Claims for Patent: 7,745,446

Summary for Patent: 7,745,446

Title:	Pyrazolo[1,5-c]pyrimidines
Abstract:	Compounds of a certain formula I ##STR00001## in which R1, R2, R3 and R4 have the meanings indicated in the description are novel compounds expected to be useful in the therapy of (hyper)proliferative diseases and/or disorders responsive to induction of apoptosis.
Inventor(s):	Maier; Thomas (Stockach, DE), Zuelch; Armin (Constance, DE), Ciossek; Thomas (Ravensburg, DE), Baer; Thomas (Reichenau, DE), Beckers; Thomas (Constance, DE)
Assignee:	Bayer Schering Pharma Aktiengesellschaft (Berlin, DE)
Application Number:	11/661,111
Patent Claims:	1. A compound of formula I ##STR00024## in which R1 is Ar1, or Har1, Har2 or Har3, or Cyc1, or Hh1, Ah1 or Ha1, in which Ar1 is optionally substituted by R11, and is phenyl, naphthyl, fluorenyl or Aa1, in which Aa1 is a bisaryl radical made up of two aryl groups, which are independently selected from the group consisting of phenyl and naphthyl, and which are linked together via a single bond, R11 is 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, halogen, nitro, hydroxyl, phenoxy, phenyl-1-4C-alkoxy, hydroxy-2-4C-alkoxy, carboxy-1-4C-alkoxy or 1-4C-alkylcarbonylamino, Har1 is optionally substituted by R12, and is an unsaturated monocyclic 5- or 6-membered heteroaryl radical comprising one to four heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulphur, in which R12 is 1-4C-alkyl, Har2 is optionally substituted by R13, and is an unsaturated fused bicyclic 9- or 10-membered heteroaryl radical comprising one to four heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulphur, in which R13 is 1-4C-alkyl, Har3 is optionally substituted by R14, and is an unsaturated fused tricyclic 13- or 14-membered heteroaryl radical comprising one to four heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulphur, in which R14 is 1-4C-alkyl, Cyc1 is a group of formula A ##STR00025## in which G is a 5- or 6-membered saturated or partially unsaturated heterocyclic ring comprising one or two heteroatoms independently selected from the group consisting of oxygen and sulfur, whereby said Cyc1 ring system is attached to the parent molecular group via any substitutable carbon atom, Hh1 is optionally substituted by R15, and is a bisheteroaryl radical made up of two heteroaryl groups, which are independently selected from the group consisting of monocyclic 5- and 6-membered heteroaryl radicals comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, and which are linked together via a single bond, in which R15 is 1-4C-alkyl, Ah1 is optionally substituted by R16, and is an arylheteroaryl radical made up of an aryl group selected from the group consisting of phenyl and naphthyl, and a heteroaryl group selected from the group consisting of monocyclic 5- and 6-membered heteroaryl radicals comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, whereby said aryl and heteroaryl groups are linked together via a single bond, in which R16 is 1-4C-alkyl, Ha1 is optionally substituted by R17, and is a heteroarylaryl radical made up of a heteroaryl group selected from the group consisting of monocyclic 5- and 6-membered heteroaryl radicals comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, and an aryl group selected from the group consisting of phenyl and naphthyl, whereby said heteroaryl and aryl groups are linked together via a single bond, in which R17 is 1-4C-alkyl, whereby each of the radicals Har1, Har2, Har3, Hh1 and Ah1 is bonded via a ring carbon atom to the pyrazolopyrimidine scaffold; R2 is hydrogen, halogen or 1-4C-alkyl; R3 is -T-R30, --U--Ar2, --V--Har4, or Cyc2, in which T is 1-4C-alkylene, R30 is --N(R301)R302, cyano, amidino, carbamoyl, guanidino, ureido, 1-4C-alkylsulfonyl, or Het2, in which R301 is hydrogen, 1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-2-4C-alkyl or 1-4C-alkoxy-2-4C-alkyl, R302 is hydrogen or 1-4C-alkyl, or R301 and R302 together and with inclusion of the nitrogen atom to which they are bonded form a radical Het1, in which Het1 is a monocylic 3- to 7-membered saturated heterocyclic ring comprising the nitrogen atom, to which R301 and R302 are attached, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen, N(R303) and sulfur, in which R303 is hydrogen, 1-4C-alkyl or 1-4C-alkoxycarbonyl, Het2 is a monocylic 3- to 7-membered saturated heterocyclic ring, which comprises one nitrogen atom and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen, N(R304) and sulfur, whereby said Het2 radical is attached to the parent molecular group via a ring carbon atom, in which R304 is 1-4C-alkyl, U is a bond, 1-4C-alkylene, or 1-4C-alkylene substituted with amino-1-4C-alkyl, Ar2 is phenyl, or R31- and /or R32-substituted phenyl, in which R31 is 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl, or --W--R311, in which W is a bond or 1-4C-alkylene, R311 has one of the meanings of R30 as defined above, R32 is halogen, V is a bond, Har4 is optionally substituted by R33, and is a monocyclic or fused bicyclic 5- to 10-membered unsaturated heteroaryl radical comprising one to four heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, whereby said Har4 radical is attached to the moiety V via a ring carbon atom, in which R33 is -Z-R331, in which Z is 1-4C-alkylene, R331 has one of the meanings of --N(R301)R302 as defined above, Cyc2 is a group of formula A ##STR00026## in which G is a 5- or 6-membered saturated heterocyclic ring comprising one nitrogen atom and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, whereby said Cyc2 ring system is attached to the parent molecular group via any substitutable carbon atom; R4 is hydrogen or halogen; or a salt thereof. 2. The compound of formula I according to claim 1 in which R1 is Ar1, or Har1, Har2 or Har3, or Cyc1, or Hh1, Ah1 or Ha1, in which Ar1 is optionally substituted by R11, and is phenyl, naphthyl, fluorenyl or Aa1, in which Aa1 is a bisaryl radical made up of two aryl groups, which are independently selected from the group consisting of phenyl and naphthyl, and which are linked together via a single bond, R11 is 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, halogen, hydroxyl, phenoxy, phenyl-1-4C-alkoxy, hydroxy-2-4C-alkoxy, carboxy-1-4C-alkoxy or 1-4C-alkylcarbonylamino, Har1 is optionally substituted by R12, and is an unsaturated monocyclic 5- or 6-membered heteroaryl radical comprising one to four heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulphur, in which R12 is 1-4C-alkyl, Har2 is optionally substituted by R13, and is an unsaturated fused bicyclic 9- or 10-membered heteroaryl radical comprising one to four heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulphur, in which R13 is 1-4C-alkyl, Har3 is optionally substituted by R14, and is an unsaturated fused tricyclic 13- or 14-membered heteroaryl radical comprising one to four heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulphur, in which R14 is 1-4C-alkyl, Cyc1 is a group of formula A ##STR00027## in which G is a 5- or 6-membered saturated or partially unsaturated heterocyclic ring comprising one or two heteroatoms independently selected from the group consisting of oxygen and sulfur, whereby said Cyc1 ring system is attached to the parent molecular group via any substitutable carbon atom, Hh1 is optionally substituted by R15, and is a bisheteroaryl radical made up of two heteroaryl groups, which are independently selected from the group consisting of monocyclic 5- and 6-membered heteroaryl radicals comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, and which are linked together via a single bond, in which R15 is 1-4C-alkyl, Ah1 is optionally substituted by R16, and is an arylheteroaryl radical made up of an aryl group selected from the group consisting of phenyl and naphthyl, and a heteroaryl group selected from the group consisting of monocyclic 5- and 6-membered heteroaryl radicals comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, whereby said aryl and heteroaryl groups are linked together via a single bond, in which R16 is 1-4C-alkyl, Ha1 is optionally substituted by R17, and is a heteroarylaryl radical made up of a heteroaryl group selected from the group consisting of monocyclic 5- and 6-membered heteroaryl radicals comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, and an aryl group selected from the group consisting of phenyl and naphthyl, whereby said heteroaryl and aryl groups are linked together via a single bond, in which R17 is 1-4C-alkyl, whereby each of the radicals Har1, Har2, Har3, Hh1 and Ah1 is bonded via a ring carbon atom to the pyrazolopyrimidine scaffold; R2 is hydrogen, halogen or 1-4C-alkyl; R3 is -T-R30, --U--Ar2, --V-Har4, or Cyc2, in which T is 1-4C-alkylene, R30 is --N(R301)R302, cyano, amidino, carbamoyl, guanidino, ureido, or Het2, in which R301 is hydrogen, 1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-2-4C-alkyl or 1-4C-alkoxy-2-4C-alkyl, R302 is hydrogen or 1-4C-alkyl, or R301 and R302 together and with inclusion of the nitrogen atom to which they are bonded form a radical Het1, in which Het1 is a monocylic 3- to 7-membered saturated heterocyclic ring comprising the nitrogen atom, to which R301 and R302 are attached, and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen, N(R303) and sulfur, in which R303 is hydrogen, 1-4C-alkyl or 1-4C-alkoxycarbonyl, Het2 is a monocylic 3- to 7-membered saturated heterocyclic ring, which comprises one nitrogen atom and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen, N(R304) and sulfur, whereby said Het2 radical is attached to the parent molecular group via a ring carbon atom, in which R304 is 1-4C-alkyl, U is a bond, 1-4C-alkylene, or 1-4C-alkylene substituted with amino-1-4C-alkyl, Ar2 is phenyl, or R31- and /or R32-substituted phenyl, in which R31 is 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl, or --W--R311, in which W is a bond or 1-4C-alkylene, R311 has one of the meanings of R30 as defined above, R32 is halogen, V is a bond, Har4 is optionally substituted by R33, and is a monocyclic or fused bicyclic 5- to 10-membered unsaturated heteroaryl radical comprising one to four heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, whereby said Har4 radical is attached to the moiety V via a ring carbon atom, in which R33 is -Z-R331, in which Z is 1-4C-alkylene, R331 has one of the meanings of --N(R301)R302 as defined above, Cyc2 is a group of formula A ##STR00028## in which G is a 5- or 6-membered saturated heterocyclic ring comprising one nitrogen atom and optionally one further heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, whereby said Cyc2 ring system is attached to the parent molecular group via any substitutable carbon atom; R4 is hydrogen; or a salt thereof. 3. The compound according to claim 1, which is either from formula Ib or from formula Ic, ##STR00029## and in which R1 is Ar1, or Har3, or Ah1 or Ha1, in which Ar1 is optionally substituted by R11, and is phenyl, naphthyl or Aa1, in which Aa1 is biphenyl, R11 is 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, halogen, hydroxyl, nitro, phenoxy, phenyl-1-4C-alkoxy, hydroxy-2-4C-alkoxy, carboxy-1-4C-alkoxy or 1-4C-alkylcarbonylamino, Har3 is dibenzofuranyl, Ah1 is a phenyl-pyridyl radical, Ha1 is optionally substituted by R17 on the pyrazolyl moiety, and is a pyrazolyl-phenyl radical, in which R17 is 1-4C-alkyl; R2 is hydrogen; R3 is T-R30, --U--Ar2, --V-Har4, or Cyc2, in which T is 1-4C-alkylene, R30 is --N(R301)R302, in which R301 is hydrogen, 1-4C-alkyl or hydroxy-2-4C-alkyl, R302 is hydrogen or 1-4C-alkyl, either U is a bond, Ar2 is R31-substituted phenyl, or R31- and R32-substituted phenyl, in which R31 is amidino, guanidino, Het2 or --W--R311, in which Het2 is piperidinyl or pyrrolidinyl, whereby said Het2 radical is attached to the parent molecular group via a ring carbon atom, W is a bond or 1-4C-alkylene, R311 has one of the meanings of R30 as defined above and R32 is halogen, or U is 1-4C-alkylene substituted with amino-1-4C-alkyl, Ar2 is R31- and R32-substituted phenyl, in which R31 is halogen, and R32 is halogen, V is a bond, Har4 is R33-substituted pyridyl, R33-substituted thiophenyl or R33-substituted furanyl, in which R33 is -Z-R331, in which Z is 1-4C-alkylene, R331 has one of the meanings of R30 as defined above, Cyc2 is ##STR00030## whereby the substituent --N(H)C(O)R3 is attached in the meta or para position with respect to the binding position in which the phenyl ring is bonded to the pyrazolopyrimidinyl-amino moiety; R4 is hydrogen or bromine; or a salt thereof. 4. The compound according to claim 1, which is either from formula Ib or from formula Ic ##STR00031## and in which R1 is Ar1, or Har3, or Ah1 or Ha1, in which either Ar1 is naphthalen-2-yl or 6-(R11)-naphthalen-2-yl, in which R11 is 1-2C-alkoxy, 2-methoxyethoxy, hydroxyl, benzyloxy or 2-hydroxyethoxy, or Ar1 is biphen-3-yl, biphen-4-yl, 2'-(R11)-biphen-3-yl, 3'-(R11)-biphen-3-yl, 4'-(R11)-biphen-3-yl, 2'-(R11)-biphen-4-yl, 3'-(R11)-biphen-4-yl or 4'-(R11)-biphen-4-yl, in which R11 is 1-2C-alkoxy, nitro, 1-2C-alkylcarbonylamino or halogen, or Ar1 is 3-(R11)-phenyl or 4-(R11)-phenyl, in which R11 is halogen, Har3 is dibenzofuran-4-yl, Ah1 is phenyl-pyridyl, Ha1 is 3-(pyrazol-1-yl)-phenyl, 3-(1N--H-pyrazolyl)-phenyl, 3-[1N-(1-2C-alkyl)-pyrazolyl]-phenyl, 4-(pyrazol-1-yl)-phenyl, 4-(1N--H-pyrazolyl)-phenyl or 4-[1N-(1-2C-alkyl)-pyrazolyl]-phenyl; R2 is hydrogen; R3 is -T-R30, --U--Ar2, --V-Har4, or Cyc2, in which T is 1-4C-alkylene, R30 is amino, either U is a bond, and Ar2 is 2-(R31)-phenyl, 3-(R31)-phenyl or 4-(R31)-phenyl, in which R31 is amino, or U is a bond, and Ar2 is 3-(R31)-phenyl or 4-(R31)-phenyl, in which R31 is guanidino, amidino or 1N--H-piperidinyl, or U is a bond, and Ar2 is 3-(R31)-phenyl, 4-(R31)-phenyl, R32-substituted 3-(R31)-phenyl, or R32-substituted 4-(R31)-phenyl, in which R31 is --W--R311, in which W is 1-4C-alkylene, R311 is --N(R301)R302, in which R301 is hydrogen, 1-2C-alkyl or 2-hydroxyethyl, R302 is hydrogen, and R32 is fluorine, or U is 1-4C-alkylene substituted with amino-1-4C-alkyl, and Ar2 is R31- and R32-substituted phenyl, in which R31 is chlorine, and R32 is chlorine, V is a bond, Har4 is R33-substituted pyridyl, or R33-substituted furanyl, in which R33 is -Z-R331, in which Z is 1-4C-alkylene, R331 is amino, Cyc2 is any one of the following radicals: ##STR00032## R4 is hydrogen or bromine; or a salt thereof. 5. The compound according to claim 1, which is either from formula Ib or from formula Ic ##STR00033## and in which R1 is Ar1, or Har3, or Ah1 or Ha1, in which either Ar1 is naphthalen-2-yl, or 6-(R11)-naphthalen-2-yl, in which R11 is 1-2C-alkoxy, 2-methoxyethoxy, hydroxyl, benzyloxy or 2-hydroxyethoxy, or Ar1 is biphen-3-yl, biphen-4-yl, 2'-(R11)-biphen-4-yl, 3'-(R11)-biphen-4-yl, 4'-(R11)-biphen-4-yl, 3'-(R11)-biphen-3-yl or 4'-(R11)-biphen-3-yl, in which R11 is 1-2C-alkoxy, nitro, fluorine or 1-2C-alkylcarbonylamino, or Ar1 is 3-(R11)-phenyl or 4-(R11)-phenyl, in which R11 is bromine or iodine, Har3 is dibenzofuran-4-yl, Ah1 is 6-phenyl-pyridin-3-yl, Ha1 is 4-[1N-(1-2C-alkyl)-pyrazol-4-yl]-phenyl; R2 is hydrogen; R3 is -T-R30, --U--Ar2, --V-Har4, or Cyc2, in which T is straight chain 1-4C-alkylene, R30 is amino, either U is a bond, and Ar2 is 4-(R31)-phenyl or 3-(R31)-phenyl, in which R31 is guanidino, or U is a bond, and Ar2 is 4-(R31)-phenyl, 3-(R31)-phenyl or 2-fluoro-4-(R31)-phenyl, in which R31 is --W--R311, in which W is methylene or ethylene, R311 is --N(R301)R302, in which R301 is hydrogen, methyl or 2-hydroxyethyl, R302 is hydrogen, or U is methylene substituted with amino-1-2C-alkyl, and Ar2 is 3,4-dichloro-phenyl, V is a bond, Har4 is R33-substituted pyridyl, or R33-substituted furanyl, in which R33 is -Z-R331, in which Z is methylene, R331 is amino, Cyc2 is 1,2,3,4-tetrahydroisoquinolin-6-yl or 1,2,3,4-tetrahydroisoquinolin-7-yl; R4 is hydrogen or bromine; or a salt thereof. 6. The compound according to claim 1, which is either from formula Ib or from formula Ic, ##STR00034## and in which R1 is Ar1, or Har3, or Ah1 or Ha1, in which either Ar1 is 6-(R11)-naphthalen-2-yl, in which R11 is 1-2C-alkoxy, 2-methoxyethoxy, hydroxyl, benzyloxy or 2-hydroxyethoxy, or Ar1 is biphen-3-yl, biphen-4-yl, 2'-(R11)-biphen-4-yl, 3'-(R11)-biphen-4-yl, 4'-(R11)-biphen-4-yl, 3'-(R11)-biphen-3-yl or 4'-(R11)-biphen-3-yl, in which R11 is methoxy, fluorine, acetylamino or nitro, Har3 is dibenzofuran-4-yl, Ah1 is 6-phenyl-pyridin-3-yl, Ha1 is 4-(1N-methyl-pyrazol-4-yl)-phenyl; R2 is hydrogen; R3 is --U--Ar2, --V-Har4, or Cyc2, in which either U is a bond, and Ar2 is 4-(R31)-phenyl or 3-(R31)-phenyl, in which R31 is guanidino, or U is a bond, and Ar2 is 4-(R31)-phenyl, 3-(R31)-phenyl or 2-fluoro-4-(R31)-phenyl, in which R31 is --W--R311, in which W is methylene or ethylene, R311 is --N(R301)R302, in which R301 is hydrogen or methyl, R302 is hydrogen, V is a bond, Har4 is 6-(aminomethyl)-pyridin-3-yl, 2-(aminomethyl)-pyridin-4-yl, 6-(aminomethyl)-pyridin-2-yl, 5-(aminomethyl)-pyridin-3-yl, 5-(aminomethyl)-pyridin-2-yl, or 5-(aminomethyl)-furan-2-yl, Cyc2 is 1,2,3,4-tetrahydroisoquinolin-6-yl or 1,2,3,4-tetrahydroisoquinolin-7-yl; R4 is hydrogen; or a salt thereof. 7. The compound according to claim 1, which is either from formula Ib or from formula Ic ##STR00035## and in which R1 is Ar1, or Har3, or Ah1 or Ha1, in which either Ar1 is 6-(R11)-naphthalen-2-yl, in which R11 is 1-2C-alkoxy, 2-methoxyethoxy, hydroxyl, benzyloxy or 2-hydroxyethoxy, or Ar1 is biphen-3-yl, biphen-4-yl, 2'-(R11)-biphen-4-yl, 3'-(R11)-biphen-4-yl, 4'-(R11)-biphen-4-yl, 3'-(R11)-biphen-3-yl or 4'-(R11)-biphen-3-yl, in which R11 is methoxy, fluorine, acetylamino or nitro, Har3 is dibenzofuran-4-yl, Ah1 is 6-phenyl-pyridin-3-yl, Ha1 is 4-(1N-methyl-pyrazol-4-yl)-phenyl; R2 is hydrogen; R3 is --U--Ar2, --V-Har4, or Cyc2, in which either U is a bond, and Ar2 is 4-(R31)-phenyl or 3-(R31)-phenyl, in which R31 is guanidino, or U is a bond, and Ar2 is 4-(R31)-phenyl, 3-(R31)-phenyl or 2-fluoro-4-(R31)-phenyl, in which R31 is --W--R311, in which W is methylene or ethylene, R311 is --N(R301)R302, in which R301 is hydrogen or methyl, R302 is hydrogen, V is a bond, Har4 is 6-(aminomethyl)-pyridin-3-yl, 2-(aminomethyl)-pyridin-4-yl, 6-(aminomethyl)-pyridin-2-yl, 5-(aminomethyl)-pyridin-3-yl, 5-(aminomethyl)-pyridin-2-yl, or 5-(aminomethyl)-furan-2-yl, Cyc2 is 1,2,3,4-tetrahydroisoquinolin-6-yl or 1,2,3,4-tetrahydroisoquinolin-7-yl; R4 is bromine; or a salt thereof. 8. The compound according to claim 2, which is either from formula Ib or from formula Ic ##STR00036## and in which R1 is Ar1, or Har3, or Ha1, in which either Ar1 is 6-(R11)-naphthalen-2-yl, in which R11 is 1-2C-alkoxy, 2-methoxyethoxy, hydroxyl, benzyloxy or 2-hydroxyethoxy, or Ar1 is biphen-4-yl, 3'-acetylamino-biphen-4-yl, 2'-(R11)-biphen-4-yl, 3'-(R11)-biphen-4-yl, or 4'-(R11)-biphen-4-yl, in which R11 is methoxy, or fluorine, Har3 is dibenzofuran-4-yl, Ha1 is 4-(1N-methyl-pyrazol-4-yl)-phenyl; R2 is hydrogen; R3 is --U--Ar2, --V-Har4, or Cyc2, in which either U is a bond, and Ar2 is 4-(R31)-phenyl, in which R31 is guanidino, or U is a bond, and Ar2 is 4-(R31)-phenyl, 3-(R31)-phenyl, or 2-fluoro-4-(R31)-phenyl, in which R31 is --W--R311, in which W is methylene or ethylene, R311 is --N(R301)R302, in which R301 is hydrogen or methyl, R302 is hydrogen, V is a bond, Har4 is 6-(aminomethyl)-pyridin-3-yl, 2-(aminomethyl)-pyridin-4-yl, 6-(aminomethyl)-pyridin-2-yl, 5-(aminomethyl)-pyridin-3-yl, 5-(aminomethyl)-pyridin-2-yl, or 5-(aminomethyl)-furan-2-yl, Cyc2 is 1,2,3,4-tetrahydroisoquinolin-6-yl or 1,2,3,4-tetrahydroisoquinolin-7-yl; R4 is hydrogen; or a salt thereof. 9. The compound according to claim 1, which is either from formula Ib or from formula Ic ##STR00037## and in which R1 is selected from the group consisting of Ar1, Har3, Ah1 and Ha1, in which either Ar1 is naphthalen-2-yl, or 6-(R11)-naphthalen-2-yl, in which R11 is methoxy, ethoxy, 2-methoxyethoxy, hydroxyl, benzyloxy or 2-hydroxyethoxy, or Ar1 is biphen-4-yl, biphen-3-yl, 2'-(R11)-biphen-4-yl, 3'-(R11)-biphen-4-yl, 4'-(R11)-biphen-4-yl, 3'-(R11)-biphen-3-yl or 4'-(R11)-biphen-3-yl, in which R11 is methoxy, fluorine, nitro or acetylamino, Har3 is dibenzofuran-4-yl, Ah1 is phenyl-pyridinyl, Ha1 is (1N-methyl-pyrazolyl)-phenyl; R2 is hydrogen; and R3 is selected from the group consisting of -T-R30, --U--Ar2, --V-Har4 and Cyc2, in which T is straight chain 1-4C-alkylene, R30 is amino, either U is a bond, and Ar2 is 4-(R31)-phenyl, or 3-(R31)-phenyl, in which R31 is guanidino, or U is a bond, and Ar2 is 4-(R31)-phenyl, 3-(R31)-phenyl or 2-fluoro-4-(R31)-phenyl, in which R31 is --W--R311, in which W is methylene or ethylene, R311 is --N(R301)R302, in which R301 is hydrogen, methyl or 2-hydroxyethyl, R302 is hydrogen, V is a bond, Har4 is R33-substituted pyridyl, or R33-substituted furanyl, in which R33 is -Z-R331, in which Z is methylene, R331 is amino, Cyc2 is 1,2,3,4-tetrahydroisoquinolin-6-yl or 1,2,3,4-tetrahydroisoquinolin-7-yl; or a salt thereof. 10. The compound, which is either from formula Ib or from formula Ic ##STR00038## and in which R1 is selected from the group consisting of: biphen-4-yl, biphen-3-yl, 4'-methoxy-biphen-4-yl, 3'-methoxy-biphen-4-yl, 2'-methoxy-biphen-4-yl, 4'-fluoro-biphen-4-yl, 3'-fluoro-biphen-4-yl, 2'-fluoro-biphen-4-yl, 3'-acetylamino-biphen-4-yl, 3'-nitro-biphen-4-yl, 4'-methoxy-biphen-3-yl, 3'-methoxy-biphen-3-yl, 3'-acetylamino-biphen-3-yl, 6-methoxy-naphthalen-2-yl, 6-ethoxy-naphthalen-2-yl, 6-(2-methoxyethoxy)-naphthalen-2-yl, 6-hydroxy-naphthalen-2-yl, 6-benzyloxy-naphthalen-2-yl, 6-(2-hydroxyethoxy)-naphthalen-2-yl, 4-[1N-methyl-pyrazol-4-yl]-phenyl, 6-phenyl-pyridin-3-yl, and dibenzofuran-4-yl; R2 is hydrogen; and R3 is selected from the group consisting of: 4-(aminomethyl)-phenyl, 3-(aminomethyl)-phenyl, 4-(2-aminoethyl)-phenyl, 3-aminopropyl, 2-fluoro-4-(aminomethyl)-phenyl, 4-(N-methyl-aminomethyl)-phenyl, 1,2,3,4-tetrahydroisoquinolin-6-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl-4-guanidino-phenyl, 4-[N-(2-hydroxyethyl)-aminomethyl]-phenyl, 6-(aminomethyl)-pyridin-3-yl, 2-(aminomethyl)-pyridin-4-yl, 6-(aminomethyl)-pyridin-2-yl, 5-(aminomethyl)-pyridin-3-yl, 5-(aminomethyl)-pyridin-2-yl, and 5-(aminomethyl)-furan-2-yl; or a salt thereof. 11. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds according to claim 1, or a salt thereof, together with a pharmaceutically acceptable carrier or diluent. 12. A combination comprising a first active ingredient, which is at least one compound according to claim 1, or a salt thereof, and a second active ingredient, which is at least one anti-cancer agent selected from the group consisting of chemotherapeutic anti-cancer agents and target-specific anti-cancer agents, for separate, sequential, simultaneous, concurrent or chronologically staggered use in chemotherapeutic therapy. 13. The combination according to claim 12, in which said chemotherapeutic anti-cancer agents are selected from (i) alkylating/carbamylating agents; (ii) platinum derivatives; (iii) antimitotic agents/tubulin inhibitors; (iv) topoisomerase inhibitors; (v) pyrimidine antagonists; (vi) purin antagonists; and (vii) folic acid antagonists. 14. The combination according to claim 12, in which said target-specific anti-cancer agents are selected from (i) kinase inhibitors; (ii) proteasome inhibitors; (iii) histone deacetylase inhibitors; (iv) heat shock protein 90 inhibitors; (v) vascular targeting agents (VAT); (vi) monoclonal antibodies Trastuzumab, Rituximab, Alemtuzumab, Tositumomab, Cetuxcimab and Bevacizumab, as well as mutants and conjugates of monoclonal antibodies Gemtuzumab ozogamicin or Ibritumomab tiuxetan; (vii) oligonucleotide based therapeutic Oblimersen; (viii) Toll-like receptor/TLR 9 agonists; (ix) protease inhibitors; (x) anti-estrogens hormonal therapeutics; (xi) anti-androgens hormonal therapeutics; (xii) luteinizing-hormone releasing hormone (LHRH) agents Leuprorelin, Goserelin or Triptorelin; (xiii) aromatase inhibitors; (xiv) bleomycin; (xv) retinoids; (xvi) DNA methyltransferase inhibitors; (xvii) alanosine; (xviii) cytokines; (xix) interferons; and (xx) death receptor agonists.

Details for Patent 7,745,446

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2024-09-06
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2024-09-06
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2024-09-06
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2024-09-06
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	05/07/2001		2024-09-06
Genzyme Corporation	LEMTRADA	alemtuzumab	Injection	103948	11/14/2014		2024-09-06
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	10/12/2004		2024-09-06