Inhibitors of peptidylarginine deiminases

Patent metadata

Field	Value
Publication number	US-11976083-B2
Application number	US-202117242617-A
Country	US
Kind code	B2
Filing date	Apr 28, 2021
Priority date	Apr 30, 2020
Publication date	May 7, 2024
Grant date	May 7, 2024

Abstract

The present disclosure relates to novel compounds for use in therapeutic treatment of a disease associated with peptidylarginine deiminases (PADs), such as peptidylarginine deiminase type 4 (PAD4). The present disclosure also relates to processes and intermediates for the preparation of such compounds, methods of using such compounds and pharmaceutical compositions comprising the compounds described herein.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, wherein:
X 1 and X 2 are C or N;
X 3 is N—R 3 or C—R 3 ; provided that two of X 1 , X 2 , and X 3 are C; where each dashed line represents an optional bond to complete valency requirements of each X 1 , X 2 and X 3 ;
X 4 is N or C—R 2 ;
X 5 is N or CR 6 ;
X 7 is N or CR 7 ;
R 1 is hydrogen, halo, —CN, —OR 12 , —N(R 12 ) 2 , —SR 12 , —C 1-8 alkyl optionally substituted with 1 to 3 Z 1 , C 3-6 cycloalkyl optionally substituted with 1 to 3 Z 1 , or 4-6 membered heterocyclyl optionally substituted with 1 to 3 Z 1 ;
R 2 is hydrogen, halo, —CN, —OR 12 , —N(R 12 ) 2 , —SR 12 , —C 1-8 alkyl optionally substituted with 1 to 3 Z 2 , C 3-6 cycloalkyl optionally substituted with 1 to 3 Z 2 , or 4-6 membered heterocyclyl optionally substituted with 1 to 3 Z 2 ;
when X 3 is N—R 3 , R 3 is hydrogen, C 1-8 alkyl optionally substituted with 1 to 3 Z 3 , C 3-10 alkenyl optionally substituted with 1 to 3 Z 3 , C 3-10 alkynyl optionally substituted with 1 to 3 Z 3 , C 3-10 cycloalkyl optionally substituted with 1 to 3 Z 3 , or 4-10 membered heterocyclyl optionally substituted with 1 to 3 Z 3 ; and
when X 3 is C—R 3 ; R 3 is hydrogen, halo, —CN, —OR 12 , —N(R 12 ) 2 , —SR 12 , C 1-8 alkyl optionally substituted with 1 to 3 Z 3 , C 2-10 alkenyl optionally substituted with 1 to 3 Z 3 , C 2-10 alkynyl optionally substituted with 1 to 3 Z 3 , C 3-10 cycloalkyl optionally substituted with 1 to 3 Z 3 , or 4-10 membered heterocyclyl optionally substituted with 1 to 3 Z 3 ; or
when R 2 is —C 1-8 alkyl, —OR 12 , or —N(R 12 ) 2 , and R 3 is C 1-8 alkyl, then R 2 and R 3 may be taken together with the atoms to which they are attached to form an optionally substituted 6 to 8 membered ring;
R 6 is hydrogen, halo, —CN, —OR 12 , —C 1-8 alkyl optionally substituted with 1 to 3 Z 6 , C 3-6 cycloalkyl optionally substituted with 1 to 3 Z 6 , or 4-6 membered heterocyclyl optionally substituted with 1 to 3 Z 6 ;
R 7 is hydrogen, halo, —CN, —OR 12 , —C 1-8 alkyl optionally substituted with 1 to 3 Z 7 , C 3-6 cycloalkyl optionally substituted with 1 to 3 Z 7 , or 4-6 membered heterocyclyl optionally substituted with 1 to 3 Z 7 ;
L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 are each independently:
C 1-10 alkylene, optionally substituted with 1 to 3 Z 8 ;
C 2-10 alkenylene, optionally substituted with 1 to 3 Z 8 ;
C 2-10 alkynylene, optionally substituted with 1 to 3 Z 8 ;
2-6 membered heteroalkylene, optionally substituted with 1 to 3 Z 8 ;
C 3 -C 10 cycloalkylene, optionally substituted with 1 to 3 Z 8 ;
4-10 membered heterocyclene, optionally substituted with 1 to 3 Z 8 ;
C 6-10 arylene, optionally substituted with 1 to 3 Z 8 ;
5-10 membered heteroarylene, optionally substituted with 1 to 3 Z 8 ; or
—O—, —N(R 8 )—, —S—, —C(O)—, —C(O)O—, —C(O)N(R 8 )—, —SO—, —SO 2 —, —SO 2 N(R 8 )—, —N(R 8 )C(O)O—, —OC(O)O—, —N(R 8 )C(O)N(R 8 )—, —N(R 8 )S(O) 2 N(R 8 )—, —N(R 8 )C(N—CN)—, —S(O)(NR 8 )—, or —S(O)(NR 8 )N(R 8 )—; and
m1, m2, m3, m4, m5, and m6 are each independently 0 or 1;
provided that L 1 m1 , L 2 m2 , L 3 m3 , L 4 m4 , L 5 m5 , and L 6 m6 taken together with the four consecutive atoms between which they are attached form an optionally substituted 11 to 20 membered macrocyclic ring;
each R 8 and R 9 is independently hydrogen, C 1-8 alkyl optionally substituted with 1 to 3 Z 1b , C 2-8 alkenyl optionally substituted with 1 to 3 Z 1b , C 2-8 alkynyl optionally substituted with 1 to 3 Z 1b , C 3-10 cycloalkyl optionally substituted with 1 to 3 Z 1b , 4-10 membered heterocyclyl optionally substituted with 1 to 3 Z 1b , C 6-10 aryl optionally substituted with 1 to 3 Z 1b , or 5-10 membered heteroaryl optionally substituted with 1 to 3 Z 1b ;
R 10 is hydrogen, —C 1-8 alkyl optionally substituted with 1 to 3 Z 10 , or C 3-6 cycloalkyl optionally substituted with 1 to 3 Z 10 ;
R 11 is hydrogen, —C 1-8 alkyl optionally substituted with 1 to 4 Z 11 , —C 3-8 cycloalkyl optionally substituted with 1 to 4 Z 11 , or 4-12-membered heterocyclyl optionally substituted with 1 to 4 Z 11 ; or
R 10 and R 11 are taken together with nitrogen to which they are attached to form a 4-12-membered heterocyclyl optionally substituted with 1 to 4 Z 11 ;
each R 12 and R 13 are independently hydrogen, C 1-8 alkyl optionally substituted with 1 to 3 Z 1b , C 2-8 alkenyl optionally substituted with 1 to 3 Z 1b , C 2-8 alkynyl optionally substituted with 1 to 3 Z 1b , C 3-10 cycloalkyl optionally substituted with 1 to 3 Z 1b , 4-10 membered heterocyclyl optionally substituted with 1 to 3 Z 1b , C 6-10 aryl optionally substituted with 1 to 3 Z 1b , or 5-10 membered heteroaryl optionally substituted with 1 to 3 Z 1b ;
each Z 1 , Z 2 , Z 3 , Z 6 , Z 7 , and Z 8 is independently oxo, halo, —NO 2 , —N 3 , —CN, C 1-8 alkyl optionally substituted by 1 to 3 Z 1a , C 2-8 alkenyl optionally substituted by 1 to 3 Z 1a , C 2-8 alkynyl optionally substituted by 1 to 3 Z 1a , C 3-8 cycloalkyl optionally substituted by 1 to 3 Z 1a , 6-10 membered aryl optionally substituted by 1 to 3 Z 1a , 4-10 membered heterocyclyl optionally substituted by 1 to 3 Z 1a , 5-10 membered heteroaryl optionally substituted with 1 to 3 Z 1a , —OR 9 , —C(O)R 9 , —C(O)OR 9 , —C(O)N(R 9 ) 2 , —N(R 9 ) 2 , —N(R 9 ) 3 + , —N(R 9 )C(O)R 9 , —N(R 9 )C(O)OR 9 , —N(R 9 )C(O)N(R 9 ) 2 , —N(R 9 )S(O) 2 (R 9 ), —NR 9 S(O) 2 N(R 9 ) 2 , —NR 9 S(O) 2 O(R 9 ), —NS(O)(R 9 ) 2 , —OC(O)R 9 , —OC(O)OR 9 , —OC(O)N(R 9 ) 2 , —Si(R 9 ) 3 , —SR 9 , —S(O)R 9 , —SF 5 , —S(O)(NR 9 )R 9 , —S(NR 9 )(NR 9 )R 9 , —S(O)(NR 9 )N(R 9 ) 2 , —S(O)(NCN)R 9 , —S(O) 2 R 9 , —S(O) 2 N(R 9 ) 2 , —C(O)N(R 9 )S(O) 2 R 9 , or —S(O) 2 N(R 9 )C(O)R 9 , wherein each Z 2 , Z 3 , Z 6 , Z 7 , and Z 8 is independently optionally substituted with 1 to 3 Z 1a ;
each Z 1a is independently oxo, halo, —NO 2 , —N 3 , —CN, C 1-8 alkyl optionally substituted by 1 to 3 Z 1b , C 2-8 alkenyl optionally substituted by 1 to 3 Z 1b , C 2-8 alkynyl optionally substituted by 1 to 3 Z 1b , C 3-8 cycloalkyl optionally substituted by 1 to 3 Z 1b , 6-10 membered aryl optionally substituted by 1 to 3 Z 1b , 4-10 membered heterocyclyl optionally substituted by 1 to 3 Z 1b , 5-10 membered heteroaryl optionally substituted with 1 to 3 Z 1b , —OR 13 , —C(O)R 13 , —C(O)OR 13 , —C(O)N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 ) 3 + , —N(R 13 )C(O)R 13 , —N(R 13 )C(O)OR 13 , —N(R 13 )C(O)N(R 13 ) 2 , —N(R 13 )S(O) 2 (R 13 ), —NR 13 S(O) 2 N(R 13 ) 2 , —NR 13 S(O) 2 O(R 13 ), —NS(O)(R 13 ) 2 , —OC(O)R 13 , —OC(O)OR 13 , —OC(O)N(R 13 ) 2 , —Si(R 13 ) 3 , —SR 13 , —S(O)R 13 , —SF 5 , —S(O)(NR 13 )R 13 , —S(NR 13 )(NR 13 )R 13 , —S(O)(NR 13 )N(R 13 ) 2 , —S(O)(NCN)R 13 , —S(O) 2 R 13 , —S(O) 2 N(R 13 ) 2 , —C(O)N(R 13 )S(O) 2 R 13 , or —S(O) 2 N(R 13 )C(O)R 13 ;
each Z 10 and Z 11 is independently selected from oxo, halo, —CN, C 1-9 alkyl optionally substituted by 1 to 3 Z 1b , C 3-8 cycloalkyl optionally substituted by 1 to 3 Z 1b , aryl optionally substituted by 1 to 3 Z 1b , 4-10 membered heterocyclyl optionally substituted by 1 to 3 Z 1b , 5-10 membered heteroaryl optionally substituted with 1 to 3 Z 1b , —OR 13 , —C(O)R 13 , —C(O)OR 13 , —C(O)N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 ) 3 + , —N(R 13 )C(O)R 13 , —N(R 13 )C(O)OR 13 , —N(R 13 )C(O)N(R 13 ) 2 , —OC(O)R 13 , —OC(O)OR 13 , —OC(O)—N(R 13 ) 2 , and —S—R 13 ; and
each Z 1b is independently oxo, hydroxy, halo, —NO

Assignees

• Gilead Sciences Inc

Inventors

• Canales Eda Y
• Chang Weng K
• Debien Laurent P
• Jansa Petr
• Loyer-Drew Jennifer A
• Martinez Luisruben P
• Perreault Stephane
• Phillips Gary B
• Pyun Hyung-Jung
• Saito Roland D
• Sangi Michael S
• Schrier Adam J
• Shatskikh Marina E
• Taylor James G
• Treiberg Jennifer A
• Van Veldhuizen Joshua J

Classifications

• C07D519/00 Primary

  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

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D471/14

  Ortho-condensed systems · CPC title

• C07D471/18 Primary

  Bridged systems · CPC title

• C07D471/22

  in which the condensed systems contains four or more hetero rings · CPC title