HETEROCYCLIC PDK1 INHIBITORS FOR USE TO TREAT CANCER

1 . A method of treating cancer in a subject in need thereof, in which cancer growth or survival is dependent on a PDK1-PIF-mediated substrate interaction, comprising administering to said subject a therapeutically effective amount of a compound of Formula I as described herein:

I

or a pharmaceutically acceptable salt thereof, in which:

R 1 is hydrogen or optionally substituted C1-6 aliphatic, or:

R 1 and a substituent on Ring A 4 are taken together with their intervening atoms to form an optionally substituted 5-7 membered partially unsaturated or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

X is —C(O)— or —S(O) 2 —,

L 1 is a covalent bond or an optionally substituted bivalent group selected from C 1-4 alkylene, C 2-4 alkenylene, or C 2-4 alkynylene wherein one or more methylene units of L 1 are optionally and independently replaced

by -Cy 1 -, —O—, —S—, —N(R 2 )—, —C(O)—, —C(O)N(R 2 )—, —N(R 2 )C(O)N(R 2 )—, —N(R 2 )C(O)—, —N(R 2 )C(O)O—, —OC(O)N(R 2 )—, —S(O) 2 —, —S(O) 2 N(R 2 )—, —N(R 2 )S(O) 2 —, —OC(O)—, or —C(O)O—;

Cy 1 is an optionally substituted bivalent ring selected from phenylene, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R 2 is hydrogen or optionally substituted C 1-6 aliphatic;

A 1 is a covalent bond or 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, alkylidenylene, or an optionally substituted alkylene chain in which one or more methylene units of L 2 are optionally and independently replaced by —O—, —S—, —N(R 2 )—, —C(O)—, —C(O)N(R 2 )—, —N(R 2 )C(O)N(R 2 )—, —N(R 2 )C(O)—, —N(R 2 )C(O)O—, —OC(O)N(R 2 )—, —S(O) 2 —, —S(O) 2 N(R 2 )—, —N(R 2 )S(O) 2 —, —OC(O)—, or —C(O)O—;

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 C1-6 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 a covalent bond or an optionally substituted C 1-4 alkylene chain in which one or more methylene units of L 3 are optionally and independently replaced by —O—, —S—, —N(R 2 )—, —C(O)—, —C(O)N(R 2 )—, —N(R 2 )C(O)N(R 2 )—, —N(R 2 )C(O)—, —N(R 2 )C(O)O—, —OC(O)N(R 2 )—, —S(O) 2 —, —S(O) 2 N(R 2 )—, —N(R 2 )S(O) 2 —, —OC(O)—, or —C(O)O—;

Ring A 3 is an optionally substituted ring selected from 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 810 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 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; wherein any substitutable carbon on Ring A 4 is optionally substituted with R 3 , R 4 , or R 5 , and any substitutable nitrogen on Ring A 4 is optionally substituted with R 6 ;

each of R 3 , R 4 , and R 5 is

independently —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 ; or:

R 3 and R 4 or R 4 and R 5 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;

each R 6 is

independently —R, —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 , or —S(O) 2 N(R′) 2 ; or:

R 3 and R 6 are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or 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;

provided that:

when A 1 is a bivalent monocyclic ring and L 1 is a covalent bond, L 2 is not —O—;

when A 1 is a bivalent monocyclic or bicyclic ring, L 1 and L 2 are not simultaneously a covalent bond; and

L 1 , A 1 , and L 2 are not simultaneously a covalent bond.

2 . The method of claim 1 , in which the compound is of Formula Is:

or a pharmaceutically acceptable salt thereof, in which:

or a pharmaceutically acceptable salt thereof, in which:

any substitutable carbon on Ring A 4 is optionally substituted with R 3 , R 4 , or R 5 , and any substitutable nitrogen on Ring A 4 is optionally substituted with R 6 ;

each of R 3 , R 4 , and R 5 is

independently —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 ; or:

R 3 and R 4 or R 4 and R 5 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;

each R 6 is independently —R, —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 , or —S(O) 2 N(R′) 2 ; or:

R 3 and R 6 are taken together with their intervening atoms to form an optionally substituted fused ring selected from a 5-6 membered saturated or 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;

R 7 is hydrogen or methyl; and

each R 8 is independently hydrogen or halo.

3 . The method of claim 1 , in which Ring A 3 is phenyl, substituted by one or two fluorines at the meta position or ortho position.

4 . The method of claim 1 , in which the compound is of Formula Iy:

in which 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 .

5 . The method of claim 4 , in which the compound is of Formula Iz:

or a pharmaceutically acceptable salt thereof.

6 . The method of claim 5 , in which the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

7 . A method of claim 1 , in which the cancer is a hematologic cancer selected from the group consisting of leukemias, lymphomas, and myelomas.

8 . A method of claim 7 , in which the hematologic cancer is selected from anaplastic large-cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, histiocytic lymphoma, T-cell leukemia, chronic lymphocytic leukemia, multiple myeloma, chronic myelogenous leukemia, acute lymphocytic (lymphoblastic) leukemia, acute myelogenous leukemia, acute myeloblastic leukemia, and plasma cell leukemia.

9 . A pharmaceutical composition for use in treating cancer in a subject, in which the growth or proliferation of the cancer is dependent on a PDK1-PIF-mediated substrate interaction, comprising a formulation including a compound of Formula I and a pharmaceutically acceptable carrier.

10 . A pharmaceutical composition for use in a combinational therapy of treating cancer in a subject, comprising a formulation including a compound of Formula I and a pharmaceutically acceptable carrier, wherein the combinational therapy further comprises an effective amount of a second anti-cancer agent.