Substituted purine derivative

Patent metadata

Field	Value
Publication number	US-10703755-B2
Application number	US-201716095822-A
Country	US
Kind code	B2
Filing date	Apr 25, 2017
Priority date	Apr 26, 2016
Publication date	Jul 7, 2020
Grant date	Jul 7, 2020

Abstract

The present invention relates to a substituted purine derivative of formula (1) wherein R 1 is alkoxy or the like, R 2 is alkyl or the like, Ring Q 1 is aryl or the like, W 1 is alkylene or the like, Ring Q 2 is aromatic carbocyclyl or the like, n is 1-4, R 3 is hydrogen atom or the like, X 1 is single bond or the like, W 2 is alkylene or the like, and R 4 is hydrogen atom or the like, or a pharmaceutically acceptable salt thereof, which has a potent inhibitory effect against TLR7, and thereby is useful for treating autoimmune disease.

First claim

The invention claimed is:

1. A compound of formula (1):

or a pharmaceutically acceptable salt thereof
wherein
R 1 is optionally-substituted C 1-6 alkoxy, optionally-substituted C 3-7 cycloalkoxy, optionally-substituted 4- to 10-membered saturated heterocyclyloxy, optionally-substituted C 1-6 alkyl, optionally-substituted C 3-7 cycloalkyl, optionally-substituted C 1-6 alkylthio, optionally-substituted 4- to 10-membered saturated heterocyclyl, optionally-substituted amino, halogen atom, or hydroxy;
R 2 is optionally-substituted C 1-6 alkyl, optionally-substituted C 3-7 cycloalkyl, or optionally-substituted amino;
W 1 is single bond, or optionally-substituted C 1-4 alkylene;
Ring Q 1 is
(1) pyridyl which may be substituted with 1-5 the same or different substituents selected from the group consisting of
(a) halogen atom,
(b) cyano,
(c) C 1-6 alkyl which may be substituted with 1-3 the same or different halogen atoms, and
(d) C 1-6 alkoxy which may be substituted with 1-3 the same or different halogen atoms, or
(2) pyrimidinyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of (a)-(d) in the above (1),
Ring Q 2 is C 6-10 aromatic carbocyclyl, or 5- to 10-membered aromatic heterocyclyl;
n is 1, 2, 3, or 4;
R 3 is, independently if there are plural R 3 , hydrogen atom, halogen atom, cyano, hydroxy, optionally-substituted C 1-6 alkyl, optionally-substituted C 1-6 alkoxy, optionally-substituted C 3-7 cycloalkyl, optionally-substituted C 3-7 cycloalkoxy, or optionally-substituted amino;
Q 2 -X 1 — is Q 2 -(single bond)-, Q 2 -(CH 2 ) m —O—, Q 2 -(CH 2 ) m —S—, Q 2 -(CH 2 ) m —S(O) 2 —, Q 2 -(CH 2 ) m —NR a S(O) 2 —, Q 2 -(CH 2 ) m —S(O) 2 NR a —, Q 2 -(CH 2 ) m —C(O)—, Q 2 -(CH 2 ) m —NR a —, Q 2 -(CH 2 ) m —NR a C(O)—, or Q 2 -(CH 2 ) m —C(O)NR a —, wherein R a is hydrogen atom or C 1-6 alkyl; m is 0, 1, or 2;
W 2 is single bond, or optionally-substituted C 1-8 alkylene; and
R 4 is hydrogen atom, —OR b (wherein R b is hydrogen atom, optionally-substituted C 1-6 alkyl, optionally-substituted C 1-6 alkylcarbonyl, optionally-substituted aminocarbonyl, or optionally-substituted C 1-6 alkylsulfonyl), —NR c R d (wherein R c is hydrogen atom or optionally-substituted C 1-6 alkyl; and R d is hydrogen atom, optionally-substituted C 1-6 alkyl, optionally-substituted C 1-6 alkylcarbonyl, optionally-substituted C 1-6 alkoxycarbonyl, or optionally-substituted C 1-6 alkylsulfonyl), optionally-substituted 4- to 10-membered saturated heterocyclyl, or optionally-substituted 5- to 10-membered heteroaryl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 1 is
(1) C 1-6 alkoxy which may be substituted with 1-3 the same or different substituents selected from the group consisting of
(a) halogen atom,
(b) hydroxy,
(c) C 1-6 alkoxy which may be substituted with 1-3 the same or different halogen atoms,
(d) C 3-7 cycloalkyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C 1-6 alkyl, and C 1-6 alkoxy,
(e) C 3-7 cycloalkoxy which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C 1-6 alkyl, and C 1-6 alkoxy,
(f) phenyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C 1-6 alkyl, and C 1-6 alkoxy,
(g) 5- or 6-membered heteroaryl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C 1-6 alkyl, and C 1-6 alkoxy, and
(h) 4- to 7-membered saturated heterocyclyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C 1-6 alkyl, and C 1-6 alkoxy,
(2) C 3-7 cycloalkoxy which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C 1-6 alkyl, and C 1-6 alkoxy,
(3) 4- to 10-membered saturated heterocyclyloxy which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C 1-6 alkyl, and C 1-6 alkoxy,
(4) C 1-6 alkyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy,
(5) C 3-7 cycloalkyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C 1-6 alkyl, and C 1-6 alkoxy,
(6) C 1-6 alkylthio which may be substituted with 1-3 the same or different halogen atoms,
(7) 4- to 10-membered saturated heterocyclyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C 1-6 alkyl, and C 1-6 alkoxy,
(8) amino which may be substituted with 1-2 the same or different C 1-6 alkyl which may be substituted with 1-3 the same or different halogen atoms,
(9) halogen atom, or
(10) hydroxy;
R 2 is C 1-6 alkyl (which may be substituted with 1-3 the same or different halogen atoms), C 3-7 cycloalkyl, or amino (which may be substituted with 1-2 the same or different C 1-6 alkyl);
Ring Q 1 is
(1) pyridyl which may be substituted with 1-5 the same or different substituents selected from the group consisting of
(a) halogen atom,
(b) cyano,
(c) C 1-6 alkyl which may be substituted with 1-3 the same or different halogen atom, and
(d) C 1-6 alkoxy which may be substituted with 1-3 the same or different halogen atoms, or
(2) pyrimidinyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of (a)-(d) in the above (1);
W 1 is single bond, or C 1-4 alkylene which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy,
Ring Q 2 is C 6-10 aromatic carbocyclyl, or 5- to 10-membered aromatic heterocyclyl;
n is 1, 2, 3, or 4;
R 3 is, independently if there are plural R 3 ,
(1) hydrogen atom,
(2) halogen atom,
(3) cyano,
(4) hydroxy,
(5) C 1-6 alkyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy,
(6) C 1-6 alkoxy which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy,
(7) C 3-7 cycloalkyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C 1-6 alkyl, and C 1-6 alkoxy,
(8) C 3-7 cycloalkoxy which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C 1-6 alkyl, and C 1-6 alkoxy, or
(9) amino which may be substituted with 1-2 the same or different C 1-6 alkyl which may be substituted with 1-3 the same or different halogen atoms;
Q 2 -X 1 — is Q 2 -(single bond)-, Q 2 -(CH 2 ) m —O—, Q 2 -(CH 2 ) m —S—, Q 2 -(CH 2 ) m —S(O) 2 —, Q 2 -(CH 2 ) m —NR a S(O) 2 —, Q 2 -(CH 2 ) m —S(O) 2 NR a —, Q 2 -(CH 2 ) m —C(O)—, Q 2 -(CH 2 ) m —NR a —, Q 2 -(CH 2 ) m —NR a C(O)—, or Q 2 -(CH 2 ) m —C(O)NR a —, wherein R a is hydrogen atom or C 1-6 alkyl; m is 0, 1, or 2;
W 2 is single bond, or C 1-8 alkylene which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy; and
R 4 is
(1) hydrogen atom,
(2) —OR b wherein R b is hydrogen atom, C 1-6 alkyl, C 1-6 alkylcarbonyl, mono- or di-C 1-6 alkyl-aminocarbonyl, or C 1-6 alkylsulfonyl,
(3) —NR c R d wherein R c is hydrogen a

Assignees

• Sumitomo Dainippon Pharma Co Ltd

Inventors

• Tojo Shingo
• Isobe Yoshiaki
• Ideue Eiji
• Fujiwara Hiroaki
• Urabe Daisuke

Classifications

• C07D473/28

  Oxygen atom · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• C07D473/34

  attached in position 6, e.g. adenine · CPC title

• C07D473/16

  two nitrogen atoms · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title