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

Patent metadata

Field	Value
Publication number	US-11325890-B2
Application number	US-202017136276-A
Country	US
Kind code	B2
Filing date	Dec 29, 2020
Priority date	Apr 22, 2011
Publication date	May 10, 2022
Grant date	May 10, 2022

Abstract

Provided herein are Diaminopyrimidine Compounds having the following structures:wherein R1, R2, R3, and R4 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 (IIa):

the method comprising oxidizing a compound of formula (IIb)

in a solvent by treatment with an oxidant selected from mCPBA, oxone, hydrogen peroxide, or 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine,
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 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 , wherein the solvent is acetone, DCM, NMP, DMF, or chloroform and the oxidizing is performed at about 0° C.

3. The method of claim 1 , wherein the method further comprises contacting a compound of formula (IIc)

with NH 4 Cl in the presence of a coupling agent and a base, in a solvent, to yield the compound of formula (IIb).

4. The method of claim 3 , wherein the solvent is NMP, DMF, DMSO, dioxane, THF, DCM, or chloroform, the coupling agent is HATU, CDI, HBTU, EDC/HOBt, or ethyl chloroformate, and the base is DIEA, TEA, or potassium carbonate.

5. The method of claim 3 , wherein the method further comprises contacting a compound of formula (IId)

with an aqueous base, in a cosolvent, to yield the compound of formula (IIc).

6. The method of claim 5 , wherein the aqueous base is aqueous sodium hydroxide, potassium hydroxide, or lithium hydroxide and the cosolvent is ethanol, methanol, isopropanol, THF, or dioxane.

7. The method of claim 5 , wherein the method further comprises contacting a compound of formula (IIe)

with R 1 NH 2 in an organic solvent, in the presence of an organic base, to yield the compound of formula (IId).

8. The method of claim 7 , wherein the organic solvent is dioxane, THF, NMP, DMF, DMSO, ethanol, methanol, or isopropanol, the base is DIEA, TEA, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium phosphate, and the contacting is performed at from about 80° C. to about 100° C.

9. The method of claim 7 , wherein the method further comprises contacting a compound of formula (IIf)

with NaSR x in an organic solvent in the presence of a catalyst to yield the compound of formula (IIe).

10. The method of claim 9 , wherein the solvent is THF, DCM, or dioxane, the catalyst is triethylbenzylammonium chloride, tetrabutylammonium chloride, or tetrabutylammonium bromide, and the contacting is performed at about −10° C.

11. The method of claim 1 , wherein the method further comprises contacting a compound of formula (IIg)

with peroxide, in the presence of a base, in a solvent, to yield the compound of formula (IIb).

12. The method of claim 11 , wherein the solvent is DMSO, NMP, DMF, ethanol, or methanol, and the base is sodium hydroxide or potassium hydroxide.

13. The method of claim 11 , wherein the method further comprises contacting a compound of formula (IIh)

with zinc and dicyanozinc, in the presence of a catalyst, in a solvent, to yield the compound of formula (IIg).

14. The method of claim 13 , wherein the catalyst is Pd(0), the solvent is DMF, DMSO, NMP, or DMA, and the contacting is performed at a temperature between about 80° C. and about 100° C.

15. The method of claim 13 , wherein the method further comprises contacting a compound of formula (IIi)

with R 1 NH 2 , in the presence of a base, in an organic solvent, to yield the compound of formula (IIh).

16. The method of claim 15 , wherein the organic solvent is n-butanol, NMP, DMF, DMSO, dioxane, or ethanol, the base is DIEA, TEA, N-methylmorpholine, 1,8-diazabicyclo-[5.4.0]undec-7-ene, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, or potassium phosphate, and the contacting is performed at a temperature between about 80° C. and about 100° C.

17. A compound of formula (IIb):

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 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, alk

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

• A61K31/505

  Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title