Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith

Patent metadata

Field	Value
Publication number	US-10919865-B2
Application number	US-201916291193-A
Country	US
Kind code	B2
Filing date	Mar 4, 2019
Priority date	Apr 22, 2011
Publication date	Feb 16, 2021
Grant date	Feb 16, 2021

Abstract

Provided herein are Diaminopyrimidine Compounds having the following structures:

wherein R 1 , R 2 , R 3 , and R 4 are as defined herein, compositions comprising an effective amount of a Diaminopyrimidine Compound, and methods for treating or preventing liver fibrotic disorders or a condition treatable or preventable by inhibition of a JNK pathway.

First claim

What is claimed is:

1. A method for preparing a compound of formula (I):

the method comprising contacting a compound of formula (Ia)

with R 1 NH 2 in a solvent, in the presence of an organic base, wherein:
R 1 is substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted saturated or partially saturated cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkyl-(saturated or partially saturated cycloalkyl), or substituted or unsubstituted alkylheterocyclyl, provided that R 1 is not 2 aminocyclohexyl;
R 2 is substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted saturated C 5-10 cycloalkyl, substituted or unsubstituted alkyl-(saturated or partially saturated cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl;
R x is a C 1-2 alkyl; and
m is 1 or 2,
wherein when a C 1-8 alky group is substituted, the C 1-8 alkyl group is substituted with halogen, alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonato, phosphine, thiocarbonyl, sulfonyl, sulfone, sulfonamide, ketone, aldehyde, ester, urea, urethane, oxime, hydroxyl amine, alkoxyamine, aralkoxyamine, N-oxide, hydrazine, hydrazide, hydrazone, azide, isocyanate, isothiocyanate, cyanate, thiocyanate, B(OH) 2 , or O(alkyl)aminocarbonyl;
wherein when a group, other than a C 1-8 alkyl group, is substituted, the group is substituted with halogen, alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonato, phosphine, thiocarbonyl, sulfonyl, sulfone, sulfonamide, ketone, aldehyde, ester, urea, urethane, oxime, hydroxyl amine, alkoxyamine, aralkoxyamine, N-oxide, hydrazine, hydrazide, hydrazone, azide, isocyanate, isothiocyanate, cyanate, thiocyanate, oxo, B(OH) 2 , O(alkyl)aminocarbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, aralkyloxy, heterocyclyloxy or heterocyclylalkoxy.

2. The method of claim 1 , further comprising preparing a compound of formula (Ia):

the method comprising oxidizing a compound of formula (Ib)

in a solvent by treatment with an oxidant selected from mCPBA, oxone, hydrogen peroxide, or 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine.

3. The method of claim 2 , further comprising preparing a compound of formula (Ib):

the method comprising contacting a compound of formula (Ic)

with NH 4 Cl, in the presence of a coupling agent and a base, in a solvent.

4. The method of claim 3 , further comprising preparing a compound of formula (Ic)

the method comprising contacting a compound of formula (Id)

with an aqueous base, in a cosolvent.

5. The method of claim 4 , further comprising preparing a compound of formula (Id)

the method comprising contacting a compound of formula (Ie)

with R 2 NH 2 in an organic solvent, in the presence of a base.

6. A method for preparing a compound of formula (I):

the method comprising
(1) contacting a compound of formula (If)

with peroxide, in the presence of a base, in a solvent to give a compound of formula (Ib)

(2) oxidizing the compound of formula (Ib) in a solvent by treatment with an oxidant selected from mCPBA, oxone, hydrogen peroxide, or 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine to give a compound of formula (Ia):

(3) contacting the compound of formula (Ia) with R 1 NH 2 in a solvent, in the presence of an organic base,
wherein:
R 1 is substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or substituted or unsubstituted alkylheterocyclyl, provided that R 1 is not 2-aminocyclohexyl;
R 2 is substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted saturated cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl;
R x is a C 1-2 alkyl; and
m is 1 or 2.

7. The method of claim 6 , further comprising preparing a compound of formula (If)

the method comprising contacting a compound of formula (Ig)

with R 2 NH 2 in an organic solvent, in the presence of a base.

8. The method of claim 1 , wherein the compound of Formula (I) is 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide.

9. A method for preparing a compound of formula (I):

the method comprising contacting a compound of formula (IIa)

with R 2 NH 2 in a solvent, in the presence of an organic base,
wherein:
R 1 is substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted saturated or partially saturated cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkyl-(saturated or partially saturated cycloalkyl), or substituted or unsubstituted alkylheterocyclyl, provided that R 1 is not 2 aminocyclohexyl;
R 2 is substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted saturated C 5-10 cycloalkyl, substituted or unsubstituted alkyl-(saturated or partially saturated cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl;
R x is a C1-2 alkyl; and
m is 1 or 2,
wherein when a C 1-8 alky group is substituted, the C 1-8 alkyl group is substituted with halogen, alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonato, phosphine, thiocarbonyl, sulfonyl, sulfone, sulfon

Assignees

• Signal Pharm Llc

Inventors

• Delgado Mercedes
• Elsner Jan
• Erdman Paul
• Hilgraf Robert
• Nagy Mark A
• Norris Stephen
• Paisner David A
• Satoh Yoshitaka
• Sloss Marianne
• Tikhe Jayashree
• Yoon Won Hyung

Classifications

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• C07D239/47

  One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine · CPC title

• C07D239/38

  One sulfur atom · CPC title

• C07D239/48 Primary

  Two nitrogen atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title