Substituted indoles and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12116358-B2
Application number	US-201917268151-A
Country	US
Kind code	B2
Filing date	Aug 14, 2019
Priority date	Aug 14, 2018
Publication date	Oct 15, 2024
Grant date	Oct 15, 2024

Abstract

Compounds of Formula I: (I) and the pharmaceutically acceptable salts and solvates thereof, wherein R 1a , R 1e , G1, G2, Q 1 , Q 2 , Q 3 , and (II) are defined as set forth in the specification, as are uses of compounds of Formula I to treat a disease, disorder, or condition such as cancer in a subject.

First claim

What is claimed is:

1. A compound of Formula IV:

wherein:
R 1d is fluoro;
Z 4 is selected from the group consisting of —O—, —C(R 28a )(R 28b )—, and —N(R 23 )—; or Z 4 is absent;
Z 5 is selected from the group consisting of —CH 2 — and —CH 2 CH 2 —;
R 11a is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclo, optionally substituted heteroaryl, and —N(R 12b )C(═O)R 13c ;
R 12b is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and heterocyclo, (C 1 -C 4 alkoxy)C 1 -C 4 alkyl, and (hydroxy)C 1 -C 4 alkyl;
R 13c is selected from the group consisting of alkyl, haloalkyl, alkoxy, (alkoxy)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycle, amino, (amino)alkyl, (C 3 -C 6 cycloalkyl)oxy, and (4- to 8-membered heterocyclo)oxy;
R 23 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl; and
R 28a and R 28b are independently selected from the group consisting of hydrogen, alkyl, and halo;

or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1 of Formula IV-A:

or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 2 , wherein:
R 11a is selected from the group consisting of:
(A) unsubstituted 4- to 14-membered heterocyclo;
(B) substituted 4- to 14-membered heterocyclo having one, two or three substituents independently selected from the group consisting of:
(i) —N(R 12a )C(═O)R 13a ; (ii) —C(═O)R 13b ; (iii) C 1 -C 4 alkyl; (iv) (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (v) (hydroxy)C 1 -C 4 alkyl; (vi) C 1 -C 4 haloalkyl; (vii) amino; (vii) hydroxy; (viii) —N(R 12a )S(═O) 2 R 24 ; (ix) —S(═O) 2 R 24 ; (x) unsubstituted C 3 -C 6 cycloalkyl; (xi) substituted C 3 -C 6 cycloalkyl having one or two substituents independently selected from the group consisting of halo, hydroxy, C 1 -C 4 alkyl, amino, and (amino)C 1 -C 4 alkyl; (xii) unsubstituted 4- to 14-membered heterocyclo; and substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C 1 -C 4 alkyl; (xiii) —C(═N—R 60 )R 61 ; and (xiv) —C(═C—NO 2 )R 64 ;
(C) unsubstituted 5- to 10-membered heteroaryl;
(D) substituted 5- or 6-membered heteroaryl having one, two, three, or four substituents independently selected from the group consisting of halo and C 1 -C 4 alkyl;
(E) C 1 -C 6 alkyl; and
(F) —N(R 12b )C(═O)R 13c ;
R 12a and R 12b are each independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, (C 1 -C 4 alkoxy)C 1 -C 4 alkyl, and (hydroxy)C 1 -C 4 alkyl;
R 13a , R 13b , and R 13c are each independently selected from the group consisting of (A) C 1 -C 6 alkyl; (B) C 1 -C 6 haloalkyl; (C) unsubstituted C 3 -C 6 cycloalkyl; (D) C 1 -C 6 alkoxy; (E) (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (F) (hydroxy)C 1 -C 4 alkyl; (G) (cyano)alkyl; (H) unsubstituted C 6 -C 10 aryl; (I) substituted C 6 -C 10 aryl, having one, two, three, or four substituents independently selected from the group consisting of halo, amino, hydroxy, and C 1 -C 4 alkyl; (J) unsubstituted 5- or 6-membered heteroaryl; (K) substituted 5- or 6-membered heteroaryl having one, two, three, or four substituents independently selected from the group consisting of halo, amino, hydroxy, and C 1 -C 4 alkyl; (L) unsubstituted 4- to 14-membered heterocyclo; (M) substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C 1 -C 4 alkyl; (N) amino; (0) (amino)alkyl; (P) (C 3 -C 6 cycloalkyl)oxy; and (Q) (4- to 8-membered heterocyclo)oxy;
R 24 is selected from the group consisting of C 1 -C 4 alkyl and (hydroxy)C 1 -C 4 alkyl;
R 60 is selected from the group consisting of cyano, nitro, hydroxy, C 1 -C 6 alkoxy, —C(═O)R 62 and —S(═O) 2 R 62 ;
R 61 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —NR 63a R 63b ;
R 62 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —NR 63a R 63b ;
R 63a is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
R 63b is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; or
R 63a and R 63b taken together with the nitrogen atom to which they are attached form a 4- to 6-membered optionally substituted heterocyclo;
R 64 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —NR 63c R 63d ;
R 63c is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; and
R 63d is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; or
R 63c and R 63d taken together with the nitrogen atom to which they are attached form a 4- to 6-membered optionally substituted heterocyclo, or a pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 3 , wherein R 11a is a substituted 4- to 14-membered heterocyclo selected from the group consisting of:

R 12a is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, (C 1 -C 4 alkoxy)C 1 -C 4 alkyl, and (hydroxy)C 1 -C 4 alkyl;
R 13a is selected from the group consisting of C 1 -C 4 alkyl; amino; unsubstituted C 3 -C 6 cycloalkyl; substituted C 3 -C 6 cycloalkyl having one or two substituents independently selected from the group consisting of halo, hydroxy, C 1 -C 4 alkyl, amino, and (amino)C 1 -C 4 alkyl; (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (hydroxy)C 1 -C 4 alkyl; unsubstituted 4- to 14-membered heterocyclo; and substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C 1 -C 4 alkyl;
R 13b is selected from the group consisting of C 1 -C 4 alkyl; amino; C 1 -C 4 haloalkyl; C 1 -C 4 alkoxy; (hydroxy)C 1 -C 4 alkyl; (C 1 -C 4 alkoxy)C 1 -C 4 alkyl; (amino)alkyl; unsubstituted C 3 -C 6 cycloalkyl; substituted C 3 -C 6 cycloalkyl having one or two substituents independently selected from the group consisting of halo, hydroxy, C 1 -C 4 alkyl, amino, and (amino)C 1 -C 4 alkyl; unsubstituted 4-to 14-membered heterocyclo; and substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C 1 -C 4 alkyl; (C 3 -C 6 cycloalkyl)oxy; and (4- to 8-membered heterocyclo)oxy;
R 21 is selected from the group consisting of hydrogen, —C(═O)R 13b , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, unsubstituted 4- to 14-membered heterocyclo, and —S(═O) 2 R 24 ;
R 22 is selected from the group consisting of C 1 -C 4 alkyl; unsubstituted C 3 -C 6 cycloalkyl; substituted C 3 -C 6 cycloalkyl having one or two substituents independently selected from the group consisting of halo, hydroxy, C 1 -C 4 alkyl, amino, and (amino)C 1 -C 4 alkyl; unsubstituted 4- to 14-membered heterocyclo; and substituted 4- to 14-membered heterocyclo having one or two substituents independently selected from the group consisting of amino, hydroxy, and C 1 -C 4 alkyl;
R 24 is selected from the group consisting of C 1 -C 4 alkyl and (hydroxy)C 1 -C 4 alkyl;
R 25 is selected from the group consis

Assignees

• Epizyme Inc

Inventors

• Lampe John
• Campbell John
• Duncan Kenneth
• Foley Megan Alene Cloonan
• Harvey Darren Martin
• Munchhof Michael John
• Thomenius Michael
• Reiter Lawrence Alan

Classifications

• C07D513/10

  Spiro-condensed systems · CPC title

• C07D498/10

  Spiro-condensed systems · CPC title

• C07D498/08

  Bridged systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title