4,6-disubstituted pyrimidines as kinase inhibitors

• US 9,393,246 B2
• Filed: 04/22/2015
• Issued: 07/19/2016
• Est. Priority Date: 10/19/2007
• Status: Active Grant

• Current Assignee: Celgene Avilomics Research Inc. (Bristol-Myers Squibb Company)
• Original Assignee: Celgene Avilomics Research Inc. (Bristol-Myers Squibb Company)
• Inventors: Singh, Juswinder, Ghosh, Shomir, Kluge, Arthur, Petter, Russell C., Tester, Richland W.
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US14/693,489
• Publication Number:
  US 20150328223A1
• Time in Patent Office: 454 Days
• Field of Search: 514/256, 544/326
• US Class Current: 1/1
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: 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
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07B 2200/05 : Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07B 59/002 : Heterocyclic compounds
• CPC Class Codes: C07D 239/47 : One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 239/48 : Two nitrogen atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C12N 9/12 : transferring phosphorus containing groups, e.g. kinases (2.7)
• CPC Class Codes: C12Y 207/10 : Protein-tyrosine kinases (2.7.10)

Abstract

The present invention provides 4,6-disubstituted pyrimidine compounds useful as kinase inhibitors, pharmaceutically acceptable compositions thereof, and methods of using the same.

Claims

1. A pharmaceutical composition comprising a compound of formula I:

2. The pharmaceutical composition according to claim 1, wherein

R¹ is -L-Y;

L is a bivalent C_2-8straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are independently replaced by —

NRC(O)—

, —

C(O)NR—

, —

N(R)SO₂—

, —

SO₂N(R)—

, —

S—

, —

S(O)—

, —

SO₂—

, —

OC(O)—

, —

C(O)O—

, cyclopropylene, —

O—

, —

N(R)—

, or —

C(O)—

; and

Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R^e groups.

3. The pharmaceutical composition according to claim 1, wherein L is —

NRC(O)CH═

CH—

, —

NRC(O)CH═

CHCH₂N(CH₃)—

, —

NRC(O)CH═

CHCH₂O—

, —

CH₂NRC(O)CH═

CH—

, —

NRSO₂CH═

CH—

, —

NRSO₂CH═

CHCH₂—

or —

NRC(O)C(═

CH₂)CH₂—

;

wherein the R group of L is H or optionally substituted C_1-6 aliphatic.

4. The pharmaceutical composition according to claim 1, wherein L is —

NHC(O)CH═

CH—

, —

NHC(O)CH═

CHCH₂N(CH₃)—

, —

NHC(O)CH═

CHCH₂O—

, —

CH₂NHC(O)CH═

CH—

, —

NHSO₂CH═

CH—

, —

NHSO₂CH═

CHCH₂—

or —

NHC(O)C(═

CH₂)CH₂—

.

5. The pharmaceutical composition according to claim 1, wherein -L-Y is —

NHC(O)CH═

CH₂.

6. The pharmaceutical composition according to claim 1, wherein R¹ is selected from:

7. The pharmaceutical composition according to claim 1, wherein the additional therapeutic agent is a chemotherapeutic agent.

8. The pharmaceutical composition according to claim 1, wherein the compound of formula I and the additional therapeutic agent are combined in a single unit dosage form.

9. The pharmaceutical composition according to claim 8, wherein the additional therapeutic agent is a chemotherapeutic agent.

10. The pharmaceutical composition according to claim 1, wherein the compound of formula I and the additional therapeutic agent are combined from separate unit dosage forms.

11. The pharmaceutical composition according to claim 10, wherein the additional therapeutic agent is a chemotherapeutic agent.