Inhibitors of peptidylarginine deiminases

Patent metadata

Field	Value
Publication number	US-11878965-B2
Application number	US-202117557860-A
Country	US
Kind code	B2
Filing date	Dec 21, 2021
Priority date	Dec 22, 2020
Publication date	Jan 23, 2024
Grant date	Jan 23, 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 thereof, wherein:
X 5 is N or C-R 5 ;
X 7 is N or C-R 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 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 3 is hydrogen, C 1-8 alkyl optionally substituted with 1 to 3 Z 1 , C 3-10 alkenyl optionally substituted with 1 to 3 Z 1 , C 3-10 alkynyl optionally substituted with 1 to 3 Z 1 , C 3-10 cycloalkyl optionally substituted with 1 to 3 Z 1 , or 4-10 membered heterocyclyl optionally substituted with 1 to 3 Z 1 ; or
R 2 and R 3 are taken together with the atoms to which they are attached to form an optionally substituted 6 to 8 membered heterocyclyl ring;
R4 is hydrogen, C 1-8 alkyl optionally substituted with 1 to 3 Z 1 , C 3-10 alkenyl optionally substituted with 1 to 3 Z 1 , C 3-10 alkynyl optionally substituted with 1 to 3 Z 1 , C 3-10 cycloalkyl optionally substituted with 1 to 3 Z′, or 4-10 membered heterocyclyl optionally substituted with 1 to 3 Z 1 ;
R 5 is hydrogen, halo, —CN, or —OR 12 ;
R 6 is

 where q is 0, 1 or 2, and
n is 0, 1, 2, 3, 4, 5, or 6;
R 7 is hydrogen, halo, —CN, or —OR 12 ;
R 9 is C 1-8 alkyl optionally substituted with 1 to 3 Z 1 , C2-8 alkenyl optionally substituted with 1 to 3 Z 1 , C2-8 alkynyl optionally substituted with 1 to 3 Z 1 , C 3-10 cycloalkyl optionally substituted with 1 to 3 Z 1 , 4-10 membered heterocyclyl optionally substituted with 1 to 3 Z 1 , C 6-10 aryl optionally substituted with 1 to 3 Z 1 , or 5-10 membered heteroaryl optionally substituted with 1 to 3 Z 1 ;
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 10 , C 3-8 cycloalkyl optionally substituted with 1 to 4 Z 10 , or 4-12-membered heterocyclyl optionally substituted with 1 to 4 Z 10 ; or
R 10 and R 11 are taken together with the nitrogen to which they are attached to form a 4-12-membered heterocyclyl optionally substituted with 1 to 4 Z 10 ;
each R 12 is independently hydrogen, C 1-8 alkyl optionally substituted with 1 to 3 Z 1b , C 3-8 alkenyl optionally substituted with 1 to 3 Z 1b , C 3-8 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 , C6-10 aryl optionally substituted with 1 to 3 Z 1b , or 5-10 membered heteroaryl optionally substituted with 1 to 3 Z 1b ;
R 13 is C 1-8 alkyl optionally substituted with 1 to 3 Z 1b , C 3-8 alkenyl optionally substituted with 1 to 3 Z 1b , C 3-8 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 15 is C 6-10 aryl optionally substituted with 1 to 3 Z 1 or 5-10 membered heteroaryl optionally substituted with 1 to 3 Z 1 ;
each R 17 is independently hydrogen, 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 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —N(R 20 ) 2 , —N(R 20 ) 3 + , —N(R 20 )C(O)R 20 , —N(R 20 )C(O)OR 20 , —N(R 20 )C(O)N(R 20 ) 2 , —N(R 20 )S(O) 2 (R 20 ), —NR 20 S(O) 2 N(R 20 ) 2 , —NR 20 S(O) 2 O(R 20 ), —NS(O)(R 20 ) 2 , —OC(O)R 20 , —OC(O)OR 20 , —OC(O)N(R 20 ) 2 , —Si(R 20 ) 3 , —SR 20 , —S(O)R 20 , —SF 5 , —S(O)(NR 20 )R 20 , —S(NR 20 )(NR 20 )R 20 , —S(O)(NR 20 )N(R 20 ) 2 , —S(O)(NCN)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —C(O)N(R 20 )S(O) 2 R 20 , or —S(O) 2 N(R 20 )C(O)R 20 ; or two R 17 on the same or different carbon atoms are taken together to form a 3-8-membered ring optionally substituted with 1 to 4 Z 1 ;
each R 18 independently hydrogen, 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 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —N(R 20 ) 2 , —N(R 20 ) 3 + , —N(R 20 )C(O)R 20 , —N(R 20 )C(O)OR 20 , —N(R 20 )C(O)N(R 20 ) 2 , —N(R 20 )S(O) 2 (R 20 ), —NR 20 S(O) 2 N(R 20 ) 2 , —NR 20 S(O) 2 O(R 20 ), —NS(O)(R 20 ) 2 , —OC(O)R 20 , —OC(O)OR 20 , —OC(O)N(R 20 ) 2 , —Si(R 20 ) 3 , —SR 20 , —S(O)R 20 , —SF 5 , —S(O)(NR 20 )R 20 , —S(NR 20 )(NR 20 )R 20 , —S(O)(NR 20 )N(R 20 ) 2 , —S(O)(NCN)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —C(O)N(R 20 )S(O) 2 R 20 , or —S(O) 2 N(R 20 )C(O)R 20 ;
each Z 1 is independently 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 20 , —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2 , —N(R 20 ) 2 , —N(R 20 ) 3 + , —N(R 20 )C(O)R 20 , —N(R 20 )C(O)OR 20 , —N(R 20 )C(O)N(R 20 ) 2 , —N(R 20 )S(O) 2 (R 20 ), —NR 20 S(O) 2 N(R 20 ) 2 , —NR 20 S(O) 2 O(R 20 ), —NS(O)(R 20 ) 2 , —OC(O)R 20 , —OC(O)OR 20 , —OC(O)N(R 20 ) 2 , —Si(R 20 ) 3 , —S(O)R 20 , —SF 5 , —S(O)(NR 20 )R 20 , —S(NR 20 )(NR 20 )R 20 , —S(O)(NR 20 )N(R 20 ) 2 , —S(O)(NCN)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —C(O)N(R 20 )S(O) 2 R 20 , or —S(O) 2 N(R 20 )C(O)R 20 ;
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 21 , —C(O)R 21 , —C(O)OR 21 , —C(O)N(R 21 ) 2 , —N(R 21 ) 2 , —N(R 21 ) 3 + , —N(R 21 )C(O)R 21 , —N(R 21 )C(O)OR 21 , —N(R 21 )C(O)N(R 21 ) 2 , —N(R 21 )S(O) 2 (R 21 ), —NR 21 S(O) 2 N(R 21 ) 2 , —NR 21 S(O) 2 O(R 21 ), —NS(O)(R 21 ) 2 , —OC(O)R 21 , —OC(O)OR 21 , —OC(O)N(R 21 ) 2 , —Si(R 21 ) 3 , —SR 21 , —S(O)R 21 , —SF 5 , —S(O)(NR 21 )R 21 , —S(NR 21 )(NR 21 )R 21 , —S(O)(NR 21 )N(R 21 ) 2 , —S(O)(NCN)R 21 , —S(O) 2 R 21 , —S(O) 2 N(R 21 ) 2 , —C(O)N(R 21 )S(O) 2 R 21 , or —S(O) 2

Assignees

• Gilead Sciences Inc

Inventors

• Byun Daniel H
• Cai Zhenhong R
• Canales Eda Y
• Debien Laurent P
• Hansen Timothy R
• Huang Richard
• Jansa Petr
• Lee Rick A
• Loyer-Drew Jennifer A
• Mcfadden Ryan
• Mitchell Michael L
• Pyun Hyung-Jung
• Saito Roland D
• Sangi Michael S
• Schrier Adam J
• Shatskikh Marina E
• Taylor James G
• Van Veldhuizen Joshua J
• Xu Lianhong

Classifications

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title