PI3 KINASE INHIBITORS AND METHODS OF THEIR USE

• US 20100075965A1
• Filed: 02/14/2007
• Published: 03/25/2010
• Est. Priority Date: 02/14/2006
• Status: Abandoned Application

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Dale, James, Knapp, Mark, Legrand, Darren Mark, Iwanowicz, Ed, Liu, Jui, Han, Wooseok, Levine, Barry, Frazier, Kelly, Hendrickson, Tom, Verhagen, Joelle, Wiesmann, Marion, Bruce, Ian, Pecchi, Sabina, Lan, Jiong, Zhang, Yanchen, Burger, Matthew, Menezes, Daniel, Costales, Abran, Smith, Aaron, Pick, Teresa, Voliva, Charles, Ni, Zhi-Jie, Merritt, Hanne, Atallah, Gordana, Bartulis, Sarah
• Application Number:
  US12/279,148
• Publication Number:
  US 20100075965A1
• Time in Patent Office: Days
• US Class Current: 514/235.800
• 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 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 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: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• 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

Abstract

Phosphatidylinositol (PI) 3 kinase inhibitor compounds, their pharmaceutically acceptable salts, and prodrugs thereof; compositions of the new compounds, either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier; and uses of the new compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases characterized by the abnormal activity of growth factors, protein serine/threonine kinases, phospholipid kinases, G-protein coupled receptors, and phosphatases.

Claims

1. A compound of Formula I or a stereoisomer, tautomer, or solvate or pharmaceutically acceptable salt thereof

wherein:

Q is O or S;

X is CR³ or N;

W is C or N;

V is CR², O or S;

L¹ is CR⁹ or N;

L² is CR⁶ or N;

R¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, cycloalkyl, substituted cycloalkyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, cycloalkyloxy, substituted cycloalkyloxy, and alkylamino;

R², R³, R⁷, and R⁹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, cycloalkyl, substituted cycloalkyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, cycloalkyloxy, substituted cycloalkyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, imino, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio;

R⁴, R⁵, and R⁶ are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, substituted amino, alkoxy, substituted alkoxy, alkyl, and substituted alkyl;

R⁸ is selected from the group consisting of hydrogen, alkyl, —

CO—

R^8a, substituted alkyl, and a three- to seven-membered ring selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; and

R^8a is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, and alkylamino.

2. A compound of claim 1 of Formula Ia or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof

wherein R², R³, R⁷, and R⁹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, cycloalkyl, substituted cycloalkyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, cycloalkyloxy, substituted cycloalkyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio.

3. A compound of claim 1 of Formula II or a stereoisomer, tautomer, or solvate or pharmaceutically acceptable salt thereof

4. A compound of claim 3 of Formula IIa or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof

wherein R², R³, R⁷, and R⁹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, cycloalkyl, substituted cycloalkyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, cycloalkyloxy, substituted cycloalkyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio.

5. A compound of claim 4 having one or more of (a)-(g):

(a) R⁸ is hydrogen;

(b) L² is N or CR⁶ where R⁶ is H;

(c) R⁷ is hydrogen, alkyl, or amino;

(d) X is N or CR³ where R³ is hydrogen, alkyl, hydroxy, or alkoxy;

(e) R⁴ is hydrogen, halo, or alkyl;

(f) R⁵ is hydrogen, halo, or alkyl; and

(g) Q is O.

6. A compound of claim 4, wherein R¹ is methyl or trifluoromethyl.

19. A compound of claim 1 that is a compound selected from Table 1 or 3 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

48. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.

57. A method for treating a cancer disorder in a patient, comprising administering to the patient a composition comprising an amount of a compound of claim 1 effective to inhibit PI3-K activity.

7-18. -18. (canceled)

20. A compound of Formula III, or a stereoisomer, tautomer, or solvate or pharmaceutically acceptable salt thereof;

wherein;

Q is O or S;

V is O or S;

L¹ is CR⁹ or N;

L² is CR⁶ or N;

R¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, cycloalkyl, substituted cycloalkyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, cycloalkyloxy, substituted cycloalkyloxy, and alkylamino;

R³, R⁷, and R⁹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, cycloalkyl, substituted cycloalkyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, cycloalkyloxy, substituted cycloalkyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, imino, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio;

R⁴, R⁵, and R⁶ are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, substituted amino, alkoxy, substituted alkoxy, alkyl, and substituted alkyl;

R⁸ is selected from the group consisting of hydrogen, alkyl, —

CO—

R^8a, substituted alkyl, and a three- to seven-membered ring selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; and

R^8a is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, and alkylamino.

21. A compound of claim 20 of Formula IIIa, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof

wherein R³, R⁷, and R⁹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, cycloalkyl, substituted cycloalkyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, cycloalkyloxy, substituted cycloalkyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio.

22. A compound of claim 21, wherein R¹ is selected from the group consisting of methyl, methoxy, morpholinyl-N-propyl, piperidyl-N-methyl, morpholinyl-N-methyl, piperidyl-N-ethoxy, piperidyl-N-propyl, methylamino, and morpholinyl-N-ethoxy.

33. A compound of claim 21 that is a compound selected from Table 2 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

23-32. -32. (canceled)

34. A compound of Formula IV, or a stereoisomer, tautomer, or solvate or pharmaceutically acceptable salt thereof,

wherein,

ring AD is selected from

Q is O or S;

L is CR⁹ or N;

R¹ represents —

Z—

Y—

R¹⁰;

Z is —

NHCH₂C(R¹¹)R¹²—

;

Y is a bond or —

CON(R¹³)—

;

R², R³, R⁷, and R⁹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, cycloalkyl, substituted cycloalkyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, cycloalkyloxy, substituted cycloalkyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio;

R⁴, R⁵, and R⁶ are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, substituted amino, alkoxy, substituted alkoxy, alkyl, and substituted alkyl;

R⁸ is selected from the group consisting of hydrogen, alkyl, —

CO—

R^8a, substituted alkyl, and a three- to seven-membered ring selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; and

R^8a is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, and alkylamino.

R¹⁰ is C₁-C₆-alkylaminocarbonyl, C₁-C₆-alkoxycarbonyl, where each alkyl is independently optionally substituted by one or more halo, hydroxyl or C₁-C₆-alkoxy groups groups, or R¹⁰ is a mono-cyclic heteroaromatic ring having one or more ring heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, said ring being optionally substituted by one or more halo, hydroxyl, C₁-C₆-alkyl or C₁-C₆-alkoxy groups, where said alkyl and alkoxy are optionally further substituted by one or more halo, hydroxyl or C₁-C₆-alkoxy groups;

R¹¹ and R¹² are independently selected from hydrogen, halo, hydroxy and C₁-C₆-alkyl where said alkyl group is optionally substituted by one or more halo, hydroxyl or C₁-C₆-alkoxy groups; and

R¹³ is hydrogen or C₁-C₆-alkyl.

35. A compound of claim 34 of Formula V, or a stereoisomer, tautomer, or solvate or pharmaceutically acceptable salt thereof,

wherein:

Q is O or S;

X is CR³ or N;

W is C or N;

V is CR², O, N, or S;

L is CR⁹ or N;

R¹ represents —

Z—

Y—

R¹⁰;

Z is —

NHCH₂C(R¹¹)R¹²—

;

Y is a bond or —

CON(R¹³)—

;

R², R³, R⁷, and R⁹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, cycloalkyl, substituted cycloalkyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, cycloalkyloxy, substituted cycloalkyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio;

R⁴, R⁵, and R⁶ are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, substituted amino, alkoxy, substituted alkoxy, alkyl, and substituted alkyl;

R⁸ is selected from the group consisting of hydrogen, alkyl, —

CO—

R^8a, substituted alkyl, and a three- to seven-membered ring selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; and

R^8a is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, and alkylamino.

R¹⁰ is C₁-C₆-alkylaminocarbonyl, C₁-C₆-alkoxycarbonyl, where each alkyl is independently optionally substituted by one or more halo, hydroxyl or C₁-C₆-alkoxy groups groups, or R¹⁰ is a mono-cyclic heteroaromatic ring having one or more ring heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, said ring being optionally substituted by one or more halo, hydroxyl, C₁-C₆-alkyl or C₁-C₆-alkoxy groups, where said alkyl and alkoxy are optionally further substituted by one or more halo, hydroxyl or C₁-C₆-alkoxy groups;

R¹¹ and R¹² are independently selected from hydrogen, halo, hydroxy and C₁-C₆-alkyl where said alkyl group is optionally substituted by one or more halo, hydroxyl or C₁-C₆-alkoxy groups; and

R¹³ is hydrogen or C₁-C₆-alkyl.

36. A compound according to claim 35 where Q is O.

37. A compound according to claim 35 where X is CH or N.

38. A compound according to claim 35 where W is N.

39. A compound according to claim 35 where V is CH.

47. A compound according to claim 35 which is selected from the group consisting of Formula Va where R¹ is NHR^1a:

R² R^1a

40-46. -46. (canceled)

49-56. -56. (canceled)

58-61. -61. (canceled)