US 2017/0247391 A1Published application

Thienopyrimidine and thienopyridine compounds and methods of use thereof

AssigneesThe Regents of the University of Michigan, Kura Oncology, Inc.

InventorsJolanta Grembecka, Tomasz Cierpicki, Dmitry Borkin, Jonathan Pollock, Hongzhi Miao, Duxin Sun, Liansheng Li, Tao Wu, Jun Feng, Pingda Ren, Yi Liu

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Abstract

The present disclosure provides compounds and methods for inhibiting the interaction of menin with its upstream or downstream signaling molecules including but not limited to MLL1, MLL2 and MLL-fusion oncoproteins. Compounds of the disclosure may be used in methods for the treatment of a wide variety of cancers and other diseases associated with one or more of MLL1, MLL2, MLL fusion proteins, and menin.

Claims165

Dependent claims

A compound having a structure of Formula (1) or (2):

or a salt thereof, wherein:
R1, R2, R4, R5, R6, and R8 are each independently selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, amine, thioalkyl, halogen, ketone, amide, cyano, sulfonyl, a carbocyclic ring, an aromatic ring, a substituted aromatic ring, a heterocyclic aromatic ring, a substituted heterocyclic aromatic ring, a substituted or non-substituted heterocyclic non-aromatic ring, carbocyclic or heterocyclic aromatic ring fused to another aromatic ring, a hydrogen bond donor, a hydrogen bond acceptor, and combinations thereof;
wherein R6 can be present at one or more of the positions of the benzyl and/or pyrrole portion of the indole ring that are not otherwise occupied by a substituent;
R3 is selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, thioalkyl, ketone, amide, sulfonyl, a carbocyclic ring, an aromatic ring, a substituted aromatic ring, a heterocyclic aromatic ring, a substituted heterocyclic aromatic ring, a substituted or non-substituted heterocyclic non-aromatic ring, carbocyclic or heterocyclic aromatic ring fused to another aromatic ring, a hydrogen bond donor, a hydrogen bond acceptor, and combinations thereof;
Y is N or C(Ra), wherein Ra is selected from hydrogen, alkyl, heteroalkyl, substituted aryl, substituted alkyl, alcohol, alkoxy, amino, cyano, sulfonyl, aldehyde, non-aromatic heterocycle, and aromatic ring;
L is present or absent, and if present it is selected from alkylene, oxalkylene and aminoalkylene;
and
R7 comprises a functional group that covalently reacts with one or more residues on menin.

5 more elements

A compound represented by the structure of Formula (3B):

or a salt thereof, wherein:
R1, R2, R4, R5, R5a, R8, and Ra are independently selected from hydrogen, halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, and —CN;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, or two substituents on the same carbon atom of an C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl come together to form a C3-10 carbocycle or 3- to 10-membered heterocycle;
and C3-10 carbocycle and 3- to 10-membered heterocycle;
or R5 and R5a together with the carbon atom to which they are attached, come together to form a C3-10 carbocycle or a 3- to 10-membered heterocycle;
wherein any C3-10 carbocycle and 3- to 10-membered heterocycle of R1, R2, R4, R5, R5a, R8, and Ra is independently optionally substituted with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R3 is selected from selected from hydrogen, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —S(O)2R20, and —S(O)2N(R20)2;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, or two substituents on the same carbon atom of an C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl come together to form a C3-10 carbocycle or 3- to 10-membered heterocycle;
and C3-10 carbocycle and 3- to 10-membered heterocycle;
wherein any C3-10 carbocycle and 3- to 10-membered heterocycle of R3 is independently optionally substituted with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R6 is independently selected at each occurrence from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, and —CN;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, or two substituents on the same carbon atom of an C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl come together to form a C3-10 carbocycle or 3- to 10-membered heterocycle;
and C3-10 carbocycle and 3- to 10-membered heterocycle;
wherein any C3-10 carbocycle and 3- to 10-membered heterocycle of R6 is independently optionally substituted with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R20 at each occurrence is independently selected from hydrogen;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR30, —SR30, —N(R30)2, —N(R30)C(O)R30, —C(O)R30, —C(O)OR30, —C(O)N(R30)2, —OC(O)R30, —S(O)2R30, —S(O)2N(R30)2, —N(R30)S(O)2R30, —NO2, —P(O)(OR30)2, —P(O)(R30)2, —OP(O)(OR30)2, and —CN;
and 3- to 10-membered heterocycle and C3-10 carbocycle;
R30 at each occurrence is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
Y is N or C(Ra);
s is selected from 0, 1, 2, 3, and 4;
and
R7 comprises a moiety that covalently reacts with one or more residues on menin.

19 more elements

A compound represented by the structure of Formula (4):

or a salt thereof, wherein:
R1, R2, R4, R5, R8, and Ra are independently selected from hydrogen, halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, and —CN;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, or two substituents on the same carbon atom of an C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl come together to form a C3-10 carbocycle or 3- to 10-membered heterocycle;
and C3-10 carbocycle and 3- to 10-membered heterocycle;
wherein any C3-10 carbocycle and 3- to 10-membered heterocycle of R1, R2, R4, R5, R8, and Ra is independently optionally substituted with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R3 is selected from selected from hydrogen, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —S(O)2R20, and —S(O)2N(R20)2;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, or two substituents on the same carbon atom of an C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl come together to form a C3-10 carbocycle or 3- to 10-membered heterocycle;
and C3-10 carbocycle and 3- to 10-membered heterocycle;
wherein any C3-10 carbocycle and 3- to 10-membered heterocycle of R3 is independently optionally substituted with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R6 is independently selected at each occurrence from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, and —CN;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, or two substituents on the same carbon atom of an C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl come together to form a C3-10 carbocycle or 3- to 10-membered heterocycle;
and C3-10 carbocycle and 3- to 10-membered heterocycle;
wherein any C3-10 carbocycle and 3- to 10-membered heterocycle of R6 is independently optionally substituted with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R20 at each occurrence is independently selected from hydrogen;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR30, —SR30, —N(R30)2, —N(R30)C(O)R30, —C(O)R30, —C(O)OR30, —C(O)N(R30)2, —OC(O)R30, —S(O)2R30, —S(O)2N(R30)2, —N(R30)S(O)2R30, —NO2, —P(O)(OR30)2, —P(O)(R30)2, —OP(O)(OR30)2, and —CN;
and 3- to 10-membered heterocycle and C3-10 carbocycle;
R30 at each occurrence is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
Y is N or C(Ra);
L is absent or selected from alkylene and heteroalkylene;
s is selected from 0, 1, 2, 3, and 4;
R7a is -G-V-R9a;
G is selected from a bond, alkylene, heteroalkylene, C3-12 carbocycle, 3- to 12-membered heterocycle, and combinations thereof, wherein G is optionally substituted with one or more R32 groups;
V is absent or selected from a C3-12 carbocycle, and 3- to 12-membered heterocycle;
wherein V is optionally substituted with one or more R32 groups;
R9a is selected from hydrogen and R32;
and
R32 at each occurrence is selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, and —CN;
C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C3-10 carbocycle, and 3- to 10-membered heterocycle;
C3-10 carbocycle and 3- to 10-membered heterocycle;
or two R32 on the same carbon atom can come together to form a C3-10 carbocycle or 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle of R32 is independently optionally substituted with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

27 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/509,989Filed 8 Sep 2015
Priority: 9 Sep 2014
Published: 31 Aug 2017
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 495/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 35/04
Antineoplastic agents: specific for metastasis
C07D 519/00
Heterocyclic compounds containing more than one system of two or more relevant
C07F 9/5325
Organo-phosphine oxides; Organo-phosphine thioxides: aromatic phosphine oxides or thioxides

Family

Application62/048,036Us provisional application · filed 9 Sep 2014
Application62/095,588Us provisional application · filed 22 Dec 2014
Application62/171,124Us provisional application · filed 4 Jun 2015
Application62/214,681Us provisional application · filed 4 Sep 2015
US 10,246,464 B2Related patent
US 2017/0247391 A1This patent

From the US filing history. Foreign family members aren’t listed.