, heteroaryl, or partially saturated heteroaryl, or two R 3 attached to the same carbon, together with the carbon atom to which they are attached, form a spiro-heterocycloalkyl; wherein heterocycloalkyl, spiro-heterocycloalkyl, heteroaryl, and partially saturated heteroaryl include 1, 2, 3 or 4 heteroatoms selected from N, S, and O, and are optionally further substituted with 1-2 C 1-3 alkyl; or ring B is a 7-10 membered N-linked heterocycloalkyl, which is further substituted with 1-3 R 3 , or a 5-10 membered N-linked heteroaryl which is further substituted with 1-3 R 3 ; wherein R 3 is, independently, at each occurrence, —N(R 3a ) 2 , —OR 3b , —C(R 3c ) 2 NH 2 , C 1-6 alkyl, heterocycloalkyl, heteroaryl, or partially saturated heteroaryl, or two R 3 attached to the same carbon, together with the carbon atom to which they are attached, form a spiro-heterocycloalkyl; wherein heterocycloalkyl, spiro-heterocycloalkyl, heteroaryl, and partially saturated heteroaryl include 1, 2, 3 or 4 heteroatoms selected from N, S, and O, and are optionally further substituted with 1-2 C 1-3 alkyl; R 3b is independently, at each occurrence, selected from hydrogen,

 and —CH 2 -aryl-CH 2 NH 2 ;
R 5 is C 1-6 cycloalkyl, or C 1-6 alkyl optionally substituted with halo, hydroxy, alkoxy, amino, C 1-6 alkylamino, C 1-6 dialkylamino, C 1-6 cycloalkyl, aryl or heteroaryl, wherein heteroaryl includes 1, 2, 3 or 4 heteroatoms selected from N, S, and O, and wherein cycloalkyl, aryl, and heteroaryl are optionally further substituted with halo, hydroxy, alkyl, or haloalkyl.

3 . The compound of claim 1 , according to the structure of Formula (II):

or a pharmaceutically acceptable salt, solvate or N-oxide thereof;
wherein
R 1a , R 1b , R 2a , and R 2b are independently, at each occurrence, selected from hydrogen, and C 1-6 alkyl;
ring A is a six-membered aryl or six-membered heteroaryl ring, where Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from C and N;
ring B is a 4-membered N-linked heterocycloalkyl, which is substituted with 1-2 R 3 ; wherein R 3 is, independently, at each occurrence, —N(R 3a ) 2 , —OR 3b , —C(R 3c ) 2 NH 2 , C 1-6 alkyl, heterocycloalkyl, heteroaryl, or partially saturated heteroaryl, or two R 3 attached to the same carbon, together with the carbon atom to which they are attached, form a spiro-heterocycloalkyl; wherein heterocycloalkyl, spiro-heterocycloalkyl, heteroaryl, and partially saturated heteroaryl in R 3 include 1, 2, 3 or 4 heteroatom

Assignees

• Sutro Biopharma Inc

Inventors

• Maderna Andreas
• Galan Adam A
• Bajjuri Krishna

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/6849

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

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title