Heterocyclic pad4 inhibitors

Patent metadata

Field	Value
Publication number	US-2025346592-A1
Application number	US-202318869244-A
Country	US
Kind code	A1
Filing date	May 26, 2023
Priority date	May 26, 2022
Publication date	Nov 13, 2025
Grant date	—

Abstract

The disclosure generally relates to compounds of Formula I, comprising a 1,6,7,8-tetrahydro-5H-imidazo[4,5-g][1,6]isoquinolin-5-one moiety directly bonded to an azaindole or indole moiety, such compounds as inhibitors of PAD4, methods for preparing these compounds pharmaceutical compositions comprising these compounds and uses of these compounds in the treatment of a disease or a disorder associated with PAD4 enzyme activity.

First claim

1 . A compound of formula I:

or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof, wherein:
X is selected from C—R 6 and N;
X′ is selected from C—R 6′ and N, wherein X and X′ are not simultaneously N;
R 1 is C 1-4 aliphatic;
R 2 is C 1-6 aliphatic substituted by 0-4 instances of R 7 ;
R 3 is C 1-6 aliphatic substituted by 0-3 instances of R 8 ;
R 4 is halogen or C 1-4 aliphatic;
R 5 is halogen;
each R 6 and R 6′ is independently selected from hydrogen, C 1-6 aliphatic, -L 1 (R 9 ) q , and —O-L 2 -(R 9 ) p ;
each R 7 is independently selected from halogen, —OR, —N(R) 2 , and -Cy;
each R 7 is independently selected from halogen, —OR, —N(R) 2 , —C(O)N(R) 2 , and -Cy;
each R 9 is independently selected from halogen, —CN, —OR, —N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —C(O)N(R) 2 , —N(R)C(O)R, —N(R)C(O)OR, —OC(O)N(R) 2 , and -Cy;
L 1 is a covalent bond or C 1-4 aliphatic;
L 2 is C 1-4 aliphatic;
each Cy is independently selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 10-membered bicyclic aryl ring, 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted by 0-3 instances of R 10 ;
each R 10 is independently selected from halogen, —OR, —N(R) 2 , —CN, —C(O)R, —C(O)OR, —C(O)N(R) 2 , oxo, and an optionally substituted group selected from C 1-6 aliphatic and a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each m and n is independently 0 or 1; and
each of p and q is independently 1-4.

2 . The compound according to claim 1 , wherein the compound is selected from a compound of formulae I-a, I-b, I-c, I-d, I-e, I-f, I-g, and I-h:

or a pharmaceutically acceptable salt thereof.

3 . The compound according to claim 2 , wherein the compound is selected from a compound of formulae I-a-i, I-a-ii, I-b-i, I-b-ii, I-c-i, I-c-ii, I-d-i, I-d-ii, I-e-i, I-e-ii, I-f-i, I-f-ii, I-g-i, I-g-ii, I-h-i, and I-h-ii:

or a pharmaceutically acceptable salt thereof.

4 . The compound according to claim 1 , wherein R 1 is —CH 3 .

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

6 . The compound according to claim 1 , wherein m is 0.

7 . The compound according to claim 1 , wherein m is 1.

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

9 . The compound according to claim 1 , wherein R 4 is C 1-6 aliphatic.

10 . The compound according claim 1 , wherein R 2 is C 1-6 aliphatic substituted by 1-4 instances of R 7 .

11 . The compound according to claim 10 , wherein R 2 is C 1-4 aliphatic substituted by 1-4 instances of R 7 .

12 . The compound according to claim 1 , wherein R 2 is selected from the group consisting of

13 . The compound according to claim 1 , wherein R 3 is selected from —CH 2 CH 3 , —CH(CH 3 ) 2 ,

14 . The compound according to claim 1 , wherein R 6 is selected from hydrogen, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CN, halogen, —OCH 3 , —N(CH 3 ) 2 ,

15 . The compound according to claim 1 , wherein R 6′ is selected from hydrogen, fluoro, chloro, —CN, —OH, —OCH 3 , —CF 3 , —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 ,

16 . A pharmaceutically acceptable composition comprising the compound according to claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

17 . A method of inhibiting PAD4 in a subject or in a biological sample comprising the step of contacting the PAD4 with a compound according to claim 1 .

18 . A method of treating a PAD4-mediated disease, disorder, or condition in a subject in need thereof comprising the step of administering to said subject the composition according to claim 16 .

19 . The method according to claim 18 , wherein the PAD4-mediated disease, disorder, or condition is selected from the group consisting of acid-induced lung injury, acne (PAPA), acute lymphocytic leukemia, acute, respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, ageing, AIDS, alcoholic hepatitis, alcoholic hepatitis, alcoholic liver disease, allergen induced asthma, allergic bronchopulmonary, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotropic lateral sclerosis, and weight loss, angina pectoris, angioedema, anhidrotic ecodermal dysplasia-ID, ankylosing spondylitis, anterior segment, inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, behcet's disease, Behcet's syndrome, Bells Palsey, berylliosis, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysm, chemical irritant-induced inflammation, chorioretinitis, chronic heart failure, chronic lung disease of prematurity, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue disease, corneal ulcer, crohn's diseas

Assignees

• Celgene Corp

Inventors

• Antropow Alyssa H
• Seletsky Boris M
• Ross Audrey Graham
• Zhu Xiao
• Gormisky Paul E
• Miao Guobin
• Niu Deqiang
• Zhu Zhendong
• Cuervo Julio Hernan

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

• A61K31/5377

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

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title