# US 11,897,866 B2 · Heteroaryl inhibitors of PAD4

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- Number: US 11,897,866 B2
- Document ID: US11897866B2
- Status: Granted
- Kind: B2
- Application number: 17/522,348
- Filed: 2021-11-09
- Published: 2022-03-17
- Granted: 2024-02-13
- Earliest claimed: 2016-02-23
- Assignees: Padlock Therapeutics, Inc.
- Applicants: Padlock Therapeutics, Inc.
- Inventors: Rajesh Devraj; Gnanasambandam Kumaravel; Holly Atton; Edward Beaumont; Elise Gadouleau; Laura Gleave; Philip Stephen Kerry; Cristina Lecci; Mirco Meniconi; Nat Monck; Jordan Palfrey; Kostas Papadopoulos; Heather Tye; Philip A. Woods
- Web page: https://patentgrep.com/patent/US11897866B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 3/14: for calcium homeostasis (vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04)
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 5/38: of the suprarenal hormones
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 7/06: Antianaemics
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 11/14: Antitussive agents
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 17/08: Antiseborrheics
- A61P 17/10: Anti-acne agents
- A61P 17/14: for baldness or alopecia
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 27/12: for cataracts
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 29/02: without antiinflammatory effect
- A61P 31/04: Antibacterial agents
- A61P 31/06: for tuberculosis
- A61P 31/10: Antimycotics
- A61P 31/18: for HIV
- A61P 31/22: for herpes viruses
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 39/02: Antidotes
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 403/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides compounds useful as inhibitors of PAD4, compositions thereof, and methods of treating PAD4-related disorders.

## Claims

### Claim 1

A compound of formula I′:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is
wherein Ring A is optionally substituted with 1-4 groups selected from fluorine, —CN, —OR, or C1-6 aliphatic optionally substituted with 1-3 fluorine atoms;
Ring B is a 5 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R1 is hydrogen, —Cy, or C1-6 aliphatic optionally substituted with —Cy and optionally further substituted with 1-4 groups selected from fluorine, —CN, or —OR;
each —Cy is independently a 6-membered aryl ring containing 0-2 nitrogen atoms, or a 4-7 membered saturated monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulphur, wherein —Cy is optionally substituted with 1-4 groups selected from fluorine, —CN, or —OR;
R2 is hydrogen, —CN, —OR, —Cy, or C1-10 aliphatic optionally substituted with —Cy and optionally further substituted with 1-5 groups selected from fluorine, —CN, or —OR; or:
two R2 groups on the same carbon are optionally taken together to form ═O;
n is 1, 2, or 3;
X1 is N or C(R3);
R3 is —R, halogen, or —OR;
each R is independently hydrogen or C1-6 aliphatic optionally substituted with 1-3 fluorine atoms;
L is selected from a covalent bond or a C1-6 membered straight or branched, saturated or unsaturated hydrocarbon chain wherein one methylene unit of L is optionally replaced by —S(O)2— or —C(O)N(Ry)—, wherein Ry is R or —CH2phenyl; and
R4 is halogen, R, phenyl, or a 5-6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulphur, wherein R4 is optionally substituted with 1-4 groups independently selected from halogen, —CN, —OR, —C(O)OH, or C1-6 aliphatic optionally substituted with 1-3 fluorine atoms;
provided the following compounds are excluded:

### Claim 2 (depends on 1)

The compound according to claim 1, wherein said compound is of formula I′-a:
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein said compound is of formula I′-b:
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1, 2, 3)

The compound according to any one of claims 1 through 3, wherein Ring A is

### Claim 5 (depends on 4)

The compound according to claim 4, wherein Ring A is

### Claim 6 (depends on 1, 2, 3, 4, 5)

The compound according to any one of claims 1 through 5, wherein Ring B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

### Claim 7 (depends on 6)

The compound according to claim 6, wherein Ring B is imidazolyl, pyrazolyl, pyrrolyl, or thiazolyl.

### Claim 8 (depends on 7)

The compound according to claim 7, wherein Ring B is pyrrolyl.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R4 is phenyl or pyridyl.

### Claim 10 (depends on 1)

The compound according to claim 1, selected from the group consisting of

### Claim 11 (depends on 1)

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

### Claim 12 (depends on 11)

The pharmaceutical composition according to claim 11, in combination with an additional therapeutic agent.

### Claim 13 (depends on 1)

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.

### Claim 14 (depends on 11)

A method of treating rheumatoid arthritis and cancer in a subject in need thereof comprising the step of administering to said subject the composition according to claim 11.

### Claim 15 (depends on 14)

The method according to claim 14, wherein said subject is a human subject.