Isoquinoline, quinoline, and quinazoline derivatives as inhibitors of hedgehog signaling

• US 9,345,699 B2
• Filed: 06/09/2010
• Issued: 05/24/2016
• Est. Priority Date: 06/09/2009
• Status: Active Grant

• Current Assignee: Nantbioscience, Inc. (NantWorks, LLC)
• Original Assignee: Nantbioscience, Inc. (NantWorks, LLC)
• Inventors: Tao, Chunlin, Sun, Xiaowen, Han, Hongna, Koroniak, Lukasz, Desai, Neil
• Primary Examiner(s): Chu, Yong
• Assistant Examiner(s): WRIGHT, SONYA N
• Application Number:
  US13/376,813
• Publication Number:
  US 20120270858A1
• Time in Patent Office: 2,176 Days
• Field of Search: 546/166, 546/144, 514/307
• US Class Current: 1/1
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 217/16 substituted by oxygen atoms
• CPC Class Codes: C07D 239/74 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
• 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 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• 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 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The invention provides isoquinoline, quinoline, and quinazoline derivatives to treat a variety of disorders, diseases and pathologic conditions, and more specifically to the use of isoquinoline, quinoline, and quinazoline derivatives to inhibit the hedgehog signaling pathway and to the use of those compounds to the treatment of hyperproliferative diseases and pathologic angiogenesis.

Claims

1. A compound as shown in Formula (I)

2. A compound as shown in Formula (Ia)

3. A compound as shown in Formula (Ib)

23. A process for making a compound of claim 1 or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms, salts and individual diastereomers thereof.

24. A pharmaceutical composition comprising at least one compound of claim 1 or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms, salts and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

4. A compound as shown in Formula (A):

5. A compound or pharmaceutically acceptable salt of claim 4, wherein:

K is selected from NR₃C(O), C(O)NR₃, SO₂NR₃, and NR₄C(O)NR₅;

A¹ is selected from phenyl and pyridyl;

R¹ is selected from H, halo, nitro, C₁-C₆ alkylsulfonyl, and C₁-C₆ alkyl;

m=0-4;

R₃, R₄ and R₅ are each independently selected from H and C₁-C₆ alkyl;

W is selected from CH and N;

Z is selected from H, halo, and C₁-C₆ alkyl.

6. A compound as shown in Formula (B):

9. The compound of claim 6, wherein the compound is as shown in Formula (ii):

10. The compound of claim 6, wherein the compound is as shown in Formula (iii):

11. The compound of claim 6, wherein the compound is as shown in Formula (iv):

12. The compound of claim 6, wherein the compound is as shown in Formula (v):

13. The compound of claim 6, wherein the compound is as shown in Formula (vi):

14. The compound of claim 6, wherein the compound is as shown in Formula (vii):

15. The compound of claim 6, wherein the compound is as shown in Formula (viii):

16. The compound of claim 6, wherein the compound is as shown in Formula (ix):

17. The compound of claim 6, wherein the compound is as shown in Formula (x):

18. The compound of claim 6, wherein the compound is as shown in Formula (xi):

19. The compound of claim 6, wherein the compound is as shown in Formula (xii):

20. The compound of claim 6, wherein the compound is as shown in Formula (xiii):

21. The compound of claim 6, wherein the compound is as shown in Formula (xiv):

7. A compound as shown in Formula (C):

22. The compound of claim 7, wherein the compound is as shown in Formula (xv):

8. A compound having the structure shown in Formula (i):