QUINOLINE DERIVATIVES AS PI3 KINASE INHIBITORS

• US 20080300239A1
• Filed: 05/16/2008
• Published: 12/04/2008
• Est. Priority Date: 05/18/2007
• Status: Active Grant

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Original Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Inventors: Knight, Steven David, Newlander, Kenneth Allen, Sarpong, Martha A., Schmidt, Stanley J., Burgess, Joelle Lorraine, Donatelli, Carla A., Adams, Nicholas D., Darcy, Michael Gerrard, Ridgers, Lance
• Granted Patent: US 8,138,347 B2
• Time in Patent Office: Days
• US Class Current: 514/223.2
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/5383 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/549 having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
• 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 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• 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 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• 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: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 285/24 : with oxygen atoms directly attached to the ring sulfur atom
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/04 : Ortho-condensed systems

Abstract

Invented is a method of inhibiting the activity/function of PI3 kinases using quinoline derivatives. Also invented is a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries by the administration of quinoline derivatives.

Claims

1. A compound of Formula (I):

in which R2 is a pyridinyl or substituted pyridinyl group,

R1 is selected from a group consisting of;

heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

each R3 and R4 is independently selected from;

hydrogen, halogen, acyl, amino, substituted amino, C1-6alkyl, substituted C1-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, alkylcarboxy, aminoalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, nitro, acyloxy, and aryloxy;

n is 1-2;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein the compound is a compound of formula (I)(G):

in which

each R1, R3, R4 and R5 is independently selected from;

hydrogen, halogen, acyl, amino, substituted amino, arylamino, acylamino, heterocycloalkylamino, C1-6alkyl, substituted C1-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, alkylcarboxy, aminoalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, acyloxy, and aryloxy;

n is 1-2, m is 0-3;

or R5 is R6, wherein R6 is —

SO2NR80 or —

NSO₂R80, in which R80 is selected from a group consisting of;

C1-C6alkyl, C1-C6cycloalkyl, C1-C6heterocycloalkyl, substituted C1-C6alkyl, substituted C1-C6cycloalkyl, substituted C1-C6heterocycloalkyl, aryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of;

C1-C6alkyl, C1-C6cycloalkyl, halogen, amino, substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or —

(CH₂)_nCOOH, or heteroaryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of;

C1-C6alkyl, C1-C6cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or —

(CH₂)_nCOOH, wherein n is 0-2;

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1, wherein the compound is a compound of formula (I)(K):

in which

R1 is selected from a group consisting of;

heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, amino, substituted amino, arylamino, acylamino, heterocycloalkylamino, alkoxy, C1-6alkyl and substituted C1-6alkyl;

each R5 is independently selected from;

hydrogen, halogen, acyl, amino, substituted amino, C1-6alkyl, substituted C1-6alkyl, cyano, hydroxyl, alkoxy;

m is 0-1;

R6 is —

SO2NR80 or —

NSO₂R80, in which R80 is selected from a group consisting of;

C1-C6alkyl, C1-C6cycloalkyl, C1-C6heterocycloalkyl, substituted C1-C6alkyl, substituted C1-C6cycloalkyl, substituted C1-C6heterocycloalkyl, aryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of;

C1-C6alkyl, C1-C6cycloalkyl, halogen, amino, substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or —

(CH₂)_nCOOH, or heteroaryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of;

C1-C6alkyl, C1-C6cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or —

(CH₂)_nCOOH, wherein n is 0-2;

or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1, wherein the compound is a compound of formula (I)(M):

in which

R1 is selected from a group consisting of;

heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, amino, substituted amino, arylamino, acylamino, heterocycloalkylamino, alkoxy, C1-6alkyl and substituted C1-6alkyl;

each R5 is independently selected from;

hydrogen, halogen, acyl, amino, substituted amino, C1-6alkyl, substituted C1-6alkyl, cyano, hydroxyl, alkoxy;

m is 0-1;

R6 is —

NSO₂R80, wherein R80 is selected from a group consisting of;

C1-C6alkyl, C1-C6cycloalkyl, C1-C6heterocycloalkyl, substituted C1-C6alkyl, substituted C1-C6cycloalkyl, substituted C1-C6heterocycloalkyl, aryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of;

C1-C6alkyl, C1-C6cycloalkyl, halogen, amino, substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or —

(CH₂)_nCOOH, or heteroaryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of;

C1-C6alkyl, C1-C6cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or —

(CH₂)_nCOOH, wherein n is 0-2;

or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1, wherein the compound is a compound of formula (I)(N):

in which

R1 is selected from a group consisting of;

heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, amino, substituted amino, arylamino, acylamino, heterocycloalkylamino, alkoxy, C1-6alkyl and substituted C1-6alkyl;

each R5 is independently selected from;

hydrogen, halogen, acyl, amino, substituted amino, C1-6alkyl, substituted C1-6alkyl, cyano, hydroxyl, alkoxy;

m is 0-1;

R6 is —

SO2NR80, wherein R80 is selected from a group consisting of;

C1-C6alkyl, C1-C6cycloalkyl, C1-C6heterocycloalkyl, substituted C1-C6alkyl, substituted C1-C6cycloalkyl, substituted C1-C6heterocycloalkyl, aryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of;

C1-C6alkyl, C1-C6cycloalkyl, halogen, amino, substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or —

(CH₂)_nCOOH, or heteroaryl optionally fused with a five-membered ring or substituted with one to five groups selected from a group consisting of;

C1-C6alkyl, C1-C6cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or —

(CH₂)_nCOOH, wherein n is 0-2;

or a pharmaceutically acceptable salt thereof.

9. A method of treating one or more disease states selected from a group consisting of:

autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries, in a human in need thereof, which method comprises administering to such human, a therapeutically effective amount of a compound according to claim 1.

10. A method of treating cancer comprises co-administration a compound according to claim 1;

and/or a pharmaceutically acceptable salt thereof; and

at least one anti-neoplastic agent, such as one selected from a group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors.

11. A method of claim 9, wherein the disease state is selected from a group consisting of:

multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosis, inflammatory bowel disease, lung inflammation, thrombosis, brain infection/inflammation, meningitis and encephalitis.

12. A method of claim 9, wherein the disease state is selected from a group consisting of:

Alzheimer'"'"'s disease, Huntington'"'"'s disease, CNS trauma, stroke and ischemic conditions.

13. A method of claim 9, wherein the disease state is selected from a group consisting of:

atherosclerosis, heart hypertrophy, cardiac myocyte dysfunction, elevated blood pressure and vasoconstriction.

14. A method of claim 9, wherein the disease state is selected from a group consisting of:

chronic obstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis, allergic diseases, asthma, stroke, ischemia-reperfusion, platelets aggregation/activation, skeletal muscle atrophy/hypertrophy, leukocyte recruitment in cancer tissue, antiogenesis, invasion metastasis, melanoma, Karposi'"'"'s sarcoma, acute and chronic bacterial and virual infections, sepsis, transplantation rejection, graft rejection, glomerulo sclerosis, glomerulo nephritis, progressive renal fibrosis, endothelial and epithelial injuries in the lung, and lung airways inflammation.

15. A method of claim 9, wherein the disease is cancer.

16. A method of claim 15 wherein the cancer is selected from a group consisting of:

brain (gliomas), glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm'"'"'s tumor, Ewing'"'"'s sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone and thyroid.

17. A method of claim 15 wherein the cancer is selected from a group consisting of:

ovarian cancer, pancreatic cancer, breast cancer, prostate cancer and leukemia.

21. A method of claim 9, wherein the compound or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition.

22. A pharmaceutical composition comprising a compound according to any claim 1 and a pharmaceutically acceptable carrier.

6. The compound of Formula (I)(M).

7. The compound of Formula (I)(N).

8. A method of inhibiting one or more phosphatoinositides 3-kinases (PI3Ks) in a human;

comprising administering to the human in need thereof a therapeutically effective amount of a compound of Formula (I)

or a pharmaceutically acceptable salt thereof,

in which

R2 is pyridinyl or substituted pyridinyl;

R1 is selected from a group consisting of;

heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

each R3 and R4 is independently selected from;

hydrogen, halogen, acyl, amino, substituted amino, C1-6alkyl, substituted C1-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, alkylcarboxy, aminoalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, nitro, acyloxy, and aryloxy;

n is 1-2;

X is C or N;

Y is C, O, N, or S;

or a pharmaceutically acceptable salt thereof.

18. A method of claim 8, wherein said PI3 kinase is a PI3α

.

19. A method of claim 8, wherein said PI3 kinase is a PI3γ

.

20. A method of claim 8, wherein said PI3 kinase is a PI3δ

.