Nova Patents
CA2608367C

Compositions and methods for inhibition of the jak pathway

Abstract

The invention encompasses compounds having formula (I-V) 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, may be therapeutically useful.

CA2608367C, drawing sheet 1
Sheet 1 of 121

Term

Term ended

Expired 8 June 2026, 0.3 years ago.

  1. Priority
  2. Filed
  3. Granted
  4. Expired
  5. Today

24 claims: 6 independent, 18 dependent

  1. 1
    CA 02608367 2013-11-05 CLAIMS 1. A compound of the formula III:R III or pharmaceutically acceptable salt thereof;wherein: X is selected from the group consisting of Ci-ioalkyl, substituted Ci-ioalkyl, Ciwalkoxy, substituted Ci-ioalkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro, C2-6alkenyl, substituted C2-6alkenyl, C2ôalkynyl and substituted C2-6alkynyl;R is hydrogen;ring A is selected from the group consisting of Cô-uaryl, Cs-isheteroaryl including 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, C3iocycloalkyl, C3-iocycloalkenyl and Ci-ioheterocyclyl including 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein ring A is not indolyl or benzimidazolyl;p is 0, 1, 2 or 3;each R 2 independently is selected from the group consisting of Ci-ioalkyl, substituted Ci-ioalkyl, Ci-ioalkoxy, substituted Ci-ioalkoxy, amino, substituted amino, Cô-uaryl, substituted Cô-uaryl, Co-uaryloxy, substituted Co-uaryloxy, cyano, C3-iocycloalkyl, substituted C3-iocycloalkyl, C3-iocycloalkoxy, substituted C3-iocycloalkoxy, C5-i5heteroaryl including 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, substituted Cs-isheteroaryl including 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, Cs-isheteroaryloxy, substituted C5îsheteroaryloxy, Ci-ioheterocyclyl including 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, substituted Ciloheterocyclyl including 1-4 heteroatoms selected from the group consisting 427 CA 02608367 2013-11-05 of oxygen, nitrogen and sulfur, Ci-ioheterocyclyloxy including 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, substituted Ci-ioheterocyclyloxy including 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, aminoacyl, aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro and halo;each of Z 1 , Z 2 , and Z 3 is carbon;q is 0, 1, 2 or 3;each R 3 independently is selected from the group consisting of hydrogen, Ciîoalkyl, substituted Ci-ioalkyl, Ci-ioalkoxy, substituted Ci-ioalkoxy, C3îocycloalkyl or substituted C3-iocycloalkyl, halo, Ci-ioheterocyclyl including 1 -4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and substituted Ci-ioheterocyclyl including 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;R 4 and R 5 independently are selected from the group consisting of hydrogen, Ciîoalkyl, substituted Ci-1 oalkyl, acyl and M + , wherein M + is a metal counterion selected from the group consisting of K + , Na + , Li + or + N(R 6 )4, wherein R 6 is hydrogen or Ci-ioalkyl, and the nitrogen of SO 2 NR 4 R 5 is Ν';or R 4 or R 5 is a divalent counterion selected from the group consisting of Ca 2+ , Mg 2 +, and Ba 2+ , and the nitrogen of SO2NR 4 R 5 is Ν';or R 4 and R 5 together with the nitrogen atom bound thereto, form a Ciîoheterocyclyl including 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur or substituted Ciloheterocyclyl including 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;or when q is 1, 2 or 3, R 5 can be joined with one R 3 group bound alpha thereto, to form a fused ring as illustrated in formula IV: (R 3 )q·, wherein W is selected from the group consisting of C1-C3 alkylene, 428 CA 02608367 2013-11-05 substituted C1-C3 alkylene, C2-C3 alkenylene and substituted C2-C3 alkenylene wherein one or more of the carbon atoms have been replaced with a moiety selected from oxygen, sulfur, S(O), S(O)2, C(O), or NR 8 where R 8 is selected from the group consisting of hydrogen and Ci-ioalkyl or is a bond participating in a -N=C< site of unsaturation;and -SO 2 NR 4 R 5 is meta to the amino group at the 2 position of pyrimidine;provided that: if p=0, then X is other than bromo;if ring A is cycloaklyl, then X is other than bromo;if P=2 and each of R 2 is methoxy, halo, trihalomethyl or trihalomethoxy, then R 4 and R 5 are other than one hydrogen and one methyl;and if ring A is phenyl, p=l and R 2 is chloro, then R 4 and R 5 are other than one hydrogen and one methyl;wherein: “Substituted alkyl” refers to an alkyl group having from 1 to 5 hydrogens replaced with substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, alkynyl, substituted alkynyl, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, silyl and trialkylsilyI;“Alkoxy” refers to the groups -O-alkyl, -O-alkenyl, and -O-alkynyl, “Substituted alkoxy” refers to the groups -O-(substituted alkyl), -O-(substituted alkenyl), and -O-(substituted alkynyl);429 CA 02608367 2013-11-05 “Substituted amino” refers to the group -NR 21 R 22 where R 21 and R 22 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -SCk-alkyl, -SO2substituted alkyl, -SCk-alkenyl, -SCk-substituted alkenyl, -SCk-cycloalkyl, -SO2substituted cylcoalkyl, -SCk-cycloalkenyl, -SCk-substituted cylcoalkenyl,-SO2-aryl, -SÛ2-substituted aryl, -SCk-heteroaryl, -SCk-substituted heteroaryl, -SCk-heterocyclyl, and -SCk-substituted heterocyclyl and wherein R 21 and R 22 are optionally joined, together with the nitrogen bound thereto to form a heterocyclyl or substituted heterocyclyl group, provided that R 21 and R 22 are both not hydrogen;“Substituted aryl” refers to aryl groups having 1 to 5 hydrogens replaced with substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl esterjamino, (carboxyl esterjoxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio;“Substituted aryloxy” refers to the group -O-(substituted aryl);“Substituted alkenyl” refers to alkenyl groups having from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, 430 CA 02608367 2013-11-05 aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio;with the proviso that any hydroxy substitution is not attached to a vinyl (unsaturated) carbon atom;“Substituted alkynyl” refers to alkynyl groups having from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio;with the proviso that any hydroxy substitution is not attached to an acetylenic carbon atom;“Substituted cycloalkyl” and “substituted cycloalkenyl” refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 substituents selected from the group consisting of oxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, 431 CA 02608367 2013-11-05 aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio;“Substituted cycloalkoxy” refers to -O-(substituted cycloalkyl);“Substituted heteroaryl” refers to heteroaryl groups that are substituted with from 1 to 5 substituents selected from the group consisting of the same group of substituents defined for substituted aryl;“Substituted heteroaryloxy” refers to the group -O-(substituted heteroaryl);“substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 of the same substituents as defined for substituted cycloalkyl;and “Substituted heterocyclyloxy” refers to the group -O-(substituted heterocycyl).
  2. 2
    A compound selected from the group consisting of N2-(3-Aminosulfonyl-4methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine and 5fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-N4-[4-(prop-2-ynyloxy)phenyl]2,4-pyrimidinediamine.
  3. 3
    A compound which is N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine.
  4. 4
    A compound which is 5-Fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine. 432 CA 02608367 2013-11-05
  5. 14
    15. A method of inhibiting an activity of a JAK kinase, comprising contacting in vitro the JAK kinase with an amount of a compound effective to inhibit an activity of the JAK kinase wherein the compound is selected from the compounds of any one of claims 1 to 11.
  6. 15
    16. A method of inhibiting a signal transduction cascade in which JAK3 kinase plays a role, comprising contacting in vitro a cell expressing a receptor involved in such a signalling cascade with a compound wherein the compound is selected from the compounds of any one of claims 1 to 11.
  7. 17
    18. The compound for use in treating a T-cell mediated autoimmune disease according to claim 17, wherein the compound is for administration in combination with, or adjunctively to, a compound selected to inhibit Syk kinase with an IC50 in the range of at least 10 μΜ. 480 CA 02608367 2013-11-05
  8. 22
    23. The compound for use according to claim 22, in which the immunosuppressant is selected from the group consisting of cyclosporine, tacrolimus, sirolimus, an inhibitor of IMPDH, mycophenolate, mycophanolate mofetil, an anti-T-cell antibody and OKT3.
  9. 24
    25. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 11, and at least one pharmaceutically acceptable excipient, diluent, preservative, or stabilizer, or mixtures thereof. 481
Independent claims9