Pteridine dione monocarboxylate transporter inhibitors

Patent metadata

Field	Value
Publication number	US-10328078-B2
Application number	US-201615545152-A
Country	US
Kind code	B2
Filing date	Jan 22, 2016
Priority date	Jan 22, 2015
Publication date	Jun 25, 2019
Grant date	Jun 25, 2019

Abstract

The invention provides compounds effective as inhibitors of monocarboxylate transporters such as MCT1 and MCT4, which can be used for treatment of medical conditions wherein treatment of the condition with a compound having an inhibitor effect on MCT1, MCT4, or both is medically indicated. Compounds of the invention can have antitumor, antidiabetes, anti-inflammatory, or immunosuppressive pharmacological effects, and can be effective for treatment of cancer and of type II diabetes.

First claim

What is claimed is:

1. A MCT-inhibitory compound of formula A or of formula B

wherein
R 1 and R 2 are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )branched alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )fluoroalkyl, a (C 6 -C 10 )aryl ring system, a 5- to 9-membered heteroaryl ring system, a (C 1 -C 6 )alkyl-(C 6 -C 10 )aryl ring system, and a (C 1 -C 6 )alkyl-(5- to 9-membered)heteroaryl ring system;
provided that when R 2 comprises an aryl or heteroaryl ring system, the ring system bears 0-2 independently selected substituents from the group consisting of fluoro, chloro, trifluoromethyl, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )fluoroalkoxy;
E is CH 2 , CH(C 1 -C 6 )alkyl, or CH(C 3 -C 7 )cycloalkyl;
J is O, S, S(O), S(O) 2 , NH, N(C 1 -C 6 )alkyl, or NC(═O)(C 1 -C 6 )alkyl;
R 3 is a monocyclic or bicyclic (C 6 -C 10 )aryl or a monocyclic or bicyclic (5- to 10-membered) heteroaryl group wherein the aryl or heteroaryl can be substituted or unsubstituted;
R 4 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )branched alkyl, (C 1 -C 6 )fluoroalkyl, (C 3 -C 7 )cycloalkyl, a (4- to 7-membered)heteroaryl, or a monocyclic or bicyclic (C 6 -C 10 )aryl or a monocyclic or bicyclic (5- to 10-membered) heteroaryl group wherein the aryl or heteroaryl can be substituted or unsubstituted;
Z is a bond, or is —O—, —CH 2 —, —CH(Me)-, —S—, —NH—, or —N(C 1 -C 6 )alkyl;
n=1, 2, 3, or 4;
the cyclic group indicated as “ring” is an aryl or heteroaryl group of any one of the following formulas:

wherein wavy lines indicate points of bonding, and wherein each M is an independently selected CH or N, provided that M group is a nitrogen atom in one or two instances;
G is S, O, NH, NMe, or NCF 3 ;
T is independently at each occurrence CH or N;
wherein R 5 is optionally present, R 5 being one to four instances of independently selected F, Cl, Br, CF 3 , (C 1 -C 6 )alkyl, OCF 3 , O(C 1 -C 6 )alkyl, or CO—(C 1 -C 6 )alkyl;

or,
the cyclic group indicated as “ring” is a (C 3 -C 7 )cycloalkyl or a saturated (3- to 7-membered)heterocyclyl comprising 1-2 heteroatoms selected from the group consisting of O, NH, N(C1-C6)alkyl, and N(C1-C6)fluoroalkyl; wherein the points of bonding may be cis or trans;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein a monocyclic R 3 is any one of

wherein X is H, (C 1 -C 6 )alkyl, or CF 3 ; and
wherein Y is optionally present and, when present, Y is 1-3 instances of a substituent selected from the group consisting of F, Cl, Br, CF 3 , CH 3 , Et, NH 2 , NH—(CH 2 ) j —CH 2 -Q, and

wherein j=2-6, and wherein Q is one of the following groups

wherein a wavy line indicates a point of bonding.

3. The compound of claim 1 , wherein a bicyclic R 3 is any one of

wherein X is H, (C 1 -C 6 )alkyl, or CF 3 ; and
wherein Y is optionally present and, when present, Y is 1-3 instances of a substituent selected from the group consisting of F, Cl, Br, CF 3 , CH 3 , Et, NH 2 , NH—(CH 2 ) j —CH 2 -Q, and

wherein j=2-6, and wherein Q is one of the following groups

wherein a wavy line indicates a point of bonding, and wherein Y can be disposed on any ring of a multi-ring system.

4. The compound of claim 1 , wherein R 1 =Me, R 2 =i-Bu, R 4 =H, Z=CH 2 , and other groups are as specified in claim 1 .

5. The compound of claim 1 of formula A wherein n=3.

6. The compound of claim 1 , wherein the compound is any one of the following, including all stereoisomeric forms, all isotopic forms, all crystalline and amorphous forms, and all pharmaceutically acceptable salt forms thereof:

7. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

Assignees

• Scripps Research Inst

Inventors

• Bannister Thomas D
• Wang Hui
• Wang Chao
• Cleveland John L

Classifications

• A61K31/525

  Isoalloxazines, e.g. riboflavins, vitamin B2 · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D475/00

  Heterocyclic compounds containing pteridine ring systems · CPC title

• A61K31/155

  Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title