Heterocyclic compounds useful as PDK1 inhibitors

Patent metadata

Field	Value
Publication number	US-10030016-B2
Application number	US-201514966821-A
Country	US
Kind code	B2
Filing date	Dec 11, 2015
Priority date	Oct 6, 2009
Publication date	Jul 24, 2018
Grant date	Jul 24, 2018

Abstract

The present invention provides compounds useful as inhibitors of PDK1. The present invention also provides compositions thereof, and methods of treating PDK1-mediated diseases.

First claim

We claim:

1. A method of treating cancer in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or optionally substituted C 1-6 aliphatic;
X is —C(O)— or —S(O) 2 —,
L 1 is a covalent bond or a C 1-4 alkylene, optionally substituted with —(CH 2 ) 0-4 R ∘ or —(CH 2 ) 0-4 OR ∘ , wherein R ∘ is hydrogen;
A 1 is an optionally substituted bivalent ring selected from 3-7 membered saturated or partially unsaturated monocyclic carbocyclylene, 7-10 membered saturated or partially unsaturated bicyclic carbocyclylene, 4-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 7-10 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenylene, 8-10 membered bicyclic arylene, 5-6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8-10 membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
L 2 is a covalent bond, or an optionally substituted alkylene chain;
Ring A 2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 10-16 membered saturated, partially unsaturated, or aromatic tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A 2 is optionally substituted with 1-4 R x groups;
each R x is independently —R, optionally substituted alkylidenyl, oxo, -halo, —NO 2 , —CN, —OR, —SR, —N(R′) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R′) 2 , —S(O) 2 N(R′) 2 , —OC(O)R, —N(R′)C(O)R, —N(R′)N(R′) 2 , —N(R′)OR, —N(R′)C(═NR′)N(R′) 2 , —C(═NR′)N(R′) 2 , —C═NOR, —N(R′)C(O)N(R′) 2 , —N(R′)S(O) 2 N(R′) 2 , —N(R′)S(O) 2 R, or —OC(O)N(R′) 2 ;
each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R′ is independently —R, or two R′ groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
L 3 is unsubstituted methylene or methylene substituted with methyl or ethyl;
Ring A 3 is an optionally substituted ring selected from a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a phenyl ring, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring A 4 is

 and
R 3 is —R, -halo, —NO 2 , —CN, —OR, —SR, —N(R′) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R′) 2 , —S(O) 2 N(R′) 2 , —OC(O)R, —N(R′)C(O)R, —N(R′)N(R′) 2 , —N(R′)OR, —N(R′)C(═NR′)N(R′) 2 , —C(═NR′)N(R′) 2 , —C═NOR, —N(R′)C(O)N(R′) 2 , —N(R′)S(O) 2 N(R′) 2 , —N(R′)S(O) 2 R, or —OC(O)N(R′) 2 ;
R 4 is —R, -halo, —NO 2 , —CN, —OR, —SR, —N(R′) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R′) 2 , —S(O)N(R′) 2 , —S(O) 2 N(R′) 2 , —OC(O)R, —N(R′)C(O)R, —N(R′)N(R′) 2 , —N(R′)OR, —N(R′)C(═NR′)N(R′) 2 , —C(═NR′)N(R′) 2 , —C═NOR, —N(R′)C(O)N(R′) 2 , —NHS(O)C 1-6 alkyl, —N(R′)S(O) 2 N(R′) 2 , —N(R′)S(O) 2 R, or —OC(O)N(R′) 2 ; or:
R 3 and R 4 are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 4-7 membered partially unsaturated carbocyclic ring, phenyl, a 5-6 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur,
wherein the cancer is associated with dysregulated Akt activation and is selected from glioma, thyroid carcinoma, breast carcinoma, lung cancer, gastric carcinoma, gastrointestinal stromal tumors, pancreatic carcinoma, bile duct carcinoma, ovarian carcinoma, endometrial carcinoma, prostate carcinoma, renal cell carcinoma, anaplastic large-cell lymphoma, leukemia, multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer;
wherein treating cancer does not encompass preventing cancer.

2. The method of claim 1 , wherein:
R 3 is hydrogen, —Cl, or —CF 3 ;
R 4 is —CN, —NO 2 , —NH 2 , —NHC(O)C 1-6 alkyl, —CO 2 H, —CO 2 C 1-4 alkyl, —C(O)N(R′) 2 , —NHS(O)C 1-6 alkyl, —NHS(O) 2 C 1-6 alkyl, —SC 1-6 alkyl, —S(O)C 1-6 alkyl, —S(O) 2 C 1-6 alkyl, —S(O)N(R′) 2 , —S(O) 2 N(R′) 2 , —CF 3 , —OCH 3 , —OCH 2 CH 3 , or benzyloxy; and
each R′ is independently hydrogen or C 1-4 alkyl, or two R′ groups on the same nitrogen are taken together with the intervening nitrogen to form an optionally substituted 5-6 membered saturated, partially unsaturated, or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

3. The method of claim 1 , wherein Ring A 3 is phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein Ring A 3 is optionally substituted with one or more halo or alkyl groups.

4. The method of claim 1 , wherein L 1 is optionally substituted C 1-3 alkylene.

Assignees

• Sunesis Pharmaceuticals Inc
• Millennium Pharm Inc
• Millenium Pharmaceuticals Inc

Inventors

• Arndt Joseph
• Chan Timothy
• Guckian Kevin
• Kumaravel Gnanasambandam
• Lee Wen-Cherng
• Lin Edward Yin-Shiang
• Scott Daniel
• Sun Lihong
• Thomas Jermaine
• Van Vloten Kurt
• Wang Deping
• Zhang Lei
• Erlanson Daniel

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D241/28

  in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms · CPC title

• C07D213/82

  in position 3 · CPC title