Heterocyclic PAD4 inhibitors

Patent metadata

Field	Value
Publication number	US-12473304-B2
Application number	US-202117799028-A
Country	US
Kind code	B2
Filing date	Feb 11, 2021
Priority date	Feb 12, 2020
Publication date	Nov 18, 2025
Grant date	Nov 18, 2025

Abstract

wherein

and X 1 -X 6 and R 1 -R 8 , along with other variables are as defined herein.

The disclosure generally relates to substituted heterocyclic compounds of Formula (Ia), which are inhibitors of PAD4, method for preparing these compounds, pharmaceutical compositions comprising these compounds and use of these compounds in the treatment of a disease or a disorder associated with PAD4 enzyme activity.

First claim

The invention claimed is:

1 . A compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:

is selected from

is selected from

X 1 is independently selected from CR 2 , and N;
X 2 is independently selected from CR 4 , and N;
X 3 is independently selected from O, and S;
X 4 is independently selected from CR 2 , and N; provided X 1 and X 4 are not both N;
X 5 is independently selected from O and S;
X 6 is independently selected from CR 4 , and N; provided 1) X 2 and X 6 are not both N; 2) when X 2 and X 6 are both CR 4 , one of R 4 is H;
R 1 is independently selected from —NH—C 1-5 alkyl optionally substituted with one or more substituents selected from F, Cl, and NH 2 , 4-10 membered heterocyclyl, and —NH-4-10 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents selected from F, Cl, CN, C 1-3 alkyl, ═N—OR b , —(CH 2 ) r OR b , —(CH 2 ) r NR a R a , —NR a C(═NH)C 1-3 alkyl, —NR a C(═O)OR b , carbocyclyl, and heterocyclyl;
R 2 is independently selected from H, F, Cl, C 1-4 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH, and —OC 1-4 alkyl;
R 3 is independently selected from H, F, Cl, CN, —C(═O)OR b , and C 1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, OH, NH 2 , and N 3 ;
R 4 is independently selected from H, F, Cl, Br, —C(═O)R b , C 1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, OH, and C 3-6 cycloalkyl, —NH—C 1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, OH, and C 3-6 cycloalkyl, —(CH 2 ) r -aryl substituted with one or more R 5 , —O—C 1-6 alkyl substituted with one or more R 5 , —(CH 2 ) r —C 3-12 cycloalkyl substituted with one or more R 5 , and —(CH 2 ) r -4-10 membered heterocyclyl comprising carbon atoms and 1-5 heteroatoms selected from N, NR 6 , O, and S and substituted with one or more R 5 ;
R 5 is independently selected from H, F, Cl, Br, CN, ═O, C 1-4 alkyl optionally substituted with one or more R e , C 2-4 alkenyl optionally substituted with one or more R e , C 2-4 alkynyl optionally substituted with one or more R e , —CR d R d ) r OR b , —(CR d R d ) r S(O) p R c , —(CR d R d ) r S(O) p NR a R a , —(CR d R d ) r NR a S(O) p R c , —(CR d R d ) r NR a R a , —(CR d R d ) r NR a C(═O)R b , —(CR d R d ) r NR a C(═O)OR b , —(CR d R d ) r NR a C(═O)NR a R a , —(CR d R d ) r C(═O)R b , —(CR d R d ) r C(═O)OR b , —(CR d R d ) r C(═O)NR a R a , —(CR d R d ) r OC(═O)R b , —(CR d R d ) r OC(═O)OR b , (CR d R d ) r O(CH 2 ) r C(═O)NR a R a , C 3-6 cycloalkyl optionally substituted with one or more R e , aryl optionally substituted with one or more R e , and heterocyclyl optionally substituted with one or more R e ;
R 6 is independently selected from H, C 1-6 alkyl optionally substituted with one or more R e , —S(O) p R c , —S(O) p NR a R a , —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , C 3-6 cycloalkyl optionally substituted with one or more R e , aryl optionally substituted with one or more R e , and heterocyclyl optionally substituted with one or more R e ;
R 7 is independently selected from H, F, and Cl;
R 8 is independently selected from H, and C 1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, and C 3-6 cycloalkyl;
R a is independently selected from H, C 1-6 alkyl optionally substituted with one or more R e , C 2-6 alkenyl optionally substituted with one or more R e , C 2-6 alkynyl optionally substituted with one or more R e , —(CH 2 ) r C 3-10 carbocyclyl optionally substituted with one or more R e , and —(CH 2 ) r -heterocyclyl optionally substituted with one or more R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with one or more R e ;
R b is independently selected from H, C 1-6 alkyl optionally substituted with one or more R e , C 2-6 alkenyl optionally substituted with one or more R e , C 2-6 alkynyl optionally substituted with one or more R e , —(CH 2 ) r —C 3-10 carbocyclyl optionally substituted with one or more R e , and —(CH 2 ) r -heterocyclyl optionally substituted with one or more R e ;
R c is independently selected from C 1-6 alkyl optionally substituted with one or more R e , C 2-6 alkenyl optionally substituted with one or more R e , C 2-6 alkynyl optionally substituted with one or more R e , —(CH 2 ) r —C 3-10 carbocyclyl optionally substituted with one or more R e , and —(CH 2 ) r -heterocyclyl optionally substituted with one or more R e ;
R d is independently selected from H, and C 1-6 alkyl optionally substituted with one or more R e ;
R e is independently selected from F, Cl, Br, CN, NH 2 , —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , ═O, OH, —OC 1-6 alkyl, —CO 2 H, C 1-6 alkyl optionally substituted with one or more R f , C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-6 cycloalkyl optionally substituted with one or more R f , —(CH 2 ) r -aryl optionally substituted with one or more R f , and —(CH 2 ) r -heterocyclyl optionally substituted with one or more R f ;
R f is independently selected from F, Cl, Br, CN, OH, OC 1-5 alkyl, C 1-5 alkyl optionally substituted with OH, C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl, and phenyl;
p, at each occurrence, is independently selected from zero, 1, and 2; and
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

2 . The compound according to claim 1 , having Formulae (IIa)-(XIII):

or a pharmaceutically acceptable salt thereof.

3 . The compound according to claim 2 , having Formula (IIa):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is independently selected from

R 2 is independently selected from H, F, Cl, C 1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH, and OC 1-3 alkyl;
R 3 is independently selected from H, F, Cl, and C 1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH;
R 4 is independently selected from H, F, Cl, —C(═O)R b , C 1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, OH, and C 3-6 cycloalkyl, —NH—C 1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, OH, and C 3-6 cycloalkyl, —(CH 2 ) r -aryl substituted with one or more R 5 , —O—C 1-6 alkyl substituted with one or more R 5 , —(CH 2 ) r —C 3-12 cycloalkyl substituted with one or more R 5 , and —(CH 2 ) r -4-10 membered heterocyclyl comprising carbon atoms and 1-5 heteroatoms selected from N, NR 6 , O, and S and substituted with one or more R 5 ;
R 5 is independently selected from H, F, Cl, ═O, C 1-4 alkyl optionally substituted with one or more R e , —(CH 2

Assignees

• Bristol Myers Squibb Co

Inventors

• Selvakumar Kumaravel
• Paidi Venkatram Reddy
• Thangathirupathy Srinivasan
• Kumar Cm Vijaya
• Alajangi Tirupathi Rao
• Sura Mallikarjun Reddy
• Mahadevu Krishna
• Sistla Ramesh Kumar
• Agarwal Piyush
• Subbiah Karuppiah Arul Mozhi
• Nair Jalathi S
• Morampudi Ooha
• Panda Manoranjan
• Tino Joseph A
• Cherney Robert J
• Duncia John V
• Gardner Daniel S
• Dhar T G Murali
• Ross Audrey Graham
• Gormisky Paul E
• Zhu Xiao
• Seletsky Boris M
• Antropow Alyssa H
• Niu Deqiang
• Zhu Zhengdong
• Miao Guobin
• Cuervo Julio Hernan

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title