1. A compound of formula (I), or a salt, N-oxide, hydrate, or solvate thereof:
wherein
ring A is an aryl or heteroaryl ring or ring system;
R1 is hydrogen, fluoro, chloro, bromo, or a radical of formula (1A):
\u2014X-Alk1-(Z)m-(Alk2)n-Q\u2003\u2003(IA)
wherein
X is a bond, \u2014O\u2014, \u2014S\u2014 \u2014S(O)\u2014, \u2014SO2\u2014, or \u2014NH\u2014,
Z is \u2014O\u2014, \u2014S\u2014, \u2014(C\u2550O)\u2014, \u2014(C\u2550S)\u2014, \u2014S(O)\u2014, \u2014SO2\u2014, \u2014NRA\u2014, or, in either orientation \u2014C(\u2550O)O\u2014, \u2014C(\u2550O)NRA\u2014, \u2014C(\u2550S)NRA\u2014, \u2014SO2NRA\u2014, \u2014NRAC(\u2550O)\u2014, or \u2014NRASO2\u2014 wherein RA is hydrogen or C1-C6 alkyl in which one or more hydrogens is optionally substituted by fluorine;
Alk1 and Alk2 are optionally substituted divalent C1-C3 alkylene or C2-C3 alkenylene radicals,
m and n are independently 0 or 1, and
Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical;
R2 is cyano (\u2014CN), fluoro, chloro, bromo, methyl, ethyl, \u2014OH, \u2014CH2OH, \u2014C(\u2550O)NH2, \u2014C(\u2550O)H, \u2014C(\u2550O)CH3, or \u2014NH2;
R3 and R4 are independently selected from hydrogen, fluoro, chloro, bromo, cyano (\u2014CN), C1-C3alkyl optionally substituted with one or more fluorine substituents, C1-C3alkoxy optionally substituted with one or more fluorine substituents, \u2014CH\u2550CH2, \u2014C\u2261CH, cyclopropyl and \u2014NH2, or R3 and R4 together represent methylenedioxy (\u2014OCH2O\u2014) or ethylenedioxy (\u2014OCH2CH2O\u2014) in either of which one or more hydrogens are optionally replaced by fluorine;
S1 is hydrogen, or a substituent selected from fluoro, chloro, bromo, cyano (\u2014CN), C1-C3alkyl optionally substituted with one or more fluorine substituents, C1-C3alkoxy optionally substituted with one or more fluorine substituents, \u2014CH\u2550CH2, \u2014C\u2261CH, cyclopropyl and \u2014NH2, or S1 and R3, or S1 and R4, together represent methylenedioxy (\u2014OCH2O\u2014) or ethylenedioxy ((\u2014OCH2 CH2O\u2014) in either of which one or more hydrogens are optionally replaced by fluorine; or SI is a radical of formula (IB):
-(Alk3)p-(Z1)q-(Alk4)r-Q1\u2003\u2003(IB)
wherein
p, q and r are independently 0 or 1;
(a) when p is 0 or 1, and q is 1, and r is 0 or 1:
Z1 is selected from the group of divalent radicals consisting of (i) \u2014S\u2014, \u2014(C\u2550O)\u2014,
\u2014(C\u2550S)\u2014, \u2014S(O)\u2014 and \u2014SO2\u2014 and (ii) \u2014N(RA)C(\u2550O)\u2014* wherein the bond marked * is attached to Q1 and (iii) in either orientation, \u2014C(\u2550O)O\u2014, \u2014C(\u2550S)NRA\u2014, and \u2014SO2NRA\u2014; and Q1 is (i) hydrogen or an optional substituent; or (ii) an optionally substituted carbocyclic or heterocyclic radical; or (iii) a radical \u2014CH2O(CH2)wxZ2 wherein Z2 is H, \u2014OH or \u2014O(C1-C3alkyl) wherein x and w are independently 1, 2 or 3; or
(b) when p is 1, and q is 1, and r is 0 or 1:
Z1 is \u2014O\u2014, and Q1 is (i) hydrogen or an optional substituent which is not linked to -(Alk3)p-(Z1)q-(Alk4)r- through a nitrogen atom; or (ii) an optionally substituted carbocyclic radical; or (iii) an optionally substituted heterocyclic ring of 5 or 6 ring atoms which is not linked to -(Alk3)p-(Z1)q-(Alk4)r- through a ring nitrogen; or (iv) a radical \u2014CH2O(CH2)wxZ2 wherein Z2 is H, \u2014OH or \u2014O(C1-C3alkyl) wherein x and w are independently 1, 2 or 3, or
(c) when p is 1, and q is 1, and r is 0 or 1:
Z1 is \u2014NRA\u2014 or \u2014C(\u2550O)N(RA)\u2014* wherein the bond marked * is attached to Q1 and Q1 is a radical \u2014CH2O(CH2)wxZ2 wherein Z2 is H, \u2014OH or \u2014O(C1-C3alkyl) wherein x and w are independently 1, 2 or 3, or
(d) when p is 0, and q is 1, and r is 0 or 1:
Z1 is \u2014O\u2014 or \u2014NRA\u2014 and Q1 is (i) hydrogen or an optional substituent which is not linked to -(Alk3)p-(Z1)q-(Alk4)r- through a nitrogen atom; or (ii) Q1 and RA, taken together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring of 5 or 6 ring atoms; or (iii) a radical \u2014CH2O(CH2)wxZ2 wherein Z2 is H, \u2014OH or \u2014O(C1-C3alkyl) wherein x and w are independently 1, 2 or 3; or
(e) when p is 0 or 1, q is 0, and r is 0 or 1:
Q1 is (i) hydrogen or an optional substituent which is not linked to -(Alk3)p-(Z1)q-(Alk4)r- through a nitrogen atom or (ii) an optionally substituted carbocyclic radical; or (iii) an optionally substituted heterocyclic of 5 or 6 ring atoms which is not linked to -(Alk3)p-(Z1)q-(Alk4)r- through a ring nitrogen; or (iv) a radical \u2014CH2O(CH2)wxZ2 wherein Z2 is H, \u2014OH or \u2014O(C1-C3alkyl) wherein x and w are independently 1, 2 or 3;
RA is hydrogen or C1-C3 alkyl optionally substituted with one or more fluorine substituents; and
Alk3 and Alk4 are divalent C1-C3 alkylene or C2-C3 alkenylene radicals, each optionally substituted by one or two substituents selected from fluoro, chloro, C1-C3alkyl optionally substituted with one or more fluorine substituents, C1-C3alkoxy optionally substituted with one or more fluorine substituents.
2. A compound as claimed in claim 1 wherein ring A is a phenyl ring.
3. A compound of formula (IC), or a salt, N-oxide, hydrate, or solvate thereof:
wherein
R1, R2, R3 and R4 are as defined in claim 1, and
S1 is hydrogen, or a substituent selected from fluoro, chloro, bromo, cyano (\u2014CN), C1-C3alkyl optionally substituted with one or more fluorine substituents, C1-C3alkoxy optionally substituted with one or more fluorine substituents, \u2014CH\u2550CH2, \u2014C\u2261CH, cyclopropyl and \u2014NH2, or S1 and R3, or S1 and R4, together represent methylenedioxy (\u2014OCH2O\u2014) or ethylenedioxy ((\u2014OCH2CH2O\u2014) in either of which one or more hydrogens are optionally replaced by fluorine;
or S1 is a radical of formula (IB):
-(Alk3)p-(Z1)q-(Alk4)r-Q1\u2003\u2003(IB)
wherein
p, q and r are independently 0 or 1;
Z1 is \u2014O\u2014, \u2014S\u2014, \u2014(C\u2550O)\u2014, \u2014(C\u2550S)\u2014, \u2014S(O)\u2014, \u2014SO2\u2014, \u2014NRA\u2014, or, in either orientation,
\u2014C(\u2550O)N(RA)\u2014 or \u2014SO2NRA\u2014;
Q1 is (i) hydrogen or an optional substituent; or (ii) an optionally substituted carbocyclic or heterocyclic radical; or (iii) a radical CH2O(CH2)wxZ2 wherein Z2 is H, \u2014OH or \u2014O(C1-C3alkyl) wherein x and w are independently 1, 2 or 3;
RA is hydrogen or C1-C3 alkyl optionally substituted with one or more fluorine substituents; and
Alk3 and Alk4 are divalent C1-C3 alkylene or C2-C3 alkenylene radicals, each optionally substituted by one or two substituents selected from fluoro, chloro, C1-C3alkyl optionally substituted with one or more fluorine substituents, C1-C3alkoxy optionally substituted with one or more fluorine substituents.
4. A compound as claimed in claim 1 wherein R1 and SI are independently selected from (a) hydrogen, methoxy, ethoxy, methylthio or ethylthio; (b) a group of formula \u2014X1-Alk5-(CO)wNRCRD wherein w is 0 or 1, X1 is \u2014O\u2014 or \u2014S\u2014, Alk5 is a straight or branched chain C1-C3alkylene radical, RC is C1-C3alkyl and RD is C1-C3alkyl or hydroxyl(C1-C3alkyl)-; and (c) a group of formula \u2014X1-Alk5-Ar wherein X1 is \u2014O\u2014 or \u2014S\u2014, Alk5 is a straight or branched chain C1-C3alkylene radical, and Ar is phenyl or a 5- or 6-membered heteroaryl ring wherein at least one hetero atom is nitrogen
5. A compound as claimed in claim 1 wherein R1 is methoxy, ethoxy, methylthio or ethylthio.
6. A compound as claimed in claim 1 wherein R2 is cyano (\u2014CN).
7. A compound as claimed claim 2 wherein R3 is in the ortho position and R4 in the para position.
8. A compound as claimed in claim 2 wherein S1 is in the meta position of the phenyl ring.
9. A compound as claimed in claim 1 wherein R3 andor R4 is selected from fluoro, chloro, bromo and methyl.
10. A compound as claimed in claim 1 having formula (ID):
or a salt, N-oxide, hydrate, or solvate thereof, wherein:
R1 and S1 are independently selected from (a) hydrogen, methoxy, ethoxy, methylthio or ethylthio; (b) a group of formula \u2014X1-Alk5-(CO)wNRCRD wherein w is 0 or 1, X1 is \u2014O\u2014 or \u2014S\u2014, Alk5 is a straight or branched chain C1-C3alkylene radical, RC is C1-C3alkyl and RD is C1-C3alkyl or hydroxyl(C1-C3alkyl)-; and (c) a group of formula \u2014X1-Alk5-Ar wherein X1 is \u2014O\u2014 or \u2014S\u2014, Alk5 is a straight or branched chain C1-C3alkylene radical, and Ar is phenyl or a 5- or 6-membered heteroaryl ring wherein at least one hetero atom is nitrogen; PROVIDED THAT R1 and S1 are not both hydrogen;
R3 is fluoro, chloro, bromo or methyl; and
R4 is fluoro, chloro, bromo methyl, ethyl, isopropyl, methoxy, or cyano.
11. A compound as claimed in claim 1 selected from the group consisting of:
4-(2,4-Dimethyl-phenyl)-1H-pyrrolo2,3-bpyridine-3-carbonitrile,
4-(2,4-Dichloro-phenyl)-1H-pyrrolo2,3-bpyridine-3-carbonitrile,
6-Chloro-4-(2,4-dichloro-phenyl)-1H-pyrrolo2,3-bpyridine-3-carbonitrile,
4-(2,4-Di chloro-5-methoxy-phenyl)-1H-pyrrolo2,3-bpyridine-3-carbonitrile,
6-Chloro-4-(2,4-dichloro-5-methoxy-phenyl)-1H-pyrrolo2,3-bpyridine-3-carbonitrile,
3-Bromo-4-(2,4-dimethyl-phenyl)-1H-pyrrolo2,3-bpyridine-3-carbonitrile,
4-(2,4-Dimethyl-phenyl)-1H-pyrrolo2,3-bpyridine-3-carbaldehyde,
4-(2,4-Difluorol-phenyl)-1H-pyrrolo2,3-bpyridine-3-carbaldehyde,
6-(2-Diethylamino-ethoxy)-4-phenyl-1H-pyrrolo2,3-bpyridine-3-carbonitrile,
4-(2,4-Dichloro-phenyl)-6-(2-diethylamino-ethoxy)-1H-pyrrolo2,3-bpyridine-3-carbonitrile,
4-(2,4-Dichloro-phenyl)-6-(3-piperidin-1-yl-propoxy)-1H-pyrrolo2,3-bpyridine-3-carbonitrile,
4-(3-Hydroxy-phenyl)-1H-pyrrolo2,3-bpyridine-3-carbonitrile,
4-3-(2-Diethylamino-ethoxy)-phenyl-1H-pyrrolo2,3-bpyridine-3-carbonitrile,
6-Chloro-4-(3-hydroxy-phenyl)-1H-pyrrolo2,3-bpyridine-3-carbonitrile, and
6-methoxy-4-(-phenyl)-1H-pyrrolo2,3-bpyridine-3-carbonitrile.
12. A pharmaceutical or veterinary composition comprising a compound as claimed in claim 1, together with one or more pharmaceutically or veterinarily acceptable carriers andor excipients.
13. (canceled)
14. A method of treatment of diseases which are responsive to inhibition of HSP90 activity in mammals, which method comprises administering to the mammal an amount of a compound as claimed in claim 1 effective to inhibit said HSP90 activity.
15. The method as claimed in claim 14 for immunosuppression or the treatment of viral disease, inflammatory diseases such as rheumatoid arthritis, asthma, multiple sclerosis, Type I diabetes, lupus, psoriasis and inflammatory bowel disease; cystic fibrosis angiogenesis-related disease such as diabetic retinopathy, haemangiomas, and endometriosis; or for protection of normal cells against chemotherapy-induced toxicity; or diseases where failure to undergo apoptosis is an underlying factor; or protection from hypoxia-ischemic injury due to elevation of Hsp70 in the heart and brain; scrapieCJD, Huntingdon’s or Alzheimer’s disease.
16. The method as claimed in claim 14, for the treatment of cancer.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method for forming a receptor pad on a laminate, comprising the steps of:
providing a circuitized substrate, wherein the substrate includes a surface having a conductive element;
mounting an external dielectric layer (EDL) on the surface;
forming an opening in the EDL to expose the conductive element and create a microvia;
treating an interior side wall surface of the microvia to promote copper adhesion; and
plating the microvia with copper.
2. The method of claim 1, wherein the plating step includes a step of electroplating the microvia.
3. The method of claim 1, wherein the plating step includes a step of electroless plating of the microvia.
4. The method of claim 1, wherein the plating step includes the step of first depositing a seed layer.
5. The method of claim 2, wherein the electroplating step includes the step of full panel electroplating with acid copper.
6. The method of claim 2, further comprising the step of performing a resist process to finalize the receptor pad.
7. The method of claim 1, further comprising the steps of:
depositing a wet solder paste onto the receptor pad; and
reflowing and washing the laminate.
8. The method of claim 1, wherein the treating step comprises the step of roughening the interior side wall surface of the microvia.
9. The method of claim 1, wherein the plating step substantially fills the microvia.
10. The method of claim 1, further comprising the step of filling the microvia with a conductive material.
11. A chip carrier structure having a receptor pad formed thereon, comprising:
a circuitized laminate having a conductive element on a surface;
an external dielectric layer (EDL) mounted on the circuitized laminate, the EDL having an opening positioned above the conductive element, the opening having interior side walls treated for copper adhesion; and
a plated layer deposited on the treated interior side walls.
12. The chip carrier of claim 11, wherein the plated layer is electroplated.
13. The chip carrier of claim 11, wherein the plated layer is electrolessly plated.
14. The chip carrier structure of claim 11, further comprising a solder paste deposit affixed to the plated layer.
15. The chip carrier of claim 11, wherein the plated layer comprises acid copper.
16. The chip carrier of claim 11, further comprising a conductive material, in contact with the plated layer, that fills the opening.
17. The chip carrier of claim 11, wherein the plated layer overlaps a top surface of the EDL.
18. An integrated circuit chip package, comprising:
a coverplate;
a stiffener;
a chip having a plurality of contacts;
a laminate having a plurality of receptor pads electrically connected to the chip contacts, the laminate having:
a circuitized substrate having conductive elements on a surface;
an external dielectric layer (EDL) mounted on the circuitized substrate, the EDL having openings positioned above each of the conductive elements forming a plurality of microvias; and
a plated layer of copper deposited in each microvia to form said plurality of receptor pads.
19. The integrated circuit chip package of claim 18, wherein the plated layer is electroplated.
20. The integrated circuit chip package of claim 18, wherein the plated layer is electroless plating.
21. The integrated circuit chip package of claim 18, further comprising solder connections between the receptor pads and the chip contacts.
22. The integrated circuit chip package of claim 18, wherein the plated layer substantially fills the microvia.
23. The integrated circuit chip package of claim 18, wherein the microvias further comprise a conductive material that fills the microvia.
24. The integrated circuit chip package of claim 18, wherein the plated layer of copper overlaps a top surface of the EDL.
25. The integrated circuit chip package of claim 18, wherein each opening in the EDL comprises interior wall surfaces treated for copper adhesion.
26. The integrated circuit chip package of claim 18, wherein each opening in the EDL comprises interior wall surfaces that are angled.