IP Library › Granted Patent US 9,024,018

Granted Patent B2

US 9,024,018 · App. 13/376,945 · Granted May 5, 2015

3-substituted-8-substituted-3H-imidazo[5,1-d][1,2,3,5]tetrazin-4-one compounds and their use

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Quick Facts

Patent No.: US 9,024,018
App. No.: 13/376,945
Granted: May 5, 2015
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention pertains generally to the field of therapeutic compounds, and more specifically to 3-substituted-8-substituted-3H-imidazo[5,1-d][1,2,3,5]tetrazin-4-one compounds of the following formula, wherein -A and —B are as defined herein (collectively referred to herein as 38TM compounds): The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit cell proliferation, and in the treatment of proliferative disorders such as cancer, etc., and methods of preparing such compounds.

Claims (504)

1. A compound of the following formula or a pharmaceutically acceptable salt thereof:

wherein:

-A is independently -A 1 , -A 3 , or -A 6 ; and

—B is independently —B 1 , —B 2 , —B 3 , —B 4 , —B 5 , —B 6 , —B 7 , —B 8 , —B 9 , —B 10 , —B 11 , B 12 , —B 13 , or —B 14 ;

wherein:

-A 1 is independently C 5-12 heteroaryl, and is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Z1 ,—CF 3 ,

—OH, —OR Z1 , —OCF 3 ,

—SR Z1 ,

—NH 2 , —NHR Z1 , —NR Z1 2 , pyrrolidino, piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Z1 ,

—C(═O)R Z1 ,

—OC(═O)R Z1 ,

—C(═O)NH 2 , —C(═O)NHR Z1 , —C(═O)NR Z1 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Z1 , —NR Z1 C(═O)R Z1 ,

—OC(═O)NH 2 , —OC(═O)NHR Z1 , —OC(═O)NR Z1 2 , —OC(═O)-pyrrolidino, —OC(═O)-piperidino, —OC(═O)-morpholino, —OC(═O)-piperizino, (N—C 1-4 alkyl)-piperizino,

—NHC(═O)OR Z1 , —NR Z1 C(═O)OR Z1 ,

—NHC(═O)NH 2 , —NHC(═O)NHR Z1 , —NHC(═O)NR Z1 2 , —NHC(═O)-pyrrolidino, —NHC(═O)-piperidino, —NHC(═O)-morpholino, —NHC(═O)-piperizino, —NHC(═O)—(N—C 1-4 alkyl)-piperizino,

—NO 2 , and —CN;

wherein each —R Z1 is independently saturated aliphatic C 1-4 alkyl, aliphatic C 3-6 alkynyl, saturated C 3-6 cycloalkyl, C 5-6 heteroaryl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl, C 5-6 heteroaryl, and -Ph is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R Z1A , —CF 3 , —OH, —OR Z1A , and —OCF 3 ,

wherein each —R Z1A is independently saturated aliphatic C 1-4 alkyl;

and additionally wherein two adjacent substituents may together form —O—CH 2 —O— or —O—CH 2 CH 2 —O—;

-A 3 is independently imidamido or substituted imidamido;

-A 6 is independently aliphatic C 2-6 alkenyl, and is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Z6A , —CF 3 ,

—OH, —OR Z6A , —OCF 3 ,

—SR Z6A ,

—NH 2 , —NHR Z6A , —NR Z6A 2 , pyrrolidino, piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Z6A ,

—C(═O)R Z6A ,

—OC(═O)R Z6A ,

—C(═O)NH 2 , —C(═O)NHR Z6A , —C(═O)NR Z6A 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Z6A , —NR Z6A C(═O)R Z6A ,

—OC(═O)NH 2 , —OC(═O)NHR Z6A , —OC(═O)NR Z6A 2 , —OC(═O)-pyrrolidino, —OC(═O)-piperidino, —OC(═O)-morpholino, —OC(═O)-piperizino, (N—C 1-4 alkyl)-piperizino,

—NHC(═O)OR Z6A , —NR Z6A C(═O)OR Z6A ,

—NHC(═O)NH 2 , —NHC(═O)NHR Z6A , —NHC(═O)NR Z6A 2 , —NHC(═O)-pyrrolidino, —NHC(═O)-piperidino, —NHC(═O)-morpholino, —NHC(═O)-piperizino, —NHC(═O)—(N—C 1-4 alkyl)-piperizino,

—NO 2 , and —CN,

wherein each —R Z6A is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or —CH 2 -Ph,

wherein each C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R Z6B , —CF 3 , —OH, —OR Z6B , and —OCF 3 ,

wherein each —R Z6B is independently saturated aliphatic C 1-4 alkyl;

and wherein:

—B 1 is independently saturated aliphatic C 1-6 alkyl;

—B 2 is independently aliphatic C 2-6 alkynyl;

—B 3 is independently mercapto-C 1-4 alkyl, sulfanyl-C 1-4 alkyl, sulfinyl-C 1-4 alkyl, or sulfonyl-C 1-4 alkyl;

—B 4 is independently hydroxy-C 1-4 alkyl or ether-C 1-4 alkyl;

—B 5 is independently phenyl-C 1-6 alkyl or C 5-6 heteroaryl-C 1-6 alkyl, and is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Y5A , —CF 3 ,

—OH, —OR Y5A , —OCF 3 ,

—SR Y5A ,

—NH 2 , —NHR Y5A , —NR Y5A 2 , pyrrolidino, piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Y5A ,

—C(═O)R Y5A ,

—OC(═O)R Y5A ,

—C(═O)NH 2 , —C(═O)NHR Y5A , —C(═O)NR Y5A 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Y5A , —NR Y5A C(═O)R Y5A ,

—OC(═O)NH 2 , —OC(═O)NHR Y5A , —OC(═O)NR Y5A 2 , —OC(═O)-pyrrolidino, —OC(═O)-piperidino, —OC(═O)-morpholino, —OC(═O)-piperizino, (N—C 1-4 alkyl)-piperizino,

—NHC(═O)OR Y5A , —NR Y5A C(═O)OR Y5A ,

—NHC (═O)NH 2 , —NHC(═O)NHR Y5A , —NHC(═O)NR Y5A 2 , —NHC(═O)-pyrrolidino, —NHC(═O)-piperidino, —NHC(═O)-morpholino, —NHC(═O)-piperizino, —NHC(═O)—(N—C 1-4 alkyl)-piperizino,

—NO 2 , and —CN,

wherein each —R Y5A is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R Y5B , —CF 3 , —OH, —OR Y5B , and —OCF 3 ,

wherein each —R Y5B is independently saturated aliphatic C 1-4 alkyl;

—B 6 is independently acyl-C 1-6 alkyl, carboxy-C 1-6 alkyl, oxyacyl-C 1-6 alkyl, or acyloxy-C 1-6 alkyl;

—B 7 is independently amido-C 1-4 alkyl or substituted amido-C 1-4 alkyl;

—B 8 is independently C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, C 3-6 heterocyclyl, or C 3-6 heterocyclyl-C 1-4 alkyl, and is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Y8A , —CF 3 ,

—OH, —OR Y8A , —OCF 3 ,

—NH 2 , —NHR Y8A , —NR Y8A 2 , pyrrolidino piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Y8A ,

—C(═O)R Y8A ,

—OC(═O)R Y8A ,

—C(═O)NH 2 , —C(═O)NHR Y8A , —C(═O)NR Y8A 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Y8A , —NR Y8A C(═O)R Y8A , and

—CN;

wherein each —R Y8A is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R Y8B , —CF 3 , —OH, —OR Y8B , and —OCF 3 ,

wherein each —R Y8B is independently saturated aliphatic C 1-4 alkyl;

—B 9 is independently halo-C 1-6 alkyl;

—B 10 is independently nitro-C 1-6 alkyl;

—B 11 is independently cyano-C 1-6 alkyl;

—B 12 is independently phosphate-C 1-6 alkyl;

—B 13 is independently carbamate-C 1-6 alkyl; and

—B 14 is independently oxime-C 1-6 alkyl.

2. A compound according to claim 1 , wherein -A is independently -A 1 ; and -A 1 is independently:

furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, or quinazolinyl;

and is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Z1 , —CF 3 ,

—OH, —OR Z1 , —OCF 3 ,

—SR Z1 ,

—NH 2 , —NHR Z1 , —NR Z1 2 , pyrrolidino, piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Z1 ,

—C(═O)R Z1 ,

—OC(═O)R Z1 ,

—C(═O)NH 2 , —C(═O)NHR Z1 , —C(═O)NR Z1 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Z1 , —NR Z1 C(═O)R Z1 ,

—OC(═O)NH 2 , —OC(═O)NHR Z1 , —OC(═O)NR Z1 2 , —OC(═O)-pyrrolidino, —OC(═O)-piperidino, —OC(═O)-morpholino, —OC(═O)-piperizino, (N—C 1-4 alkyl)-piperizino, NHC(═O)OH, NHC(═O)OR Z1 , —NR Z1 C(═O)OR Z1 ,

—NO 2 , and —CN;

wherein each —R Z1 is independently saturated aliphatic C 1-4 alkyl, aliphatic C 3-6 alkynyl, saturated C 3-6 cycloalkyl, C 5-6 heteroaryl, -Ph, or —CH 2 -Ph,

wherein each —R Z1A is independently saturated aliphatic C 1-4 alkyl;

and additionally wherein two adjacent substituents may together form —O—CH 2 —O— or —O—CH 2 CH 2 —O—.

3. A compound according to claim 2 , wherein -A 1 is independently oxazolyl, thiazolyl, imidazolyl, or oxadiazolyl, and is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Z1 , —CF 3 ,

—OH, —OR Z1 , —OCF 3 ,

—SR Z1 ,

—NH 2 , —NHR Z1 , —NR Z1 2 , pyrrolidino, piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Z1 ,

—C(═O)R Z1 ,

—OC(═O)R Z1 ,

—C(═O)NH 2 , —C(═O)NHR Z1 , —C(═O)NR Z1 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Z1 , —NR Z1 C(═O)R Z1 ,

—OC(═O)NH 2 , —OC(═O)NHR Z1 , —OC(═O)NR Z1 2 , —OC(═O)-pyrrolidino, —OC(═O)-piperidino, —OC(═O)-morpholino, —OC(═O)-piperizino, (N—C 1-4 alkyl)-piperizino,

—NHC(═O)OR Z1 , —NR Z1 C(═O)OR Z1 ,

—NHC(═O)NH 2 , —NHC(═O)NHR Z1 , —NHC(═O)NR Z1 , —NHC(═O)-pyrrolidino, —NHC(═O)-piperidino, —NHC(═O)-morpholino, —NHC(═O)-piperizino, —NHC(═O)—(N—C 1-4 alkyl)-piperizino,

—NO 2 , and —CN;

wherein each —R Z1 is independently saturated aliphatic C 1-4 alkyl, aliphatic C 3-6 alkynyl, saturated C 3-6 cycloalkyl, C 5-6 heteroaryl, -Ph, or —CH 2 -Ph,

wherein each —R Z1A is independently saturated aliphatic C 1-4 alkyl;

and additionally wherein two adjacent substituents may together form —O—CH 2 —O—or —O—CH 2 CH 2 —O—.

4. A compound according to claim 2 , wherein -A 1 is independently imidazolyl, and is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Z1 , —CF 3 ,

—OH, —OR Z1 , —OCF 3 ,

—SR Z1 ,

—NH 2 , —NHR Z1 , —NR Z1 2 , pyrrolidino, piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Z1 ,

—C(═O)R Z1 ,

—OC(═O)R Z1 ,

—C(═O)NH 2 , —C(═O)NHR Z1 , —C(═O)NR Z1 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Z1 , —NR Z1 C(═O)R Z1 ,

—OC(═O)NH 2 , —OC(═O)NHR Z1 , —OC(═O)NR Z1 2 , —OC(═O)-pyrrolidino, —OC(═O)-piperidino, —OC(═O)-morpholino, —OC(═O)-piperizino, (N—C 1-4 alkyl)-piperizino,

—NHC(═O)OR Z1 , —NR Z1 C(═O)OR Z1 ,

—NO 2 , and —CN;

wherein each —R Z1 is independently saturated aliphatic C 1-4 alkyl, aliphatic C 3-6 alkynyl, saturated C 3-6 cycloalkyl, C 5-6 heteroaryl, -Ph, or —CH 2 -Ph,

wherein each —R Z1A is independently saturated aliphatic C 1-4 alkyl;

and additionally wherein two adjacent substituents may together form —O—CH 2 —O— or —O—CH 2 CH 2 —O—.

5. A compound according to claim 2 , wherein -A 1 is independently imidazol-2-yl, and is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Z1 , —CF 3 ,

—OH, —OR Z1 , —OCF 3 ,

—SR Z1 ,

—NH 2 , —NHR Z1 , —NR Z1 2 , pyrrolidino, piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Z1 ,

—C(═O)R Z1 ,

—OC(═O)R Z1 ,

—C(═O)NH 2 , —C(═O)NHR Z1 , —C(═O)NR Z1 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Z1 , —NR Z1 C(═O)R Z1 ,

—OC(═O)NH 2 , —OC(═O)NHR Z1 , —OC(═O)NR Z1 2 , —OC(═O)-pyrrolidino, —OC(═O)-piperidino, —OC(═O)-morpholino, —OC(═O)-piperizino, (N—C 1-4 alkyl)-piperizino,

—NHC(═O)OR Z1 , —NR Z1 C(═O)OR Z1 ,

—NO 2 , and —CN;

wherein each —R Z1 is independently saturated aliphatic C 1-4 alkyl, aliphatic C 3-6 alkynyl, saturated C 3-6 cycloalkyl, C 5-6 heteroaryl, -Ph, or —CH 2 -Ph,

wherein each —R Z1A is independently saturated aliphatic C 1-4 alkyl;

and additionally wherein two adjacent substituents may together form —O—CH 2 —O— or —O—CH 2 CH 2 —O—.

6. A compound according to claim 2 , which is a compound selected from the following compounds:

Code No.

Structure

WW-001

WW-002

WW-003

WW-004

WW-005

WW-006

WW-007

WW-008

WW-009

WW-010

WW-011

WW-012

WW-013

WW-014

WW-015

WW-016

WW-017

WW-018

WW-019

WW-020

WW-021

WW-022

WW-023

WW-024

WW-025

WW-026

WW-027

WW-028

WW-029

WW-030

WW-031

WW-032

WW-033

WW-034

WW-035

WW-036

WW-037

WW-038

WW-039

WW-040

WW-041

WW-042

WW-043

WW-044

WW-045

WW-046

WW-047

WW-048

WW-049

WW-050

WW-051

WW-052

WW-053

WW-054

WW-055

WW-056

WW-057

WW-058

WW-059

WW-060

WW-061

WW-062

WW-063

WW-064

WW-065

WW-066

or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 , wherein -A is independently -A 3 ; and -A 3 is independently:

—C(═NH)NH 2 , —C(═NH)NHR Z3 , or —C(═NH)NR Z3 2 , —C(═NH)-pyrrolidino, —C(═NH)-piperidino, —C(═NH)-morpholino, —C(═NH)-piperizino, or —C(═NH)—N—C 1-4 alkyl)-piperizino,

wherein:

—R Z3 is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, C 5-6 heteroaryl, —CH 2 —C 5-6 heteroaryl, -Ph, or —CH 2 -Ph,

wherein each of said C 1-4 alkyl, C 3-6 cycloalkyl, C 5-6 heteroaryl, and -Ph is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Z3A , —CF 3 ,

—OH, —OR Z3A , —OCF 3 ,

—SR Z3A ,

—NH 2 , —NHR Z3A , —NR Z3A 2 , pyrrolidino, piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Z3A ,

—C(═O)R Z3A ,

—OC(═O)R Z3A ,

—C(═O)NH 2 , —C(═O)NHR Z3A , —C(═O)NR Z3A 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Z3A , —NR Z3A C(═O)R Z3A ,

—OC(═O)NH 2 , —OC(═O)NHR Z3A , —OC(═O)NR Z3A 2 , —OC(═O)-pyrrolidino, —OC(═O)-piperidino, —OC(═O)-morpholino, —OC(═O)-piperizino, (N—C 1-4 alkyl)-piperizino,

—NHC(═O)OR Z3A , —NR Z3A C(═O)OR Z3A ,

—NHC(═O)NH 2 , —NHC(═O)NHR Z3A , —NHC(═O)NR Z3A 2 , —NHC(═O)-pyrrolidino, —NHC(═O)-piperidino, —NHC(═O)-morpholino, —NHC(═O)-piperizino, —NHC(═O)—(N—C 1-4 alkyl)-piperizino,

—NO 2 , and —CN,

wherein each —R Z3A is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R Z3B , —CF 3 , —OH, —OR Z3B , and —OCF 3 ,

wherein each —R Z3B is independently saturated aliphatic C 1-4 alkyl.

8. A compound according to claim 7 , which is the following compound:

Code No.

Structure

SS-001

or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 , wherein -A is independently -A 6 ; and -A 6 is independently:

-L 6 -R Z6 ,

wherein:

-L 6 - is independently aliphatic C 2-6 alkenyl, and

—R Z6 is independently C 5-6 heteroaryl or -Ph,

wherein each of said C 5-6 heteroaryl and -Ph is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Z6A , —CF 3 ,

—OH, —OR Z6A , —OCF 3 ,

—SR Z6A ,

—NH 2 , —NHR Z6A , —NR Z6A 2 , pyrrolidino, piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Z6A ,

—C(═O)R Z6A ,

—OC(═O)R Z6A ,

—C(═O)NH 2 , —C(═O)NHR Z6A , —C(═O)NR Z6A 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Z6A , —NR Z6A C(═O)R Z6A ,

—OC(═O)NH 2 , —OC(═O)NHR Z6A , —OC(═O)NR Z6A 2 , —OC(═O)-pyrrolidino, —OC(═O)-piperidino, —OC(═O)-morpholino, —OC(═O)-piperizino, (N—C 1-4 alkyl)-piperizino,

—NHC(═O)OR Z6A , —NR Z6A C(═O)OR Z6A ,

—NO 2 , and —CN,

wherein each —R Z6A is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or —CH 2 -Ph,

wherein each C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R Z6B , —CF 3 , —OH, —OR Z6B , and —OCF 3 ,

wherein each —R Z6B is independently saturated aliphatic C 1-4 alkyl.

10. A compound according to claim 9 which is a compound selected from the following compounds:

Code No.

Structure

MM-001

MM-002

MM-003

MM-004

or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1 , wherein —B is independently —B 1 .

12. A compound according to claim 11 , wherein —B 1 is independently -Me.

13. A compound according to claim 1 , wherein —B is independently —B 2 .

14. A compound according to claim 13 , wherein —B 2 is independently —CH 2 —C≡CH.

15. A compound according to claim 1 , wherein —B is independently —B 3 ; and —B 3 is independently:

-L Y3 —SH, -L Y3 —S—R Y3 , -L Y3 -S(═O)—R Y3 , or L Y3 -S(═O) 2 —R Y3 ,

wherein:

-L Y3 - is independently saturated aliphatic C 1-4 alkylene, and

—R Y3 is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, C 5-6 heteroaryl, —CH 2 —C 5-6 heteroaryl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl, C 5-6 heteroaryl, and -Ph is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Y3A , —CF 3 ,

—OH, —OR Y3A , —OCF 3 ,

—SR Y3A ,

—NH 2 , —NHR Y3A , —NR Y3A 2 , pyrrolidino, piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Y3A ,

—C(═O)R Y3A ,

—OC(═O)R Y3A ,

—C(═O)NH 2 , —C(═O)NHR Y3A , —C(═O)NR Y3A 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Y3A , —NR Y3A C(═O)R Y3A ,

—OC(═O)NH 2 , —OC(═O)NHR Y3A , —OC(═O)NR Y3A 2 , —OC(═O)-pyrrolidino, —OC(═O)-piperidino, —OC(═O)-morpholino, —OC(═O)-piperizino, (N—C 1-4 alkyl)-piperizino,

—NHC(═O)OR Y3A , —NR Y3A C(═O)OR Y3A ,

—NHC(═O)NH 2 , —NHC(═O)NHR Y3A , —NHC(═O)NR Y3A 2 , —NHC(═O)-pyrrolidino, —NHC(═O)-piperidino, —NHC(═O)-morpholino, —NHC(═O)-piperizino, —NHC(═O)—(N—C 1-4 alkyl)-piperizino,

—NO 2 , and —CN,

wherein each —R Y3A is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R Y3B , —CF 3 , —OH, —OR Y3B , and —OCF 3 ,

wherein each —R Y3B is independently saturated aliphatic C 1-4 alkyl.

16. A compound according to claim 15 , wherein —B 3 is independently —CH 2 —S-Me, —CH 2 —S(═O)-Me, or —CH 2 —S(═O) 2 -Me.

17. A compound according to claim 1 , wherein —B is independently —B 4 ; and —B 4 is independently:

-L Y4 -OH or -L Y4 -O—R Y4 ,

wherein:

-L Y4 - is independently saturated aliphatic C 1-4 alkylene, and

—R Y4 is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, C 5-6 heteroaryl, —CH 2 —C 5-6 heteroaryl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl, C 5-6 heteroaryl, and -Ph is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Y4A , —CF 3 ,

—OH, —OR Y4A , —OCF 3 ,

—SR Y4A ,

—NH 2 , —NHR Y4A , —NR Y4A 2 , pyrrolidino, piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Y4A ,

—C(═O)R Y4A ,

—OC(═O)R Y4A ,

—C(═O)NH 2 , —C(═O)NHR Y4A , —C(═O)NR Y4A 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Y4A , —NR Y4A C(═O)R Y4A ,

—OC(═O)NH 2 , —OC(═O)NHR Y4A , —OC(═O)NR Y4A 2 , —OC(═O)-pyrrolidino, —OC(═O)-piperidino, —OC(═O)-morpholino, —OC(═O)-piperizino, (N—C 1-4 alkyl)-piperizino,

—NHC(═O)OR Y4A , —NR Y4A C(═O)OR Y4A ,

—NHC(═O)NH 2 , —NHC(═O)NHR Y4A , —NHC(═O)NR Y4A 2 , —NHC(═O)-pyrrolidino, —NHC(═O)-piperidino, —NHC(═O)-morpholino, —NHC(═O)-piperizino, —NHC(═O)—(N—C 1-4 alkyl)-piperizino,

—NO 2 , and —CN,

wherein each —R Y4A is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R Y4B , —CF 3 , —OH, —OR Y4B , and —OCF 3 ,

wherein each —R Y4B is independently saturated aliphatic C 1-4 alkyl.

18. A compound according to claim 17 , wherein —B 4 is independently —CH 2 —O-Me.

19. A compound according to claim 1 , wherein —B is independently —B 5 ; and —B 5 is independently:

-L Y5 -Ar Y5 ,

wherein:

-L Y5 - is independently saturated aliphatic C 1-4 alkylene, and

-Ar Y5 is independently C 5-6 heteroaryl or -Ph,

wherein each of said C 5-6 heteroaryl and -Ph is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Y5A , —CF 3 ,

—OH, —OR Y5A , —OCF 3 ,

—SR Y5A ,

—NH 2 , —NHR Y5A , —NR Y5A 2 , pyrrolidino, piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Y5A ,

—C(═O)R Y5A ,

—OC(═O)R Y5A ,

—C(═O)NH 2 , —C(═O)NHR Y5A , —C(═O)NR Y5A 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Y5A , —NR Y5A C(═O)R Y5A ,

—OC(═O)NH 2 , —OC(═O)NHR Y5A , —OC(═O)NR Y5A 2 , —OC(═O)-pyrrolidino, —OC(═O)-piperidino, —OC(═O)-morpholino, —OC(═O)-piperizino, (N—C 1-4 alkyl)-piperizino,

—NHC(═O)OR Y5A , —NR Y5A C(═O)OR Y5A ,

—NHC(═O)NH 2 , —NHC(═O)NHR Y5A , —NHC(═O)NR Y5A 2 , —NHC(═O)-pyrrolidino, —NHC(═O)-piperidino, —NHC(═O)-morpholino, —NHC(═O)-piperizino, —NHC(═O)—(N—C 1-4 alkyl)-piperizino,

—NO 2 , and —CN,

wherein each —R Y5A is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R Y5B , —CF 3 , —OH, —OR Y5B , and —OCF 3 ,

wherein each —R Y5B is independently saturated aliphatic C 1-4 alkyl.

20. A compound according to claim 19 , wherein —B 5 is —CH 2 -Ph.

21. A compound according to claim 1 , wherein —B is independently —B 6 ; and —B 6 is independently:

-L Y6 -C(═O)R Y6 , -L Y6 -C(═O)OH, -L Y6 -C(═O)OR Y6 , or -L Y6 -O—C(═O)R Y6 ,

wherein:

-L Y6 - is independently saturated aliphatic C 1-4 alkylene, and

—R Y6 is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, C 5-6 heteroaryl, —CH 2 —C 5-6 heteroaryl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl, C 5-6 heteroaryl, and -Ph is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Y6A , —CF 3 ,

—OH, —OR Y6A , —OCF 3 ,

—SR Y6A ,

—NH 2 , —NHR Y6A , —NR Y6A 2 , pyrrolidino, piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Y6A ,

—C(═O)R Y6A ,

—OC(═O)R Y6A ,

—C(═O)NH 2 , —C(═O)NHR Y6A , —C(═O)NR Y6A 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Y6A , —NR Y6A C(═O)R Y6A ,

—OC(═O)NH 2 , —OC(═O)NHR Y6A , —OC(═O)NR Y6A 2 , —OC(═O)-pyrrolidino, —OC(═O)-piperidino, —OC(═O)-morpholino, —OC(═O)-piperizino, (N—C 1-4 alkyl)-piperizino,

—NHC(═O)OR Y6A , —NR Y6A C(═O)OR Y6A ,

—NHC(═O)NH 2 , —NHC(═O)NHR Y6A , —NHC(═O)NR Y6A 2 , —NHC(═O)-pyrrolidino, —NHC(═O)-piperidino, —NHC(═O)-morpholino, —NHC(═O)-piperizino, —NHC(═O)—(N—C 1-4 alkyl)-piperizino,

—NO 2 , and —CN,

wherein each —R Y6A is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R Y6B , —CF 3 , —OH, —OR Y6B , and —OCF 3 ,

wherein each —R Y6B is independently saturated aliphatic C 1-4 alkyl.

22. A compound according to claim 21 , wherein —B 6 is independently —CH 2 —C(═O)—O-Et.

23. A compound according to claim 1 , wherein —B is independently —B 7 ; and —B 7 is independently:

-L Y7 -C(═O)NH 2 , -L Y7 -C(═O)NHR Y7 , -L Y7 -C(═O)NR Y7 2 , -L Y7 -C(═O)-pyrrolidino, -L Y7 -C(═O)-piperidino, -L Y7 -C(═O)-morpholino, -L Y7 -C(═O)-piperizino, or -L Y7 -C(═O)—(N—C 1-4 alkyl)-piperizino,

wherein:

-L Y7 - is independently saturated aliphatic C 1-4 alkylene, and

—R Y7 is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, C 5-6 heteroaryl, —CH 2 —C 5-6 heteroaryl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl, C 5-6 heteroaryl, and -Ph is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Y7A , —CF 3 ,

—OH, —OR Y7A , —OCF 3 ,

—SR Y7A ,

—NH 2 , —NHR Y7A , —NR Y7A 2 , pyrrolidino, piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Y7A ,

—C(═O)R Y7A ,

—OC(═O)R Y7A ,

—C(═O)NH 2 , —C(═O)NHR Y7A , —C(═O)NR Y7A 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Y7A , —NR Y7A C(═O)R Y7A ,

—OC(═O)NH 2 , —OC(═O)NHR Y7A , —OC(═O)NR Y7A 2 , —OC(═O)-pyrrolidino, —OC(═O)-piperidino, —OC(═O)-morpholino, —OC(═O)-piperizino, (N—C 1-4 alkyl)-piperizino,

—NHC(═O)OR Y7A , —NR Y7A C(═O)OR Y7A ,

—NHC(═O)NH 2 , —NHC(═O)NHR Y7A , —NHC(═O)NR Y7A 2 , —NHC(═O)-pyrrolidino, —NHC(═O)-piperidino, —NHC(═O)-morpholino, —NHC(═O)-piperizino, —NHC(═O)—(N—C 1-4 alkyl)-piperizino,

—NO 2 , and —CN,

wherein each —R Y7A is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R Y7B , —CF 3 , —OH, —OR Y7B , and —OCF 3 ,

wherein each —R Y7B is independently saturated aliphatic C 1-4 alkyl.

24. A compound according to claim 23 , wherein —B 7 is independently: —CH 2 —C(═O)NH 2 , —CH 2 —C(═O)NHMe, —CH 2 —C(═O)NMe 2 , —CH 2 CH 2 —C(═O)NH 2 , —CH 2 CH 2 —C(═O)NHMe, —CH 2 CH 2 —C(═O)NMe 2 , —CH 2 —C(═O)-piperidino, or —CH 2 CH 2 —C(═O)-piperidino.

25. A compound according to claim 1 , wherein —B is independently —B 8 ; and —B 8 is independently:

—R Y8 or -L Y8 -R Y8 ,

wherein:

-L Y8 - is independently saturated aliphatic C 1-4 alkylene, and

—R Y8 is independently saturated C 3-6 cycloalkyl or saturated C 3-6 heterocyclyl,

wherein each of said C 3-6 cycloalkyl and C 3-6 heterocyclyl is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Y8A , —CF 3 ,

—OH, —OR Y8A , —OCF 3 ,

—NH 2 , —NHR Y8A , —NR Y8A 2 , pyrrolidino piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Y8A ,

—C(═O)R Y8A ,

—OC(═O)R Y8A ,

—C(═O)NH 2 , —C(═O)NHR Y8A , —C(═O)NR Y8A 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Y8A , —NR Y8A C(═O)R Y8A , and

—CN;

wherein each —R Y8A is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R Y8B , —CF 3 , —OH, —OR Y8B , and —OCF 3 ,

wherein each —R Y8B is independently saturated aliphatic C 1-4 alkyl.

26. A compound according to claim 1 , wherein —B is independently —B 9 .

27. A compound according to claim 26 , wherein —B 9 is independently selected from: —CH 2 F, —CH 2 CH 2 F, —CHF 2 , —CH 2 CHF 2 , —CF 3 , and —CH 2 CF 3 .

28. A compound according to claim 1 , wherein —B is independently —B 10 .

29. A compound according to claim 28 , wherein —B 10 is independently —CH 2 —NO 2 .

30. A compound according to claim 1 , wherein —B is independently —B 11 .

31. A compound according to claim 30 , wherein —B 11 is independently —CH 2 —CN.

32. A compound according to claim 1 , wherein —B is independently —B 12 ; wherein —B 12 is independently:

-L 12 -P(═O)(OH) 2 , L Y12 -P(OH)(OR Y12 ), or -P(═O)(OR Y12 ) 2 ,

wherein:

-L Y12 - is independently saturated aliphatic C 1-4 alkylene, and

each —R Y12 is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, C 5-6 heteroaryl, —CH 2 —C 5-6 heteroaryl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl, C 5-6 heteroaryl, and -Ph is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Y12A , —CF 3 ,

—OH, —OR Y12A , —OCF 3 ,

—NH 2 , —NHR Y12A , —NR Y12A 2 , pyrrolidino piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Y12A ,

—C(═O)R Y12A ,

—OC(═O)R Y12A ,

—C(═O)NH 2 , —C(═O)NHR Y12A , —C(═O)NR Y12A 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Y12A , —NR Y12A C(═O)R Y12A , and

—CN;

wherein each —R Y12A is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R Y12B , —CF 3 , —OH, —OR Y12B , and —OCF 3 ,

wherein each —R Y12B is independently saturated aliphatic C 1-4 alkyl.

33. A compound according to claim 32 , wherein —B 12 is —CH 2 -P(═O)(OEt) 2 .

34. A compound according to claim 1 , wherein —B is independently —B 13 ; wherein —B 13 is independently:

-L Y13 -NH—C(═O)OH, -L Y13 -NH—C(═O)—R Y13 , -L Y13 -NR Y13 —C(═O)OH, or -L Y13 -NR Y13 —C(═O)—R Y13 ,

wherein:

-L Y13 - is independently saturated aliphatic C 1-4 alkylene, and

each —R Y13 is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, C 5-6 heteroaryl, —CH 2 —C 5-6 heteroaryl, fluorenyl, —CH 2 —Fluorenyl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl, C 5-6 heteroaryl, fluorenyl and -Ph is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Y13A , —CF 3 ,

—OH, —OR Y13A , —OCF 3 ,

—NH 2 , —NHR Y13A , —NR Y13A 2 , pyrrolidino piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Y13A ,

—C(═O)R Y13A ,

—OC(═O)R Y13A ,

—C(═O)NH 2 , —C(═O)NHR Y13A , —C(═O)NR Y13A 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Y13A , —NR Y13A C(═O)R Y13A , and

—CN;

wherein each —R Y13A is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R Y13B , —CF 3 , —OH, —OR Y13B , and —OCF 3 ,

wherein each —R Y13B is independently saturated aliphatic C 1-4 alkyl.

35. A compound according to claim 1 , wherein —B is independently —B 14 ; wherein —B 14 is independently:

-L Y14 —CH(═N—O—H), -L Y14 -CH(═N—O—R Y14 ), -L Y14 -CR Y14 (═N—O——H), or -L Y14 -CR Y14 (═N—O—R Y14 ),

wherein:

-L Y14 - is independently saturated aliphatic C 1-4 alkylene, and

each —R Y14 is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, C 5-6 heteroaryl, —CH 2 —C 5-6 heteroaryl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl, C 5-6 heteroaryl, and -Ph is optionally substituted with one or more groups selected from:

—F, —Cl, —Br, —I,

—R Y14A , —CF 3 ,

—OH, —OR Y14A , —OCF 3 ,

—NH 2 , —NHR Y14A , 13 NR Y14A 2 , pyrrolidino, piperidino, morpholino, piperizino, (N—C 1-4 alkyl)-piperizino,

—C(═O)OH, —C(═O)OR Y14A ,

—C(═O)R Y14A ,

—OC(═O)R Y14A ,

—C(═O)NH 2 , —C(═O)NHR Y14A , —C(═O)NR Y14A 2 , —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—(N—C 1-4 alkyl)-piperizino,

—NHC(═O)R Y14A , NR Y14A C(═O)R Y14A , and

—CN;

wherein each —R Y14A is independently saturated aliphatic C 1-4 alkyl, saturated C 3-6 cycloalkyl, -Ph, or —CH 2 -Ph,

wherein each of said C 3-6 cycloalkyl and -Ph is optionally substituted with one or more substituents selected from —F, —Cl, —Br, —I, —R Y14B, _CF 3 , —OH, — oRy14B , and —OCF 3 ,

wherein each —R Y14B is independently saturated aliphatic C 1-4 alkyl.

36. A compound according to claim 35 , wherein —B 14 is independently —CH 2 —C(Et)(═N—O-Me).

37. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

38. A method of preparing a pharmaceutical composition comprising the step of admixing a compound according to claim 1 , and a pharmaceutically acceptable carrier or diluent.

39. A method of treatment of glioma comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to claim 1 .

Assignments (2)

MERGER Recorded Aug 8, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 061102/0145 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 10, 2019

From: PHARMINOX LIMITED

To: MERCK SHARP & DOHME CORP.

Reel/Frame 047953/0346 →