US2012010206A1PendingUtilityA1
Imidazolopyridine compounds useful for the treatment of degenerative and inflammatory diseases
Est. expiryDec 1, 2026(~0.4 yrs left)· nominal 20-yr term from priority
Inventors:Paul EdwardsSébastien Laurent Xavier MartinaMartin James Inglis AndrewsGregory BarBrigitte AllartAndrew BurrittXueliang TaoFriedrich Kroll
A61P 43/00A61P 29/00A61P 25/28C07D 471/04A61P 19/02
38
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Claims
Abstract
Novel imidazolopyridine compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, ECM degradation, joint degradation and/or inflammation, and others.
Claims
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3 . A compound according to formula III:
wherein
R 1 represents H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, CF 3 , CN, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted monocyclic aryl, optionally substituted monocyclic heteroaryl, CNHNR a R b , —COR a , —OR a , —OC(O)—C 1 -C 6 alkyl, (CH 2 ) a COOR a , C(O)NR a R b , S(O) 2 (CH 2 ) a N(R a R b ), SR a , SO(CH 2 ) a NR a R b , S(O) 2 —R a , SOR a , (CH 2 ) a NR a R b , (CH 2 ) a N(R a )S(O) 2 —C 1 -C 6 alkyl, (CH 2 ) a NR a S(O)—C 1 -C 6 alkyl, NR a CO—R b , NH—CO—CO—OR a ; each of which may be optionally substituted with one or more groups selected from H, halogen, OH, C 1 -C 6 alkyl, NH 2 , N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), heterocycloalkyl, cycloalkyl or CF 3 ;
R 2 is selected from substituted or unsubstituted isoindolyl;
R 3 , R 4 , R 5 and R 6 are selected from H, OH, OMe, OC 3 H 5 , F, Cl, Me, Et, SO 2 Me, CF 3 and OCF 3 ;
CY is selected from substituted or unsubstituted aryl, substituted or unsubstituted pyridyl, and substituted or unsubstituted pyrimidine;
R a and R b each independently represent H, halogen, C 1 -C 6 alkyl, (CH 2 ) a —N(C 1 -C 6 alkyl)(C 1 -C 6 -alkyl), (CH 2 ) a -monocyclic aryl, (CH 2 ) a -monocyclic heteroaryl, (CH 2 ) a -cycloalkyl or (CH 2 ) a -heterocycloalkyl, each of which may be optionally substituted with one or more groups selected from halogen, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , —NR c R d , NR e COR d , heteroaryl, heterocycloalkyl, substituted heterocycloalkyl or —CF 3 ; or R a and R b may, if joined to the same atom, represent together with the nitrogen to which they are attached a heterocycloalkyl group which may be optionally substituted with one or more groups selected from halogen, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , —NR c R d , —NR c COR d , —C(O)NR c R d , optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted cycloalkyl or —CF 3 ;
R c and R d each independently represent H, C 1 -C 6 alkyl; and
“a” is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt, solvate or prodrug thereof or stereoisomers, isotopic variants or tautomers thereof.
4 . A compound according to claim 3 , wherein CY is selected from substituted phenyl, substituted pyridyl, and substituted pyrimidine.
5 . A compound according to claim 3 , wherein CY is selected from:
and wherein R 1 is as described for formula III; the subscript n1 is selected from 1-4; and each R 1b is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, cyano, and halo.
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12 . A compound according to claim 3 , wherein R 3 , R 4 , R 5 and R 6 are all H.
13 . A compound according to claim 3 , wherein CY is selected from substituted phenyl, substituted pyridyl, and substituted pyrimidine; and R 1 is
-L-R 1a ; and wherein L is selected from bond, alkylene, —CO—, and —SO 2 —; and R 1a is selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl and substituted or unsubstituted aminoalkyl.
14 . A compound according to claim 13 , wherein the compound is according to formula IIIa, IIIb, IIIc or IIId:
wherein L and R 1a are as defined in claim 13 , the subscript n1 is selected from 1-4; and each R 1b is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, cyano, and halo.
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16 . A compound according to claim 14 , wherein L is —CO— or SO 2 —;
R 1a is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroarylalkyl.
17 . A compound according to claim 14 , wherein L is —CO— or SO 2 —; and R 1a is substituted or unsubstituted amino.
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19 . A compound according to claim 14 , wherein L is a bond, —CO—, SO 2 , and —(CH 2 ) m1 —; the subscript m1 is selected from 1-4; and R 1a is
and wherein the ring P is substituted or unsubstituted heterocycloalkyl.
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34 . A compound according to claim 14 , wherein the compound is according to formula IVa, IVb, IVc, or IVd:
and wherein L is bond, —CO—, SO 2 , and —(CH 2 ) m1 —; the subscript m1 is selected from 1-4; the ring P is substituted or unsubstituted heterocycloalkyl; each R 1b is independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, cyano, and halo; the subscript n1, is selected from 1-4; and R 2 is independently selected from substituted or unsubstituted isoindolyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, isotopic variants and tautomers thereof.
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36 . A compound according to claim 34 , wherein L is a single bond.
37 . A compound according to claim 34 , wherein L is —CO—.
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44 . A compound according to claim 34 , wherein the compound is according to formula Va, Vb, Vc, Vd, Ve, Vf, Vg, Vh or Vi:
and wherein R 2 is independently selected from substituted or unsubstituted isoindolyl, each R 1b is independently selected from Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 , CF 2 CF 3 or OCF 3 , R 1c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl, each R 1d is independently selected from H, Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 , CF 2 CF 3 or OCF 3 , each n1 is independently an integer between 0 and 2 and each n2 is independently an integer between 0 and 2.
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51 . A compound according to claim 34 , wherein the compound is according to formula VIa, VIb, VIc, VId, VIe, or VIf:
and wherein R 2 is substituted or unsubstituted isoindolyl, each R 1b is independently selected from Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 , CF 2 CF 3 or OCF 3 and R 1c is selected from hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; each R 1d is independently selected from H, Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 , CF 2 CF 3 or OCF 3 , each n1 is independently an integer between 0 and 2 and each n2 is independently an integer between 0 and 2.
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58 . A compound according to claim 34 , wherein the compound is according to formula VIm, VIn, or VIo:
and wherein R 2 is substituted or unsubstituted isoindolyl; each R 1b is independently selected from Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 CF 2 CF 3 or OCF 3 , each R 1d is independently selected from H, Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 , CF 2 CF 3 or OCF 3 , each n1 is independently an integer between 0 and 2 and each n2 is independently an integer between 0 and 2; and R 1c1 is H, Me, F, Cl, or OH.
59 . A compound according to claim 34 , wherein the compound is according to formula VIIIa, VIIIb, VIIIc, VIIId, VIIIe, VIIIf, VIIIh, VIIIi:
and wherein R 2 is substituted or unsubstituted isoindolyl; A is CH or N; and R 1c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyl.
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66 . A compound according to claim 3 , wherein the compound is according to formula IXa or IXb:
and wherein R 2 is independently selected from substituted or unsubstituted isoindolyl; each R a and R b is independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyl.
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85 . A compound according to claim 3 , wherein R 2 is
and wherein the subscript m is selected from 1-4 and each R 9d is independently H, substituted or unsubstituted alkyl or halo.
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124 . A compound according to claim 3 , wherein the compound is according to formula XVa, XVb, XVc, XVd, XVe, XVf, XVg, XVh, XVi, XVj, XVk or XVl:
and wherein R 1b is selected from Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 , CF 2 CF 3 or OCF 3 , R 1c is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl, each R 1d is independently selected from H, Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 , CF 2 CF 3 or OCF 3 , each n1 is independently an integer between 0 and 2 and each n2 is independently an integer between 0 and 2.
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131 . A compound according to claim 3 wherein the compound is according to formula XVm, XVn, or XVo,
and wherein R 2 is substituted or unsubstituted isoindolyl, each R 1b is independently selected from Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 , CF 2 CF 3 or OCF 3 , each R 1d is independently selected from H, Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 , CF 2 CF 3 or OCF 3 , each n1 is independently an integer between 0 and 2 and each n2 is independently an integer between 0 and 2; and R 1c1 is H, Me, F, Cl, or OH.
132 . A compound according to claim 14 , wherein the compound is according to formula XVIa, XVI, XVIc, XVId, XVIe, or XVIf:
133 . A compound according to claim 14 , wherein the compound is according to formula XVIIa, XVIIb, XVIIc, XVIId, XVIIe, or XVIIf:
wherein A is CH or N; and R 1c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyl.
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140 . A compound according to claim 3 , wherein the compound is according to formula XVIa, or XVIb:
and wherein each R a and R b is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyl.
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166 . A pharmaceutical composition comprising an effective therapeutically effective amount of a matrix metallo proteinase expression inhibiting compound according to of claim 3 , in admixture with a pharmaceutically acceptable carrier.
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170 . A method of treatment of a condition characterized by abnormal matrix metalloproteinase expression, which comprises administering a therapeutically effective amount of a matrix metallo proteinase expression inhibiting compound according to claim 3 .
171 . A method of treatment of a condition selected from diseases involving degradation of extra-cellular matrix, which comprises administering a therapeutically effective matrix metalloproteinase expression inhibiting amount of a compound according to claim 3 .
172 . A method of treatment of a condition selected from diseases involving abnormal cellular expression of MMP1, which comprises administering a therapeutically effective matrixmetallo proteinase expression inhibiting amount of a compound according to claim 3 .
173 . A method of treatment or prevention of inflammatory diseases, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to claim 3 .
174 . A method of treatment or prevention of rheumatoid arthritis, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to claim 3 .
175 . A compound selected from:
176 . A compound according to claim 34 , wherein R 2 is
and wherein the subscript m is selected from 1-4 and each R 9d is independently H, substituted or unsubstituted alkyl or halo.Cited by (0)
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