# US 2014/0194449 A1 · Optically active pyrazolylaminoquinazoline, and pharmaceutical compositions and methods of use thereof

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- Number: US 2014/0194449 A1
- Document ID: US20140194449A1
- Status: Published application
- Kind: A1
- Application number: 14/204,884
- Filed: 2014-03-11
- Published: 2014-07-10
- Earliest claimed: 2010-09-01
- Assignees: Ambit Biosciences Corporation
- Applicants: Ambit Biosciences Corp.
- Inventors: Mark W. HOLLADAY; Eduardo SETTI
- Web page: https://patentgrep.com/patent/US20140194449A1

## CPC

- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61P 13/12: of the kidneys
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- B01D 15/3833: {Chiral chromatography}
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- 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
- B01D: SEPARATION (separating solids from solids by wet methods B03B, B03D; by pneumatic jigs or tables B03B; by other dry methods B07; magnetic or electrostatic separation of solid materials from solid materials or fluids, separation by high-voltage electric fields B03C; centrifuges, vortex apparatus B04; presses per se for squeezing-out liquid from liquid-containing material B30B9/02; treatment of water C02F, e.g. softening by ion-exchange C02F1/42; {arrangements of air intake cleaners in gas turbine plants F02C7/05} ; arrangements or mounting of filters in air-conditioning, air-humidification or ventilation F24F13/28)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Provided herein is an optically active pyrozolylaminoquinazaline, and pharmaceutical compositions thereof. Also provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a JAK-mediated condition, disorder, or disease. Further provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a proliferative disease, inflammatory disease, or renal disease.

## Claims

### Claim at position 1

1-19. (canceled)

### Claim 20

A method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject an optically active (R)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein the compound has an enantiomeric excess of no less than about 80%.

### Claim 21 (depends on 20)

The method of claim 20, wherein the proliferative disease is cancer.

### Claim 22 (depends on 20)

The method of claim 20, wherein the proliferative disease is leukemia.

### Claim 23 (depends on 20)

The method of claim 20, wherein the proliferative disease is selected from renal carcinoma, melanoma, breast cancer, head and neck cancer, pancreatic cancer, gastric cancer, prostate cancer, ovarian cancer, brain cancer, lymphoproliferative diseases, myeloma, multiple myeloma, myeloproliferative disorders, polycythemia vera (PCV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), chronic myelomonocytic leukemia (CMML), systemic mastocytosis (SM), idiopathic myelofibrosis (IMF), leukemia, V617F leukemia, myeloid leukemia, CML, acute myeloid leukemia (AML), a subtype of AML, acute megakaryoblastic leukemia (AMKL), imatinib-resistance CML, myeloproliferative diseases, polycythemia vera (PCV), essential thrombocythemia, and idiopathic myelofibrosis (IMF).

### Claim 24

A method of treating, preventing, or ameliorating one or more symptoms of a JAK-mediated condition, disorder, or disease in a subject, comprising administering to the subject an optically active (R)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein the compound has an enantiomeric excess of no less than about 80%.

### Claim 25 (depends on 24)

The method of claim 24, wherein the JAK-mediated condition, disorder, or disease is cancer.

### Claim 26 (depends on 24)

The method of claim 24, wherein the JAK-mediated condition, disorder, or disease is leukemia.

### Claim 27 (depends on 24)

The method of claim 24, wherein the JAK-mediated condition, disorder, or disease is an inflammatory disease.

### Claim 28

A method of inhibiting the growth of a cell, comprising contacting the cell with an optically active (R)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein the compound has an enantiomeric excess of no less than about 80%.

### Claim 29 (depends on 28)

The method of claim 28, wherein the cell is a cancerous cell.

### Claim 30

A method of modulating the activity of a JAK kinase, comprising contacting the kinase with an optically active (R)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein the compound has an enantiomeric excess of no less than about 80%.

### Claim 31 (depends on 30)

The method of claim 30, wherein the kinase is constitutively activated.

### Claim 32

(canceled)

### Claim 33

(canceled)

### Claim 34

(canceled)

### Claim 35 (depends on 20)

The method of claim 20, wherein the compound is a salt.

### Claim 36 (depends on 35)

The method of claim 35, wherein the salt is a hydrochloride salt.

### Claim 37 (depends on 35)

The method of claim 35, wherein the salt is an esylate salt.

### Claim 38 (depends on 20)

The method of claim 20, having an enantiomeric excess of no less than about 90%.

### Claim 39 (depends on 20)

The method of claim 20, having an enantiomeric excess of no less than about 95%.

### Claim 40 (depends on 20)

The method of claim 20, wherein the compound is substantially pure.

### Claim 41 (depends on 40)

The method of claim 40, wherein the compound has a purity of at least about 50%.

### Claim 42 (depends on 40)

The method of claim 40, wherein the compound has a purity of at least about 90%.

### Claim 43 (depends on 42)

The method of claim 42, wherein the compound selectively inhibits JAK2.

### Claim 44 (depends on 43)

The method of claim 43, wherein the compound selectively inhibits JAK2 over JAK3.

### Claim 45

A method of treating, preventing, or ameliorating one or more symptoms of an inflammatory disease in a subject, comprising administering to the subject an optically active (R)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein the compound has an enantiomeric excess of no less than about 80%.

### Claim 46 (depends on 45)

The method of claim 45, wherein the inflammatory disease is selected from asthma, hypereosinophilic syndrome (HES), dermatitis, asthma, Castleman's disease, arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, chronic obstructive pulmonary disease (COPD), dry eye syndrome, keratoconjuctivitis sicca (KCS), inflammatory bowel disease, Crohn's disease, ulcerative colitis (UC), systemic lupus erythematosis (SLE), multiple sclerosis, tissue transplant rejection, graft-versus-host disease, wound healing, kidney disease, thyroiditis, sarcoidosis, type-I diabetes, psoriasis, inflammatory diseases of the eye including conjunctivitis, uveitis, iritis, scleritis, inflammatory diseases of the respiratory tract, inflammatory diseases of the upper respiratory tract, rhinitis, sinusitis, inflammatory diseases of the lower respiratory tract, bronchitis, inflammatory myopathy, myocarditis, ischemia reperfusion injuries related to an inflammatory ischemic event, a stroke, cardiac arrest, systemic inflammatory response syndrome (SIRS), and sepsis.