# US 11,299,486 B2 · Benzazole compounds and methods for making and using the compounds

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- Number: US 11,299,486 B2
- Document ID: US11299486B2
- Status: Granted
- Kind: B2
- Application number: 16/928,413
- Filed: 2020-07-14
- Published: 2020-10-29
- Granted: 2022-04-12
- Earliest claimed: 2015-08-04
- Assignees: Rigel Pharmaceuticals, Inc.
- Applicants: Rigel Pharmaceuticals, Inc.
- Inventors: Rose Yen; Yan Chen; Rajinder Singh; Vanessa Taylor
- Web page: https://patentgrep.com/patent/US11299486B2

## CPC

- C07D 413/14: containing three or more hetero rings
- 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
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/06: Antianaemics
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 17/14: for baldness or alopecia
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/06: Antimigraine agents
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- 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 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

Disclosed are novel benzazole compounds and compositions comprising the compounds. The compounds are useful as kinase inhibitors including interleukin receptor associated kinases (IRAK) inhibitors. Also disclosed are methods of making and using the compounds and compositions. The disclosed compounds and/or compositions may be used to treat or prevent an IRAK-associated disease or condition.

## Claims

### Claim 1

A method of treating a hematological malignancy in a subject, comprising administering to the subject an effective amount of a compound having a formula
or a pharmaceutically acceptable salt thereof, wherein:
X is O or S;
Het-1 is heterocyclyl;
R1 and R2 independently are H, aliphatic, heteroaliphatic, heterocyclyl, aryl, araliphatic, or together with the nitrogen to which they are attached, form a heterocyclic ring;
R3, R4, R5, R6 and R9 independently are H, aliphatic, halo, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl or haloalkyl;
R7 is H, aliphatic, heteroaliphatic, heterocyclyl, aryl or araliphatic;
each R8 independently is aliphatic, halo, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl or haloalkyl; and
m is from 0 to 3;
wherein treating the hematological malignancy comprises slowing the development of the malignancy, stabilizing the malignancy, or causing regression of the malignancy or a symptom thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein:
Het-1 is heteroaryl;
R1 is H or alkyl, and R2 is aliphatic or heteroaliphatic;
R5 is amino, aryl or heteroaryl;
at least one R8 is —NH2, —CH3, —CF3, —CF2H or —CH2CF3; or
a combination thereof.

### Claim 3 (depends on 1)

The method of claim 1, wherein:
is selected from
R5 is selected from
or
a combination thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the R1—N—R2 moiety is selected from
Ra is aliphatic, haloalkyl or acyl;
n is 1 or 2; and
p is 0, 1 or 2.

### Claim 5 (depends on 1)

The method of claim 1, wherein the hematological malignancy is a leukemia or lymphoma.

### Claim 6 (depends on 1)

The method of claim 1, wherein the hematological malignancy is chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, cutaneous T cell lymphoma, chronic lymphocytic leukemia, pleural effusion lymphoma, smoldering or indolent multiple myeloma, lymphoplasmacytic lymphoma, myelodysplastic syndrome, myelofibrosis, polycythemia vera, diffuse large B-cell lymphoma, Hodgkins or Non-Hodgkins lymphoma, Waldenström's macroglobulinemia or Burkitt lymphoma/leukemia.

### Claim 7 (depends on 1)

The method of claim 1, further comprising administering an additional therapeutic agent.

### Claim 8 (depends on 7)

The method of claim 7, wherein the additional therapeutic agent is a B-cell lymphoma 2 (BCL2) inhibitor, a kinase inhibitor, an antibody, or a combination thereof.

### Claim 9 (depends on 8)

The method of claim 8, wherein the B-cell lymphoma 2 (BCL2) inhibitor is ABT-199 or ABT737.

### Claim 10 (depends on 8)

The method of claim 8, wherein the kinase inhibitor is a Btk inhibitor, CDK inhibitor, EGFR inhibitor, Mek inhibitor, Raf inhibitor, VEGFR inhibitor, BCR-Abl inhibitor, PI3-kinase inhibitor, Syk inhibitor, JAK inhibitor, or a combination thereof.

### Claim 11 (depends on 8)

The method of claim 8, wherein the kinase inhibitor is ibrutinib, palbociclib, afatinib, erlotinib, gefitinib, lapatinib, vandetinib, trametinib, dabrafenib, sorafenib, vemurafenib, axitinib, lenvatinib, nintedanib, pazopanib, bosutinib, dasatinib, imatinib, nilotinib, idelalisib, fostamatinib, baricitinib, ruxolitinib, tofacitinib, or a combination thereof.