Back to results
US 2006/0040955 A1Published application
4-pyrimidineamine compounds and their uses as anti-proliferative agents
AssigneeRigel Pharmaceuticals, Inc.
InventorsRajinder Singh, Ankush Argade, David Carroll, Tarikere Gururaja, Taisei Kinoshita
Life of this patent
Estimating the term…
Abstract
The present disclosure provides 4-pyrimidineamine compounds having antiproliferative activity, compositions comprising the compounds and methods of using the compounds to inhibit cellular proliferation and to treat proliferative diseases such as tumorigenic cancers.
Claims24
A compound according to structural formula (I):
- including prodrugs, salts, hydrates, solvates and N- and/or S-oxides thereof, wherein:
- R2 is selected from hydroxy, lower alkoxy optionally substituted with one or more of the same or different Rd groups, C5-C14 aryloxy optionally substituted with one or more of the same or different Rd groups, a lower alkyl-, aryl- or arylalkyl-sulfonate optionally substituted with one or more of the same or different Rd groups, C5-C14 aryl optionally substituted with one or more of the same or different Rd groups, C6-C20 arylalkyl optionally substituted with one or more of the same or different Rd groups, 5-14-membered heteroaryl optionally substituted with one or more of the same or different Rd groups and 6-20 membered heteroarylalkyl optionally substituted with one or more of the same or different Rd groups;
- R4′ is a lower alkyl optionally substituted with one or more of the same or different Re groups;
- R5 is an electronegative group;
- R8 is selected from hydrogen and halo;
- R9 is selected from hydroxy, lower alkoxy optionally substituted with one or more of the same or different Re groups, trifluoromethoxy and halo, or, alternatively, R9 is taken together with R10 to form a heteroalkylene bridge of the formula —O—(CRaRa)n—O—, where n is 1, 2 or 3;
- R10 is selected from lower alkyl, lower alkoxy and halo or, alternatively, R10 is taken together with R9 to form a heteroalkylene bridge of the formula —O—(CRaRa)n—O—, where n is 1, 2 or 3;
- each Ra is, independently of the others, selected from hydrogen and lower alkyl;
- each Rc is, independently of the other, selected from hydrogen and lower alkyl, or alternatively, two Rc groups bonded to the same nitrogen atom may be taken together with that atom to form a 5 to 7-membered heterocyclic ring that may optionally include from 1 to 4 of the same or different additional heteroatoms selected from O, N and S, and which may further optionally include a lower alkyl substituent at one or more available carbon and/or nitrogen atoms;
- each Rd is, independently of the others, selected from a water-solubilizing group, hydroxy, lower alkoxy, and —C(O)Ra and —(CH2)mNRcRc, where m is 0, 1, 2 or 3;
- and
- Re is selected from —NRcRc, —C(O)ORa and —C(O)NRcRc,
- with the proviso that the compound is not N4-phenyl-2-(2-methyl-4-methoxy-pyrid-6-yl)-5-methoxy-4N-methyl-4-pyrimidineamine.
10 more elements
The compound of claim 55 in which the phenyl is di-substituted at the 3- and 4-positions.
A pharmaceutical composition comprising a 4-pyrimidinediamine compound and a pharmaceutically acceptable carrier, excipient and/or diluent, wherein said pyrimidineamine compound has the structural formula (I):
- including prodrugs, salts, hydrates, solvates and N- and/or S-oxides thereof, wherein:
- R2 is selected from hydroxy, lower alkoxy optionally substituted with one or more of the same or different Rd groups, C5-C14 aryloxy optionally substituted with one or more of the same or different Rd groups, lower alkyl-, aryl- or arylalkyl-sulfonate optionally substituted with one or more of the same or different Rd groups, halo, C5-C14 aryl optionally substituted with one or more of the same or different Rd groups, C6-C20 arylalkyl optionally substituted with one or more of the same or different Rd groups, 5-14-membered heteroaryl optionally substituted with one or more of the same or different Rd groups and 6-20 membered heteroarylalkyl optionally substituted with one or more of the same or different Rd groups;
- R4 is a lower alkyl optionally substituted with one or more of the same or different Re groups;
- R5 is an electronegative group;
- R8 is selected from hydrogen and halo;
- R9 is selected from hydroxy, lower alkoxy optionally substituted with one or more of the same or different Re groups, trifluoromethoxy and halo, or, alternatively, R9 is taken together with R10 to form a heteroalkylene bridge of the formula —O—(CRaRa)n—O—, where n is 1, 2 or 3;
- R10 is selected from lower alkyl, lower alkoxy and halo or, alternatively, R10 is taken together with R9 to form a heteroalkylene bridge of the formula —O—(CRaRa)n—O—, where n is 1, 2 or 3;
- each Ra is, independently of the others, selected from hydrogen and lower alkyl;
- each Rc is, independently of the other, selected from hydrogen and lower alkyl, or alternatively, two Rc groups bonded to the same nitrogen atom may be taken together with that atom to form a 5 to 7-membered heterocyclic ring that may optionally include from 1 to 4 of the same or different additional heteroatoms selected from O, N and S, and which may further optionally include a lower alkyl substituent at one or more available carbon and/or nitrogen atoms;
- each Rd is, independently of the others, selected from a water-solubilizing group, hydroxy, lower alkoxy, and —C(O)Ra and —(CH2)mNRcRc, where m is 0, 1, 2 or 3;
- and
- Re is selected from —NRcRc, —C(O)ORa and —C(O)NRcRc.
9 more elements
A method of inhibiting proliferation of an abnormal cell, comprising contacting the cell with an amount of a compound according to structural formula (I) effective to inhibit its proliferation:
- including prodrugs, salts, hydrates, solvates and N- and/or S-oxides thereof, wherein:
- R2 is selected from hydroxy, lower alkoxy optionally substituted with one or more of the same or different Rd groups, C5-C14 aryloxy optionally substituted with one or more of the same or different Rd groups, lower alkyl-, aryl- or arylalkyl-sulfonate optionally substituted with one or more of the same or different Rd groups, halo, C5-C14 aryl optionally substituted with one or more of the same or different Rd groups, C6-C20 arylalkyl optionally substituted with one or more of the same or different Rd groups, 5-14-membered heteroaryl optionally substituted with one or more of the same or different Rd groups and 6-20 membered heteroarylalkyl optionally substituted with one or more of the same or different Rd groups;
- R4′ is a lower alkyl optionally substituted with one or more of the same or different Re groups;
- R5 is an electronegative group;
- R8 is selected from hydrogen and halo;
- R9 is selected from hydroxy, lower alkoxy optionally substituted with one or more of the same or different Re groups, trifluoromethoxy and halo, or, alternatively, R9 is taken together with R10 to form a heteroalkylene bridge of the formula —O—(CRaRa)n—O—, where n is 1, 2 or 3;
- R10 is selected from lower alkyl, lower alkoxy and halo or, alternatively, R10 is taken together with R9 to form a heteroalkylene bridge of the formula —O—(CRaRa)n—O—, where n is 1, 2 or 3;
- each Ra is, independently of the others, selected from hydrogen and lower alkyl;
- each Rc is, independently of the other, selected from hydrogen and lower alkyl, or alternatively, two Rc groups bonded to the same nitrogen atom may be taken together with that atom to form a 5 to 7-membered heterocyclic ring that may optionally include from 1 to 4 of the same or different additional heteroatoms selected from O, N and S, and which may further optionally include a lower alkyl substituent at one or more available carbon and/or nitrogen atoms;
- each Rd is, independently of the others, selected from a water-solubilizing group, hydroxy, lower alkoxy, and —C(O)Ra and —(CH2)nNRcRc, where m is 0, 1, 2 or 3;
- and
- Re is selected from —NRcRc, —C(O)ORa and —C(O)NRcRc.
9 more elements
A method of treating a proliferative disease, comprising administering to a subject in need thereof an amount of a compound according to structural formula (I) effect to treat the proliferative disease:
- including prodrugs, salts, hydrates, solvates and N— and/or S-oxides thereof, wherein:
- R2 is selected from hydroxy, lower alkoxy optionally substituted with one or more of the same or different Rd groups, C5-C14 aryloxy optionally substituted with one or more of the same or different Rd groups, lower alkyl-, aryl- or arylalkyl-sulfonate optionally substituted with one or more of the same or different Rd groups, halo, C5-C14 aryl optionally substituted with one or more of the same or different Rd groups, C6-C20 arylalkyl optionally substituted with one or more of the same or different Rd groups, 5-14-membered heteroaryl optionally substituted with one or more of the same or different Rd groups and 6-20 membered heteroarylalkyl optionally substituted with one or more of the same or different Rd groups;
- R4′ is a lower alkyl optionally substituted with one or more of the same or different Re groups;
- R5 is an electronegative group;
- R8 is selected from hydrogen and halo;
- R9 is selected from hydroxy, lower alkoxy optionally substituted with one or more of the same or different Re groups, trifluoromethoxy and halo, or, alternatively, R9 is taken together with R10 to form a heteroalkylene bridge of the formula —O—(CRaRa)n—O—, where n is 1, 2 or 3;
- R10 is selected from lower alkyl, lower alkoxy and halo or, alternatively, R10 is taken together with R9 to form a heteroalkylene bridge of the formula —O—(CRaRa), —O—, where n is 1, 2 or 3;
- each Ra is, independently of the others, selected from hydrogen and lower alkyl;
- each Rc is, independently of the other, selected from hydrogen and lower alkyl, or alternatively, two Rc groups bonded to the same nitrogen atom may be taken together with that atom to form a 5 to 7-membered heterocyclic ring that may optionally include from 1 to 4 of the same or different additional heteroatoms selected from O, N and S, and which may further optionally include a lower alkyl substituent at one or more available carbon and/or nitrogen atoms;
- each Rd is, independently of the others, selected from a water-solubilizing group, hydroxy, lower alkoxy, and —C(O)Ra and —(CH2)mNRcRc, where m is 0, 1, 2 or 3;
- and
- Re is selected from —NRcRc, —C(O)ORa and —C(O)NRcRc.
9 more elements
Dependencies are inferred from the claim text.