Heterocyclic pad4 inhibitors

Patent metadata

Field	Value
Publication number	US-2025353848-A1
Application number	US-202318869248-A
Country	US
Kind code	A1
Filing date	May 26, 2023
Priority date	May 26, 2022
Publication date	Nov 20, 2025
Grant date	—

Abstract

The disclosure generally relates to 3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one compounds of Formula I, which are 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 1 ;
R 4 is halogen;
R 5 is halogen;
each R 6 and R 6′ is independently selected from hydrogen, halogen, —OR, —N(R) 2 , —OC(O)R, —N(R)C(O)R, —O-L-(R 9 ) p , —Cy, and optionally substituted C 1-6 aliphatic;
each R 7 is independently selected from halogen, —OR, —N(R) 2 , and —Cy;
each R 8 is independently selected from halogen, —OR, —N(R) 2 , and —Cy;
each R 9 is independently selected from halogen, —OR, —N(R) 2 , and —Cy;
L is a covalent bond or 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, and a 5- to 6-membered 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
p 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-b-i, I-c-i, I-d-i, I-e-i, I-f-i, I-g-i, and I-h-i:

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 m is 1.

6 . The compound according to claim 5 , wherein R 4 is fluoro or chloro.

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

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

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

10 . The compound according to claim 9 , wherein R 2 is C 1-4 aliphatic substituted by 1-2 instances of R 7 .

11 . The compound according to claim 1 , wherein at least one R 7 is halogen.

12 . The compound according to claim 11 , wherein the at least one R 7 is fluoro.

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

14 . The compound according to claim 1 , wherein R 3 is selected from

15 . The compound according to claim 1 , wherein R 6 is selected from hydrogen, —CH 3 , —OCH 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 disease, cryopyrin-associated periodic syndromes, cyrptococcosis, cystic fibrosis, deficiency of the interleukin-1-receptor antagonist (DTRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diffuse intrinsic pontine glioma, endometriosis, endotoxemia, epicondylitis, erythroblastopenia, familial amyloidotic polyneuropathy, familial cold urticarial, familial mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerular nephritis, gout, gouty arthritis, graft-versus-host disease, gut diseases, head injury, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Scholein purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster and simplex, HIV-1, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia D with recurrent fever (HIDS), hypoplastic and other anemias, hypoplastic anemia, idiopathic thrombocytopenic purpura, incontinentia pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, iritis, irritant-induced inflammation, ischemia/reperfusion, juvenil

Assignees

• Celgene Corp

Inventors

• Antropow Alyssa H
• Seletsky Boris M
• Ross Audrey Graham
• Zhu Xiao
• Gormisky Paul E
• Miao Guobin

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

• C07B59/002

  Heterocyclic compounds · CPC title

• A61K31/5377

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

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title