Quinazolines for PDK1 inhibition

• US 7,932,262 B2
• Filed: 04/05/2007
• Issued: 04/26/2011
• Est. Priority Date: 04/06/2006
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Jain, Rama, Amiri, Payman, Wang, Xiaojong M., Aikawa, Mina, Ng, Simon, Shu, Wei, Basham, Stephen E., Dove, Jeffrey, Murray, Jeremy M., Subramanian, Sharadha, Rico, Alice, Jansen, Johanna M., Wagman, Allan S., Warne, Robert L., Ramurthy, Savithri, Lin, Xiaodong, Pfister, Keith B., Wang, Weibo, Zhou, Yasheen
• Primary Examiner(s): Wilson; James O
• Assistant Examiner(s): McDowell; Brian
• Application Number:
  US12/295,967
• Publication Number:
  US 20100048561A1
• Time in Patent Office: 1,482 Days
• Field of Search: 544/292
• US Class Current: 514/266.4
• 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 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic 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 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 239/94 Nitrogen atoms
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 : 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 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 451/06 : Oxygen atoms
• CPC Class Codes: C07D 453/02 : containing not further condensed quinuclidine ring systems

Abstract

The invention provides quinazoline compounds that are inhibitors of PDK1. Also provided are pharmaceutical compositions including the compounds, and methods of treating proliferative diseases, such as cancers, with the compounds or compositions.

Claims

1. A compound of Formula I:

2. The compound of claim 1, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is substituted phenyl.

3. The compound of claim 1, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is phenyl substituted with a group of formula —

X¹N(R₅₀₁)(R₅₀₂);

wherein X¹ is a covalent bond, SO₂, or C(═

O); and

R₅₀₁ and R₅₀₂ are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl;

or R₅₀₁ and R₅₀₂, taken together with the nitrogen atom to which they are attached, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from C_1-3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino.

4. The compound of claim 3, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein —

N(R₅₀₁)(R₅₀₂) forms —

NH₂, —

NH—

CH(CH₃)₂, —

NH—

(CH₂)₂—

O—

CH₃, —

NH—

cyclopropyl, morpholin-4-yl, 4-methyl-piperizine-1-yl, or —

NH—

(CH₂)₂-pyrrolidin-1-yl.

5. The compound of claim 1, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein —

L—

A¹ is a heterocyclyloxy group having the structure;

6. The compound of claim 5, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein W¹ is R¹ and W² is —

L—

A¹.

7. The compound of claim 6, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is phenyl substituted with a group of formula —

X¹—

N(R₅₀₁)(R₅₀₂);

wherein X¹ is a covalent bond, SO₂, or C(═

O); and

R₅₀₁ and R₅₀₂ are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl;

or R₅₀₁ and R₅₀₂, taken together with the nitrogen atom to which they are attached, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from C_1-3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino.

8. The compound of claim 7, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein —

N(R₅₀₁)(R₅₀₂) forms —

NH₂, —

NH—

CH(CH₃)₂, —

NH—

(CH₂)₂—

O—

CH₃, —

NH—

cyclopropyl, morpholin-4-yl, 4-methyl-piperizine-1-yl, or —

NH—

(CH₂)₂-pyrrolidin-1-yl.

9. The compound of claim 8, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R² is heteroaryl or substituted heteroaryl.

10. The compound of claim 5, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein W¹ is —

L—

A¹ and W² is R¹.

11. The compound of claim 10, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is phenyl substituted with a group of formula —

X¹—

N(R₅₀₁)(R₅₀₂);

wherein X¹ is a covalent bond, SO₂, or C(═

O); and

R₅₀₁ and R₅₀₂ are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl;

or R₅₀₁ and R₅₀₂, taken together with the nitrogen atom to which they are attached, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from C_1-3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino.

12. The compound of claim 11, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein —

N(R₅₀₁)(R₅₀₂) forms —

NH₂, —

NH—

CH(CH₃)₂, —

NH—

(CH₂)₂—

O—

CH₃, —

NH—

cyclopropyl, morpholin-4-yl, 4-methyl-piperizine-1-yl, or —

NH—

(CH₂)₂-pyrrolidin-1-yl.

13. The compound of claim 12, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R² is heteroaryl or substituted heteroaryl.

14. The compound of claim 5, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R¹ is H, halogen, cyano;

or phenyl optionally substituted with —

C(═

O)—

N(R⁵⁰¹)(R⁵⁰²);

or a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently selected from O, S and N, that is optionally substituted with up to three substituents selected from alkyl, alkoxy and —

N(R₅₀₁)(R₅₀₂);

or a group of formula;

15. The compound of claim 1, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein W¹ is heteroaryl or substituted heteroaryl.

16. The compound of claim 1, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein W² is heteroaryl or substituted heteroaryl.

17. The compound of claim 1, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R² is heteroaryl or substituted heteroaryl.

24. The compound of claim 1, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein A¹ is optionally substituted by halo, hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, or substituted amino.

18. A compound of Formula I:

19. The compound of claim 18, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is phenyl or substituted phenyl.

20. The compound of claim 19, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is phenyl substituted with a group of formula —

X¹—

N(R₅₀₁)(R₅₀₂);

wherein X¹ is a covalent bond, SO₂, or C(═

O); and

R₅₀₁ and R₅₀₂ are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl;

or R₅₀₁ and R₅₀₂, taken together with the nitrogen atom to which they are attached, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from C_1-3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino.

21. The compound of claim 20, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein —

N(R₅₀₁)(R₅₀₂) forms —

NH₂, —

NH—

CH(CH₃)₂, —

NH—

(CH₂)₂—

O—

CH₃, —

NH-cyclopropyl, morpholin-4-yl, 4-methyl-piperizine-1-yl, or —

NH—

(CH₂)₂-pyrrolidin-1-yl.

22. The compound of claim 18, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein one of R² and R³ is heteroaryl or substituted heteroaryl.

23. A pharmaceutical composition comprising a compound of Formula I: