IP Library Granted Patent US 7,863,270
Granted Patent B2
US 7,863,270 · App. 11/433,603 · Granted Jan 4, 2011

IL-12 modulatory compounds

View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 7,863,270
App. No.
11/433,603
Granted
Jan 4, 2011
Kind
B2
Abstract

The invention relates to cyclic hydrazone compounds and compositions including the cyclic hydrazone compounds according to formula (I): The compounds (and compositions) are useful, inter alia, in modulating IL-12 production and processes mediated by IL-12.

Claims (58)

1. A compound represented by formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

ring A is a ring system selected from the group consisting of:

wherein:

represents the point of attachment; and each ring system is optionally substituted with one or more substituents;

R 1 , for each occurrence, is independently, H or a lower alkyl;

R c , for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, —OR k , —SR k , —NR h R j , hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or mercaptoalkoxy;

R g , for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, —OR k , —SR k , —NR h R j , hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, mercaptoalkoxy, —C(O)R c , —OC(O)R c , —SC(O)R c , —NRkC(O)R c , —C(S)R c , —OC(S)R c , —SC(S)R c , —NRkC(S)R c , —C(NR)R c , —OC(NR)R c , —SC(NR)R c , —NRkC(NR)R c , —S(O) 2 R c , —S(O)R c , —NR k S(O) 2 R c , —OS(O) 2 R c , —OP(O)R c R c , —P(O)R c R c , halo, cyano, nitro, nitroso, or azide;

R h and R j , for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R h and R j taken together with the nitrogen to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;

R k , for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, or an optionally substituted heteroaryl;

ring E is optionally substituted with one to four substituents selected from a lower alkyl, a halo, an amino, a lower alkyl amino, a lower dialkyl amino, a cyano, a nitro, a lower haloalkyl, a hydroxyl, and a lower hydroxyalkyl;

V is CR g , Q and U are N;

X 1 is O;

X 2 is O;

Y 1 is O;

R 7 and R 8 , for each occurrence, are independently, H or a lower alkyl; and R 9 is H, an alkyl, an aralkyl, or an alkylcarbonyl;

q is 0, 1, 2, or 3.

2. The compound of claim 1 , wherein ring A is optionally substituted with from one to three substituents selected from the group consisting of a lower alkyl, a lower alkoxy, ═O, nitro, cyano, hydroxy, amino, lower alkyl amino, lower dialkyl amino, mercapto, lower alkyl sulfanyl, halo, or haloalkyl.

3. A compound selected from the group consisting of:

5-Methyl-3-{[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazono}-1,3-dihydro-indol-2-one;

N-(6-Methyl-chroman-4-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(6-Methyl-indan-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(Indan-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(Benzofuran-3-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(3-Methyl-indan-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(4-Methyl-indan-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(5-Methoxy-indan-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(6-Methoxy-indan-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(Indan-2-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(3,4-Dihydro-2H-naphthalen-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(Chroman-4-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(6-Methoxy-3,4-dihydro-2H-naphthalen-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(7-Methoxy-3,4-dihydro-2H-naphthalen-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(7-Nitro-3,4-dihydro-2H-naphthalen-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(6-Hydroxy-3,4-dihydro-2H-naphthalen-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(5,7-Dimethyl-3,4-dihydro-2H-naphthalen-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(6,7-Dimethoxy-3,4-dihydro-2H-naphthalen-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(4-Methyl-3,4-dihydro-2H-naphthalen-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

1-Methyl-3-{[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazono}-1,3-dihydro-indol-2-one;

N-(4-Hydroxy-indan-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(5-Hydroxy-indan-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

3-{[6-Morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazono}-2,3-dihydro-benzofuran-6-ol;

N-(5-Hydroxy-3,4-dihydro-naphthalen-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(6-Fluoro-chroman-4-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(5-Fluoro-indan-1-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(6,7-Dihydro-5H-benzo[1,2,5]oxadiazol-4-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-[6-Morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-N′-(octahydro-naphthalen-1-ylidene)-hydrazine;

N-(4-tert-Butyl-cyclohexylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(2-Methyl-cyclohexylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-Cyclopentylidene-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-Bicyclo[2.2.1]hept-2-ylidene-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(6-Chloro-thiochroman-4-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(6-Chloro-1,1-dioxo-1λ 6 -thiochroman-4-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(6-Methyl-chromen-4-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

N-(6-Chloro-chromen-4-ylidene)-N′-[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine; and

N-(6,7-Dihydro-5H-benzofuran-4-ylidene)-N′-[6-morpholin-4-yl-2-(morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazine;

or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a compound of claim 1 or 3 and a pharmaceutically acceptable carrier.

Assignments (5)
SECURITY INTEREST Recorded Feb 18, 2026
From: ORPHAI THERAPEUTICS INC.
To: ACADIA WOODS PARTNERS, LLC, AS AGENT
Reel/Frame 074910/0274 →
SECURITY INTEREST Recorded Jul 17, 2025
From: MADRIGAL PHARMACEUTICALS, INC.
To: LSI FINANCING LLC, AS ADMINISTRATIVE AGENT
Reel/Frame 072038/0693 →
SECURITY INTEREST Recorded Jun 23, 2025
From: ORPHAI THERAPEUTICS INC.
To: ACADIA WOODS PARTNERS, LLC
Reel/Frame 071697/0788 →
CHANGE OF NAME Recorded May 3, 2021
From: SYNTA PHARMACEUTICALS CORP.
To: MADRIGAL PHARMACEUTICALS, INC.
Reel/Frame 056121/0785 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 18, 2006
From: DEMKO, ZACHARY; SUN, LIJUN; NG, HOWARD P.
To: SYNTA PHARMACEUTICALS CORP.
Reel/Frame 018134/0927 →