1H-pyrazolo[4,3-d]pyrimidine compounds as toll-like receptor 7 (TLR7) agonists

Patent metadata

Field	Value
Publication number	US-12485123-B2
Application number	US-202117792878-A
Country	US
Kind code	B2
Filing date	Jan 26, 2021
Priority date	Jan 27, 2020
Publication date	Dec 2, 2025
Grant date	Dec 2, 2025

Abstract

Compounds according to formula I are useful as agonists of Toll-like receptor 7 (TLR7). Such compounds can be used in cancer treatment, especially in combination with an anti-cancer immunotherapy agent, or as a vaccine adjuvant.

First claim

What is claimed is:

1 . A compound having a structure according to formula I

wherein
Ar is

W is H, halo, C 1 -C 3 alkyl, CN, (C 1 -C 4 alkanediyl) OH,

each X is independently N or CR 2 ;
R 1 is (C 1 -C 5 alkyl),
(C 2 -C 5 alkenyl),
(C 1 -C 8 alkanediyl) 0-1 (C 3 -C 6 cycloalkyl),
(C 1 -C 8 alkanediyl) 0-1 (C 5 -C 10 spiroalkyl),
(C 2 -C 8 alkanediyl) OH,
(C 2 -C 8 alkanediyl)O(C 1 -C 3 alkyl),
(C 1 -C 4 alkanediyl) 0-1 (5-6 membered heteroaryl),
(C 1 -C 4 alkanediyl) 0-1 phenyl,
(C 1 -C 4 alkanediyl) CF 3 ,
(C 2 -C 8 alkanediyl) N [C(═O)](C 1 -C 3 alkyl),
or
(C 2 -C 8 alkanediyl) NR x R y ;

each R 2 is independently H, O(C 1 -C 3 alkyl), S (C 1 -C 3 alkyl), SO 2 (C 1 -C 3 alkyl), C 1 -C 3 alkyl, O(C 3 -C 4 cycloalkyl), S(C 3 -C 4 cycloalkyl), SO 2 (C 3 -C 4 cycloalkyl), C 3 -C 4 cycloalkyl, Cl, F, CN, or [C(═O)] 0-1 NR x R y ;
R 3 is H, halo, OH, CN,
NH 2 ,
NH [C(═O)] 0-1 (C 1 -C 8 alkyl),
N(C 1 -C 5 alkyl) 2 ,
NH [C(═O)] 0-1 (C 1 -C 4 alkanediyl) 0-1 (C 3 -C 8 cycloalkyl),
NH [C(═O)] 0-1 (C 1 -C 4 alkanediyl) 0-1 (C 4 -C 10 bicycloalkyl),
NH [C(═O)] 0-1 (C 1 -C 4 alkanediyl) 0-1 (C 5 -C 10 spiroalkyl),
N(C 3 -C 6 cycloalkyl) 2 ,
O(C 1 -C 4 alkanediyl) 0-1 (C 3 -C 8 cycloalkyl),
O(C 1 -C 4 alkanediyl) 0-1 (C 4 -C 8 bicycloalkyl),
O(C 1 -C 4 alkanediyl) 0-1 (C 5 -C 10 spiroalkyl),
O(C 1 -C 4 alkanediyl) 0-1 (C 1 -C 6 alkyl),
N [C 1 -C 3 alkyl]C(═O) (C 1 -C 6 alkyl),
NH(SO 2 ) (C 1 -C 8 alkyl),
NH(SO 2 ) (C 1 -C 4 alkanediyl) 0-1 (C 3 -C 8 cycloalkyl),
NH(SO 2 ) (C 1 -C 4 alkanediyl) 0-1 (C 4 -C 10 bicycloalkyl),
NH(SO 2 ) (C 1 -C 4 alkanediyl) 0-1 (C 5 -C 10 spiroalkyl),
a 6-membered aromatic or heteroaromatic moiety,
a 5-membered heteroaromatic moiety, or
a moiety having the structure

R 4 is NH 2 ,
NH(C 1 -C 5 alkyl),
N(C 1 -C 5 alkyl) 2 ,
NH(C 1 -C 4 alkanediyl) 0-1 (C 3 -C 8 cycloalkyl),
NH(C 1 -C 4 alkanediyl) 0-1 (C 4 -C 10 bicycloalkyl),
NH(C 1 -C 4 alkanediyl) 0-1 (C 5 -C 10 spiroalkyl),
N(C 3 -C 6 cycloalkyl) 2 ,
or
a moiety having the structure

R 5 is H, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 3 -C 6 cycloalkyl, halo, O(C 1 -C 5 alkyl), (C 1 -C 4 alkanediyl) OH, (C 1 -C 4 alkanediyl)O(C 1 -C 3 alkyl), phenyl, NH(C 1 -C 5 alkyl), 5 or 6 membered heteroaryl,

R 6 is NH 2 ,
(NH) 0-1 (C 1 -C 5 alkyl),
N(C 1 -C 5 alkyl) 2 ,
(NH) 0-1 (C 1 -C 4 alkanediyl) 0-1 (C 3 -C 8 cycloalkyl),
(NH) 0-1 (C 1 -C 4 alkanediyl) 0-1 (C 4 -C 10 bicycloalkyl),
(NH) 0-1 (C 1 -C 4 alkanediyl) 0-1 (C 5 -C 10 spiroalkyl),
N(C 3 -C 6 cycloalkyl) 2 ,
or
a moiety having the structure

R x and R y are independently H or C 1 -C 3 alkyl or R x and R y combine with the nitrogen to which they are bonded to form a 3- to 7-membered heterocycle;
n is 1, 2, or 3;
and
p is 0, 1, 2, or 3;
wherein in R 1 , R 2 , R 3 , R 4 , R 5 , and R 6
an alkyl, cycloalkyl, alkanediyl, bicycloalkyl, spiroalkyl, cyclic amine, 6-membered aromatic or heteroaromatic moiety, 5-membered heteroaromatic moiety or a moiety of the formula

is optionally substituted with one or more substituents selected from OH, halo, CN, (C 1 -C 3 alkyl), O(C 1 -C 3 alkyl), C(═O) (C 1 -C 3 alkyl), SO 2 (C 1 -C 3 alkyl), NR x R y , (C 1 -C 4 alkanediyl) OH, (C 1 -C 4 alkanediyl)O(C 1 -C 3 alkyl);
and
an alkyl, alkanediyl, cycloalkyl, bicycloalkyl, spiroalkyl, or a moiety of the formula

may have a CH 2 group replaced by O, SO 2 , CF 2 , C(═O), NH,
N [C(═O)] 0-1 (C 1 -C 3 alkyl),
N [C(═O)] 0-1 (C 1 -C 4 alkanediyl) 0-1 CF 3 ,
or
N [C(═O)] 0-1 (C 1 -C 4 alkanediyl) 0-1 (C 3 -C 8 cycloalkyl).

2 . The compound according to claim 1 , having a structure according to formula (Ia)

3 . The compound according to claim 1 , having a structure according to formula (Ib)

4 . The compound according to claim 3 , wherein R 3 is

5 . The compound according to claim 4 , wherein R 1 is

and
R 5 is H or Me.

6 . The compound according to claim 1 , having a structure according to formula (Ic)

7 . The compound according to claim 6 , wherein R 4 is

8 . The compound according to claim 7 , wherein R 1 is

and
R 5 is H or Me.

9 . A compound having a structure according to formula (Id)

wherein W is

10 . A compound having a structure according to formula (Ie)

wherein
R 1 is

R 5 is H or Me; and
R 7 is H, C 1 -C 8 alkyl, or C 3 -C 6 cycloalkyl; wherein the cycloalkyl group optionally has a CH 2 group replaced by O, NH, or N(C 1 -C 3 )alkyl.

Assignees

• Bristol Myers Squibb Co

Inventors

• Zhang Qian
• Gangwar Sanjeev
• Gavai Ashvinikumar V
• Cong Qiang
• Poudel Yam B
• He Liqi
• Sivaprakasam Prasanna
• Tarby Christine M

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K39/3955

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title