# US 9,518,046 B2 · Substituted aminopyrimidine compounds and methods of use

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- Number: US 9,518,046 B2
- Document ID: US9518046B2
- Status: Granted
- Kind: B2
- Application number: 14/658,189
- Filed: 2015-03-15
- Published: 2016-11-03
- Granted: 2016-12-13
- Earliest claimed: 2015-03-15
- Assignees: Calitor Sciences, LLC; Sunshine Lake Pharma Co., Ltd.
- Applicants: Calitor Sciences, LLC; Sunshine Lake Pharma Co., Ltd.
- Inventors: Ning Xi; Liang Wang; Zuping Wu; Xuejin Feng; Yanjun Wu
- Web page: https://patentgrep.com/patent/US9518046B2

## CPC

- C07D 413/14: containing three or more hetero rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/02: Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
- 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 11/02: Nasal agents, e.g. decongestants
- 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 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- 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 25/28: 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/02: Local antiseptics
- A61P 31/12: Antivirals
- A61P 31/16: for influenza or rhinoviruses
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- 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 401/14: containing three or more hetero rings
- C07D 403/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The invention relates to the preparation and use of new aminopyrimidine derivatives as drug candidates in free form or in pharmaceutically acceptable salt form and formulations thereof for the modulation of a disorder or disease which is mediated by the activity of the PI3K enzymes. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of disorders or diseases, such as disorders of immunity and inflammation in which PI3K enzymes play a role in leukocyte function, and hyperproliferative disorders associated with PI3K activity, including but not restricted to leukemias and solid tumors, in mammals, especially humans.

## Claims

### Claim 1

A compound having Formula (I):
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein:
X is (C3-C7)heterocyclyl, —(C1-C4)alkylene-(C3-C7)heterocyclyl, (C6-C10)aryl, —(C1-C4)alkylene-(C6-C10)aryl, 5-10 membered heteroaryl, or —(C1-C4)alkylene-(5-10 membered heteroaryl), wherein X is optionally substituted by 1, 2, 3, 4, or 5 R1 groups;
Y is
wherein Y is optionally substituted by 1, 2, 3, or 4 R2 groups;
each R1 and R2 is independently H, F, Cl, Br, CN, NO2, oxo (═O), —C(═O)Ra, —C(═O)ORa, —C(═O)NRaRb, —OC(═O)NRaRb, —OC(═O)ORa, —N(Rc)C(═O)NRaRb, —N(Rc)C(═O)ORa, —N(Rc)C(═O)Ra, —S(═O)2NRaRb, —S(═O)2Ra, —N(Rc)S(═O)2Ra, —N(Rc)—(C1-C4)alkylene-S(═O)2Ra, —(C1-C4)alkylene-C(═O)NRaRb, —(C1-C4)alkylene-N(Rc)C(═O)NRaRb, —(C1-C4)alkylene-N(Rc)C(═O)ORa, —(C1-C4)alkylene-OC(═O)NRaRb, —(C1-C4)alkylene-S(═O)2NRaRb, —(C1-C4)alkylene-N(Rc)S(═O)2Ra, ORa, NRaRb, —(C1-C4)alkylene-ORa, —(C1-C4)alkylene-NRaRb, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, —(C1-C4)alkylene-(C3-C8)cycloalkyl, (C3-C7)heterocyclyl, —(C1-C4)alkylene-(C3-C7)heterocyclyl, (C6-C10)aryl, —(C1-C4)alkylene-(C6-C10)aryl, 5-10 membered heteroaryl, or —(C1-C4)alkylene-(5-10 membered heteroaryl), wherein each of the (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, —(C1-C4)alkylene-(C3-C8)cycloalkyl, (C3-C7)heterocyclyl, —(C1-C4)alkylene-(C3-C7)heterocyclyl, (C6-C10)aryl, —(C1-C4)alkylene-(C6-C10)aryl, 5-10 membered heteroaryl and —(C1-C4)alkylene-(5-10 membered heteroaryl) is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, Cl, Br, CN, ORa, NRaRb, (C1-C6)alkyl, —(C1-C4)alkylene-ORa and —(C1-C4)alkylene-NRaRb;
each R3 and R4 is independently H, F, CN, —C(═O)Ra, —C(═O)ORa, —C(═O)NRaRb, —(C1-C4)alkylene-C(═O)NRaRb, —(C1-C4)alkylene-N(Rc)C(═O)NRaRb, —(C1-C4)alkylene-N(Rc)C(═O)ORa, —(C1-C4)alkylene-OC(═O)NRaRb, —(C1-C4)alkylene-S(═O)2NRaRb, —(C1-C4)alkylene-N(Rc)S(═O)2Rb, —(C1-C4)alkylene-ORa, —(C1-C4)alkylene-NRaRb, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, —(C1-C4)alkylene-(C3-C8)cycloalkyl, (C3-C7)heterocyclyl, —(C1-C4)alkylene-(C3-C7)heterocyclyl, (C6-C10)aryl, —(C1-C4)alkylene-(C6-C10)aryl, 5-10 membered heteroaryl, or —(C1-C4)alkylene-(5-10 membered heteroaryl), wherein each of the (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, —(C1-C4)alkylene-(C3-C8)cycloalkyl, (C3-C7)heterocyclyl, —(C1-C4)alkylene-(C3-C7)heterocyclyl, (C6-C10)aryl, —(C1-C4)alkylene-(C6-C10)aryl, 5-10 membered heteroaryl and —(C1-C4)alkylene-(5-10 membered heteroaryl) is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, Cl, Br, CN, ORa, NRaRb, (C1-C6)alkyl, —(C1-C4)alkylene-ORa and —(C1-C4)alkylene-NRaRb; or R3 and R4, together with the carbon atom they are attached to, form an optionally substituted 3-8 membered carbocyclic or heterocyclic ring; and
each Ra, Rb and Rc is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, —(C1-C4)alkylene-(C3-C6)cycloalkyl, (C3-C6)heterocyclyl, —(C1-C4)alkylene-(C3-C6)heterocyclyl, (C6-C10)aryl, —(C1-C4)alkylene-(C6-C10)aryl, 5-10 membered heteroaryl, or —(C1-C4)alkylene-(5-10 membered heteroaryl), wherein each of the (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, —(C1-C4)alkylene-(C3-C6)cycloalkyl, (C3-C6)heterocyclyl, —(C1-C4)alkylene-(C3-C6)heterocyclyl, (C6-C10)aryl, —(C1-C4)alkylene-(C6-C10)aryl, 5-10 membered heteroaryl and —(C1-C4)alkylene-(5-10 membered heteroaryl) is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, Cl, CN, N3, OH, NH2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy and (C1-C6)alkylamino; or Ra and Rb, together with the nitrogen atom they are attached to, form an optionally substituted 3-8 membered heterocyclic ring.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein X is (C3-C7)heterocyclyl or 5-10 membered heteroaryl, wherein X is optionally substituted by 1, 2, 3, or 4 R1 groups.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein each R1 and R2 is independently H, F, Cl, CN, oxo (═O), —C(═O)ORa, —C(═O)NRaRb, —N(Rc)C(═O)NRaRb, —N(Rc)C(═O)ORa, —N(Rc)C(═O)Ra, —S(═O)2NRaRb, —N(Rc)S(═O)2Ra, —N(Rc)—(C1-C4)alkylene-S(═O)2Ra, —(C1-C4)alkylene-C(═O)NRaRb, —(C1-C4)alkylene-N(Rc)C(═O)NRaRb, —(C1-C4)alkylene-S(═O)2NRaRb, —(C1-C4)alkylene-N(Rc)S(═O)2Ra, ORa, NRaRb, —(C1-C4)alkylene-ORa, —(C1-C4)alkylene-NRaRb, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, —(C1-C4)alkylene-(C3-C8)cycloalkyl, (C3-C7)heterocyclyl, —(C1-C4)alkylene-(C3-C7)heterocyclyl, phenyl, —(C1-C4)alkylene-phenyl, or 5-6 membered heteroaryl, wherein each of the (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, —(C1-C4)alkylene-(C3-C8)cycloalkyl, (C3-C7)heterocyclyl, —(C1-C4)alkylene-(C3-C7)heterocyclyl, phenyl, —(C1-C4)alkylene-phenyl and 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, CN, ORa, NRaRb, (C1-C3)alkyl, —(C1-C4)alkylene-ORa and —(C1-C4)alkylene-NRaRb.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein each R3 and R4 is independently H, F, CN, —C(═O)NRaRb, —(C1-C2)alkylene-C(═O)NRaRb, —(C1-C2)alkylene-N(Rc)C(═O)NRaRb, —(C1-C2)alkylene-N(Rc)C(═O)ORa, —(C1-C2)alkylene-OC(═O)NRaRb, —(C1-C2)alkylene-S(═O)2NRaRb, —(C1-C2)alkylene-N(Rc)S(═O)2Rb, —(C1-C2)alkylene-ORa, —(C1-C2)alkylene-NRaRb, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, —(C1-C2)alkylene-(C3-C6)cycloalkyl, (C3-C5)heterocyclyl, —(C1-C2)alkylene-(C3-C5) heterocyclyl, phenyl, —(C1-C2)alkylene-phenyl, 5-membered heteroaryl, or —(C1-C2)alkylene-(5-membered heteroaryl), wherein each of the (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, —(C1-C2)alkylene-(C3-C6)cycloalkyl, (C3-C5)heterocyclyl, —(C1-C2)alkylene-(C3-C5)heterocyclyl, phenyl, —(C1-C2)alkylene-phenyl, 5-membered heteroaryl and —(C1-C2)alkylene-(5-membered heteroaryl) is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, Cl, Br, CN, ORa, NRaRb, (C1-C6)alkyl, —(C1-C4)alkylene-ORa and —(C1-C4)alkylene-NRaRb; or R3 and R4, together with the carbon atom they are attached to, form an optionally substituted 3-8 membered carbocyclic or heterocyclic ring.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein each Ra, Rb and Rc is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, —(C1-C4)alkylene-(C3-C6)cycloalkyl, (C3-C6)heterocyclyl, —(C1-C4)alkylene-(C3-C6)heterocyclyl, or 5-10 membered heteroaryl, wherein each of the (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, —(C1-C4)alkylene-(C3-C6)cycloalkyl, (C3-C6)heterocyclyl, —(C1-C4)alkylene-(C3-C6)heterocyclyl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, CN, N3, OH, NH2, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C4)alkoxy and (C1-C4)alkylamino.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein X is a monovalent heterocyclyl or heteroaryl group derived from one of the following structures:
and wherein X is optionally substituted by 1, 2, or 3 R1 groups.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein Y is
and wherein Y is optionally substituted by 1 or 2 R2 groups.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein each R1 and R2 is independently H, F, Cl, CN, oxo (═O), —C(═O)ORa, —C(═O)NRaRb, —N(Rc)C(═O)NRaRb, —N(Rc)C(═O)ORa, —N(Rc)C(═O)Ra, —S(═O)2NRaRb, —N(Rc)S(═O)2Ra, ORa, NRaRb, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, —(C1-C2)alkylene-(C3-C6)cycloalkyl, (C3-C5)heterocyclyl, —(C1-C2)alkylene-(C3-C5)heterocyclyl, phenyl, or —(C1-C2)alkylene-phenyl, wherein each of the (C1-C3)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, —(C1-C2)alkylene-(C3-C6)cycloalkyl, (C3-C5)heterocyclyl, —(C1-C2)alkylene-(C3-C5)heterocyclyl, phenyl and —(C1-C2)alkylene-phenyl is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, CN, ORa NRaRb and (C1-C3)alkyl.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein each R3 and R4 is independently H, F, CN, (C1-C3)alkyl, (C3-C6)cycloalkyl, (C3-C5)heterocyclyl, or —(C1-C2)alkylene-(C3-C5)heterocyclyl, wherein each of the (C1-C3)alkyl, (C3-C6)cycloalkyl, (C3-C5)heterocyclyl and —(C1-C2)alkylene-(C3-C5)heterocyclyl is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, Cl, Br, CN, ORa, NRaRb, (C1-C6)alkyl, —(C1-C4)alkylene-ORa and —(C1-C4)alkylene-NRaRb; or R3 and R4, together with the carbon atom they are attached to, form an optionally substituted 3-8 membered carbocyclic or heterocyclic ring.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein each Ra, Rb and Rc is independently H, (C1-C3)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (C3-C5)heterocyclyl, or 5-6 membered heteroaryl, wherein each of the (C1-C3)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (C3-C5)heterocyclyl and 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, CN, OH, NH2, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy and (C1-C3)alkylamino.

### Claim 11 (depends on 1)

The compound of claim 1 having one of the following structures:

### Claim 12 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1, and one or more pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles or a combination thereof.

### Claim 13 (depends on 12)

The pharmaceutical composition according to claim 12 further comprising one or more therapeutic agents.

### Claim 14 (depends on 1)

A method of treating a disorder mediated by inappropriate PI3-kinase activity comprising administering a therapeutically effective amount of the compound according to claim 1, to a patient in need thereof, wherein the disorder is rheumatoid arthritis.

### Claim 15 (depends on 12)

A method of treating a disorder mediated by inappropriate PI3-kinase activity comprising administering the pharmaceutical composition according to claim 12, to a patient in need thereof, wherein the disorder is rheumatoid arthritis.