IP Library › Granted Patent US 8,268,851
Granted Patent B2
US 8,268,851 · App. 12/645,349 · Granted Sep 18, 2012

Compositions and methods for inhibition of the JAK pathway

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 8,268,851
App. No.
12/645,349
Granted
Sep 18, 2012
Kind
B2
Abstract

The invention encompasses compounds having formula I and the compositions and methods using these compounds in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK3, are therapeutically useful.

Claims (109)

1. A compound of formula I:

wherein:

p is 0, 1, 2, or 3;

q is 0, 1, 2, or 3;

X is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, —C(O)N(R 4 )R 5 , cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl or substituted cycloalkynyl;

Y is a straight or branched chain C 1-6 alkylene group, cycloalkylene or substituted cycloalkylene;

R 1 is hydrogen, alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl;

each R 2 independently is alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, —C(O)N(R 4 )R 5 , nitro or halo;

each R 3 independently is alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro or halo;

each R 4 independently is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl or M + , wherein M + is K + , Na + , Li + or + N(R 9 ) 4 , wherein each R 9 independently is hydrogen or alkyl, and the nitrogen immediately adjacent to R 5 is anionic; or

R 4 and R 5 together with the intervening atom or atoms bound thereto, form a heterocyclyl or substituted heterocyclyl group;

each R 5 independently is hydrogen, alkyl, substituted alkyl, amino, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, carboxyl, carboxyl ester or acyl;

R 6 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or acyl; or

R 6 is a straight or branched chain C 1-6 alkylene group, cycloalkylene or substituted cycloalkylene, linking the nitrogen bearing R 6 and the ring bearing Y

R 7 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or acyl;

R 8 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or acyl; or

R 7 and R 8 together, with nitrogen to which they are bound, form a heterocyclyl or substituted heterocyclyl group;

wherein at least one of R 7 and R 8 is non-hydrogen; and

each of R 6 , R 7 , and R 8 optionally are M + , wherein M + is K + , Na + , Li + or + N(R 9 ) 4 , wherein each R 9 independently is hydrogen or alkyl, and the nitrogen bearing M + is anionic.

2. The compound of claim 1 , wherein R 1 is hydrogen.

3. The compound of claim 2 , wherein X is alkyl, substituted alkyl or halo.

4. The compound of claim 1 , wherein R 4 is hydrogen and R 5 is hydrogen.

5. The compound of claim 1 , wherein Y is methylene.

6. The compound of claim 1 , wherein R 6 is hydrogen, R 7 is C 1-3 alkyl and R 8 is C 1-3 alkyl.

7. The compound of claim 1 , wherein each of R 2 and R 3 , independently, is lower alkyl or lower alkoxy.

8. The compound of claim 1 , according to Formula II:

wherein

p is 0, 1, 2, or 3;

q is 0, 1, 2, or 3;

X is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, —C(O)N(R 4 )R 5 , cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl or substituted cycloalkynyl;

Y is a straight or branched chain C 1-6 alkylene group, cycloalkylene or substituted cycloalkylene;

R 1 is hydrogen, alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl;

each R 2 independently is alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, —C(O)N(R 4 )R 5 , nitro or halo;

each R 3 independently is alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro or halo;

each R 4 independently is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, carboxyl, carboxyl ester, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl or M + , wherein M + is K + , Na + , Li + or + N(R 9 ) 4 , wherein each R 9 independently is hydrogen or alkyl, and the nitrogen immediately adjacent to R 5 is anionic; or

R 4 and R 5 together with the intervening atom or atoms bound thereto, form a heterocyclyl or substituted heterocyclyl group;

each R 5 independently is hydrogen, alkyl, substituted alkyl, amino, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, carboxyl, carboxyl ester or acyl;

R 7 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or acyl;

R 8 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or acyl; or

R 7 and R 8 together, with nitrogen to which they are bound, form a heterocyclyl or substituted heterocyclyl group;

R 10 is a straight or branched chain C 1-6 alkylene group, cycloalkylene or substituted cycloalkylene; and

each of R 7 and R 8 optionally are M + , wherein M + is K + , Na + , Li + or + N(R 9 ) 4 , wherein each R 9 independently is hydrogen or alkyl, and the nitrogen bearing M + is anionic.

9. The compound of claim 8 , wherein p is zero and each of R 6 and Y, independently, is a straight or branched chain C 1-6 alkylene group.

10. The compound of claim 9 , wherein each of R 6 and Y, independently, is methylene or ethylene.

11. The compound of claim 1 , according to formula III:

wherein:

p is 0, 1, 2, or 3;

q is 0, 1, 2, or 3;

X is alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, —C(O)N(R 4 )R 5 , cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl or substituted cycloalkynyl;

each R 2 independently is alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, —C(O)N(R 4 )R 5 or halo;

each R 3 independently is alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy or halo;

R 6 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or acyl;

R 7 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or acyl;

R 8 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or acyl; or

R 7 and R 8 together, with nitrogen to which they are bound, form a heterocyclyl or substituted heterocyclyl group;

wherein at least one of R 7 and R 8 is non-hydrogen; and

each of R 6 , R 7 , and R 8 optionally are substituted with M + , wherein M + is K + , Na + , Li + or + N(R 9 ) 4 , wherein each R 9 independently is hydrogen or alkyl, and the nitrogen bearing M + is anionic.

12. The compound of claim 1 , according to formula IV:

wherein:

p is 0, 1, 2, or 3;

q is 0, 1, 2, or 3;

X is alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, —C(O)N(R 4 )R 5 , cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl or substituted cycloalkynyl;

each R 2 independently is alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, —C(O)N(R 4 )R 5 or halo;

each R 3 independently is alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy or halo;

R 6 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or acyl;

R 7 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or acyl;

R 8 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or acyl; or

R 7 and R 8 together, with nitrogen to which they are bound, form a heterocyclyl or substituted heterocyclyl group;

wherein at least one of R 7 and R 8 is non-hydrogen; and

each of R 6 , R 7 , and R 8 optionally are substituted with M + , wherein M + is K + , Na + , Li + or + N(R 9 ) 4 , wherein each R 9 independently is hydrogen or alkyl, and the nitrogen bearing M + is anionic.

13. A compound which is:

I-1: N2-(3-Aminosulfonylphenyl)-5-chloro-N4-[4-[(N,N-dimethylsulfamoylamino)methyl]phenyl]-2,4-pyrimidinediamine;

I-2: N2-(4-Aminosulfonylphenyl)-5-chloro-N4-[4-[(N,N-dimethylsulfamoylamino)methyl]phenyl]-2,4-pyrimidinediamine;

I-3: N2-(3-Aminosulfonylphenyl)-N4-[4-[(N,N-dimethylsulfamoylamino)methyl]phenyl]-5-methyl-2,4-pyrimidinediamine;

I-4: N2-(4-Aminosulfonylphenyl)-N4-[4-[(N,N-dimethylsulfamoylamino)methyl]phenyl]-5-methyl-2,4-pyrimidinediamine;

I-5: N2-(3-Aminosulfonylphenyl)-5-chloro-N4-[4-[(N-ethylsulfamoylamino)methyl]phenyl]-2,4-pyrimidinediamine;

I-6: N2-(4-Aminosulfonylphenyl)-5-chloro-N4-[4-[(N-ethylsulfamoylamino)methyl]phenyl]-2,4-pyrimidinediamine;

I-7: N2-(3-Aminosulfonylphenyl)-N4-[4-[(N-ethylsulfamoylamino)methyl]phenyl]-5-methyl-2,4-pyrimidinediamine;

I-8: N2-(4-Aminosulfonylphenyl)-N4-[4-[(N-ethylsulfamoylamino)methyl]phenyl]-5-methyl-2,4-pyrimidinediamine;

I-9: N2-(3-Aminosulfonylphenyl)-5-chloro-N4-[3-[(N-ethylsulfamoylamino)methyl]phenyl]-2,4-pyrimidinediamine;

I-10: N2-(4-Aminosulfonylphenyl)-5-chloro-N4-[3-[(N-ethylsulfamoylamino)methyl]phenyl]-2,4-pyrimidinediamine;

I-11: N2-(3-Aminosulfonylphenyl)-N4-[3-[(N-ethylsulfamoylamino)methyl]phenyl]-5-methyl-2,4-pyrimidinediamine;

I-12: N2-(4-Aminosulfonylphenyl)-N4-[3-[(N-ethylsulfamoylamino)methyl]phenyl]-5-methyl-2,4-pyrimidinediamine;

I-13: N2-(3-Aminosulfonylphenyl)-N4-[3-[(N-ethylsulfamoylamino)methyl]phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-14: N2-(4-Aminosulfonylphenyl)-N4-[3-[(N-ethylsulfamoylamino)methyl]phenyl]-5-fluoro-2,4-pyrimidinediamine;

I-15: N2-(3-Aminosulfonylphenyl)-5-chloro-N4-[4-[(N-ethylsulfamoylamino)methyl]-2-methylphenyl]-2,4-pyrimidinediamine;

I-16: N2-(4-Aminosulfonylphenyl)-5-chloro-N4-[4-[(N-ethylsulfamoylamino)methyl]-2-methylphenyl]-2,4-pyrimidinediamine;

I-17: N2-(4-Aminosulfonyl-3,5-dimethylphenyl)-5-chloro-N4-[4-[(N-ethylsulfamoylamino)methyl]-2-methylphenyl]-2,4-pyrimidinediamine;

I-18: N2-(3-Aminosulfonylphenyl)-5-chloro-N4-[4-[(N-cyclopropylsulfamoylamino)methyl]phenyl]-2,4-pyrimidinediamine;

I-19: N2-(4-Aminosulfonylphenyl)-5-chloro-N4-[4-[(N-cyclopropylsulfamoylamino)methyl]phenyl]-2,4-pyrimidinediamine;

I-20: N2-(4-Aminosulfonyl-3,5-dimethylphenyl)-5-chloro-N4-[4-[(N-cyclopropylsulfamoyl-amino)methyl]phenyl]-2,4-pyrimidinediamine;

I-21: N2-(3-Aminosulfonylphenyl)-N4-[4-[(N-cyclopropylsulfamoylamino)methyl]phenyl]-5-methyl-2,4-pyrimidinediamine;

I-22: N2-(4-Aminosulfonylphenyl)-N4-[4-[(N-cyclopropylsulfamoylamino)methyl]phenyl]-5-methyl-2,4-pyrimidinediamine;

I-23: N2-(4-Aminosulfonyl-3,5-dimethylphenyl)-N4-[4-[(N-cyclopropylsulfamoylamino)methyl]phenyl]-5-methyl-2,4-pyrimidinediamine;

I-24: N2-(3-Aminosulfonylphenyl)-5-chloro-N4-[4-[(N-cyclopropylsulfamoylamino)methyl]-2-methylphenyl]-2,4-pyrimidinediamine;

I-25: N2-(4-Aminosulfonylphenyl)-5-chloro-N4-[4-[(N-cyclopropylsulfamoylamino)methyl]-2-methylphenyl]-2,4-pyrimidinediamine;

I-26: N2-(4-Aminosulfonyl-3,5-dimethylphenyl)-5-chloro-N4-[4-[(N-cyclopropylsulfamoyl-amino)methyl]-2-methylphenyl]-2,4-pyrimidinediamine;

I-27: N4-[3-(N-ethyl-N-propionyl)aminosulfonyl-(N-propionyl)aminomethyl]phenyl-5-methyl-N2-(3-propionylaminosulfonyl)phenyl-2,4-pyrimidinediamine;

I-28: N4-[3-(N-ethyl-N-propionyl)aminosulfonyl-(N-propionyl)aminomethyl]phenyl-5-methyl-N2-(3-propionylaminosulfonyl)phenyl-2,4-pyrimidinediamine sodium salt;

I-29: N2-(3-aminosulfonyl-4-methyl)phenyl-N4-(3-ethylaminosulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine;

I-30: N2-(3-aminosulfonyl)phenyl-N4-(3-N,N-dimethylaminosulfonylaminomethyl)-5-methyl-2,4-pyrimidinediamine;

I-31: N2-(4-aminosulfonyl)phenyl-N4-(3-N,N-dimethylaminosulfonylaminomethyl)-5-methyl-2,4-pyrimidinediamine;

I-32: N2-(3-aminosulfonyl-4-methyl)phenyl-N4-(3-N,N-dimethylaminosulfonylamino-methyl)-5-methyl-2,4-pyrimidinediamine;

II-1: N2-(3-aminosulfonyl-4-methyl)phenyl-N4-(2-N,N-dimethylaminosulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-fluoro-2,4-pyrimidinediamine;

II-2: N2-(3-aminosulfonyl-4-methyl)phenyl-N4-(2-N,N-dimethylaminosulfonyl-2,3-dihydro-1H-isoindol-5-yl)-5-fluoro-2,4-pyrimidinediamine;

II-3: N2-(4-aminosulfonyl)phenyl-N4-(2-N,N-dimethylaminosulfonyl-2,3-dihydro-1H-isoindol-5-yl)-5-methyl-2,4-pyrimidinediamine;

II-4: N2-(3-aminosulfonyl)phenyl-N4-(2-N,N-dimethylaminosulfonyl-2,3-dihydro-1H-isoindol-5-yl)-5-methyl-2,4-pyrimidinediamine; or

II-5: N2-(3-aminosulfonyl-4-methyl)phenyl-N4-(2-N,N-dimethylaminosulfonyl-2,3-dihydro-1H-isoindol-5-yl)-5-methyl-2,4-pyrimidinediamine.

14. A pharmaceutical formulation comprising a compound according to claim 1 .

Assignments (2)
SECURITY INTEREST Recorded Aug 25, 2022
From: RIGEL PHARMACEUTICALS, INC.
To: MIDCAP FINANCIAL TRUST
Reel/Frame 061327/0712 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 26, 2010
From: BHAMIDIPATI, SOMASEKHAR; LI, HUI; SINGH, RAJINDER; TAYLOR, VANESSA; CLOUGH, JEFFREY; MCMURTRIE, DARREN
To: RIGEL PHARMACEUTICALS, INC.
Reel/Frame 023851/0244 →