# US 11,299,494 B2 · Substituted imidazo[1,2-b]pyridazines as interleukin-23 and interferon-α modulators

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- Number: US 11,299,494 B2
- Document ID: US11299494B2
- Status: Granted
- Kind: B2
- Application number: 16/461,479
- Filed: 2017-11-16
- Published: 2021-10-21
- Granted: 2022-04-12
- Earliest claimed: 2016-11-17
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: David S. Weinstein; John V. Duncia; Steven H. Spergel
- Web page: https://patentgrep.com/patent/US11299494B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/02: Immunomodulators
- C07D 519/00: 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of formula (I) or a stereoisomer or pharmaceutically-acceptable salt thereof, are useful in the modulation of IL-12, IL-23 and/or IFNα, by acting on Tyk-2 to cause signal transduction inhibition.

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein:
R1 is NH2 or NHC1-C6 alkyl;
R2 is H, C1-C6 alkyl, or C3-C10 cycloalkyl, wherein the C3-C10 cycloalkyl is monocyclic or bicyclic;
R3 is H, C1-C6 alkyl, C1-C6 alkyl-OH, or C3-C8 cycloalkyl;
R4 is:
R5 is H, C1-C4 alkyl, C(O)NR6R7, C(O)OH, or OC1-C4 alkyl;
R6 is H or C1-C4 alkyl;
R7 is H, C1-C4 alkyl, C1-C4 alkyl-OH, heterocyclyl, or C6-C8 aryl, wherein the heterocyclyl is optionally substituted with 1 or 2 independently selected R8 substituents; or
R6 and R7, taken together with the nitrogen atom to which they are attached, form a 4- to 8-membered heterocyclyl, wherein the 4- to 8-membered heterocyclyl is optionally substituted with 1 or 2 independently selected R8 substituents; and
each R8 is independently H, halo, C1-C4 alkyl, or OH.

### Claim 2 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1 is NHC1-C4 alkyl.

### Claim 3 (depends on 2)

The compound according to claim 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R2 is C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is monocyclic or bicyclic.

### Claim 4 (depends on 3)

The compound according to claim 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each R8 is independently H, C1-C4 alkyl, or OH.

### Claim 5 (depends on 4)

The compound according to claim 4, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
R6 is H; and
R7 is H, C1-C4 alkyl, C1-C4 alkyl-OH, heterocyclyl, or C6-C8 aryl, wherein the heterocyclyl is optionally substituted with 1 or 2 independently selected R8 substituents; or
R6 and R7, taken together with the nitrogen atom to which they are attached, form a 4- to 8-membered heterocyclyl, wherein the 4- to 8-membered heterocyclyl is optionally substituted with 1 or 2 independently selected R8 substituents.

### Claim 6 (depends on 5)

The compound according to claim 5, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R4 is:

### Claim 7 (depends on 5)

The compound according to claim 5, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R4 is:

### Claim 8 (depends on 5)

The compound according to claim 5, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R4 is:

### Claim 9 (depends on 5)

The compound according to claim 5, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R4 is:

### Claim 10 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R4 is:

### Claim 11 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R4 is:

### Claim 12 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and at least one compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

### Claim 13 (depends on 1)

A method for modulating interleukin-23 activity or interferon-alpha activity in a patient, wherein the method comprises administering to the patient in need of such treatment a therapeutically effective amount of at least one compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the patient has an autoimmune disease or an inflammatory disease.

### Claim 15 (depends on 14)

The method according to claim 14, wherein the autoimmune disease or the inflammatory disease is selected from the group consisting of acute myelogenous leukemia, acute pancreatitis, acute synovitis, adult respiratory distress syndrome, Alzheimer's disease, an allergy, an allograft rejection, an angiogenic disorder, asthma, atherosclerosis, atopic dermatitis, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, bone resorption disease, cachexia, cardiac hypertrophy, cardiac reperfusion injury, cerebral ischemia, cerebral malaria, chronic active hepatitis, chronic myelogenous leukemia, chronic obstructive pulmonary disease, chronic pancreatitis, chronic pulmonary inflammatory disease, chronic thyroiditis, a condition associated with prostaglandin endoperoxidase synthase-2, Crohn's disease, cutaneous lupus, diabetes, discoid lupus erythematosus, a disease characterized by massive neutrophil infiltration, endotoxemia fever due to infection, glomerulonephritis, gout, gouty arthritis, graft versus host disease, Graves' disease, inflammatory bowel disease, an inflammatory reaction induced by an endotoxin, influenza, an ischemia in heart attack, an ischemia in stroke, Kaposi's sarcoma, keloid formation, lupus nephritis, metastatic melanoma, multiple myeloma, multiple sclerosis, muscle degeneration, a myalgia due to infection, myasthenia gravis, myocardial ischemia, a neurodegenerative disease caused by traumatic injury, organ hypoxia, osteoarthritis, osteoporosis, pancreatic B-cell disease, Parkinson's disease, pemphigus vulgaris, psoriasis, psoriatic arthritis, pulmonary sarcoidosis, pyresis, Reiter's syndrome, renal reperfusion injury, rheumatoid arthritis, rheumatoid spondylitis, rubella arthritis, scar tissue formation, scleroderma, sepsis, septic shock, shigellosis, silicosis, stroke, systemic lupus erythematosis, thrombin-induced platelet aggregation, thrombocytopenia, thrombosis, toxic shock syndrome, traumatic arthritis, tuberculosis, ulcerative colitis, vascular hyperplasia, and a viral disease.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the angiogenic disorder is an ocular neovasculization, an infantile hemangioma, or a solid tumor.

### Claim 17 (depends on 15)

The method according to claim 15, wherein the cachexia is cachexia secondary to infection.

### Claim 18 (depends on 15)

The method according to claim 15, wherein the viral disease is an acute hepatitis infection, anthrogryposis-renal dysfunction-cholestasis syndrome, cytomegalovirus retinitis, herpes, or a human immunodeficiency virus infection.

### Claim 19 (depends on 18)

The method according to claim 18, wherein the acute hepatitis infection is hepatitis A, hepatitis B, or hepatitis C.

### Claim 20 (depends on 18)

The method according to claim 18, wherein the human immunodeficiency virus infection is acquired immunodeficiency syndrome.