Claims
- 1. A compound of formula I whereinX is CO or SO2; R1 and R2 are each independently H, C1-C10alkyl optionally substituted with one or more halogen, hydroxy, C1-C4alkoxy, CO2R8, CONR9R10, C3-C7cycloalkyl or optionally substituted phenyl groups, or phenyl optionally substituted with one to three halogen, hydroxy, C1-C6haloalkyl, C1-C4alkoxy, CO2R11, NR12R13 or CN groups; R3 is H, F, Cl, Br or I; R4 and R5 are each independently H, NH2, CH2CH2OCH2CH2OCH2CH2NH2 or a C1-C6alkyl group optionally substituted with one or two CN, OR14, NR15R16, CO2R17 or C3-C7cycloalkyl group, phenyl optionally substituted with one or two halogen, CN, OR14, NR15R16, CO2R17, COR18, an optionally substituted C1-C6alkyl or an optionally substituted C2-C6alkenyl group, benzyl optionally substituted with one or two halogen, OR14, COR18, or a C1-C3alkyl group optionally substituted with one OR14 group, or pyridinyl optionally substituted with one or two halogen, OR14, NR15R16 or CO2R17 groups, or R4 and R5 may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one double bond, a benzofused ring or an additional heteroatom selected from O, NR19 or S; R6 is phenyl optionally substituted with one to three halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6alkylthio, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SOnR20, SO2NR21R22, CO2R23 or NR24R25 groups, cycloheteroalkyl optionally substituted with one or more halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6alkylthio, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SOnR20, SO2NR21,R22, CO2R23 or NR24R25 groups, or heteroaryl optionally substituted with one or more halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6alkylthio, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SOnR20, SO2NR21R22, CO2R23 or NR24R25 groups; R8, R11, R17, R18 and R23 are each independently H or a C1-C6alkyl, C3-C7 cycloalkyl, C1-C6haloalkyl, phenyl, C5-C7cycloheteroalkyl or heteroaryl group each optionally substituted; R9, R10, R12, R13, R15, R16, R21, R22, R24 and R25 are each independently H or a C1-C6alkyl, C3-C7cycloalkyl, C1-C6haloalkyl, phenyl, C5-C7cycloheteroalkyl or heteroaryl group each optionally substituted or each of R9 and R10 or R12 and R13 or R15 and R16 or R21 and R22 or R24 and R25 may be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing another heteroatom selected from O, N or S; n is 0 or an integer of 1 or 2; R14 is H, C1-C3alkyl or C1-C3haloalkyl; R19 is H or C1-C3alkyl; and R20 is a C1-C6alkyl, C3-C7cycloalkyl, C1-C6haloalkyl, phenyl, C5-C7cycloheteroalkyl or heteroaryl group each optionally substituted; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
- 2. The compound according to claim 1 wherein X is CO.
- 3. The compound according to claim 1 wherein R1 is H.
- 4. The compound according to claim 1 wherein R1 is H, the compound according to claim 1 wherein R6 is a phenyl group optionally substituted with one or two CN, NO2, halogen, CF3, C1-C3alkoxy or CO2R23 groups.
- 5. The compound according to claim 2 wherein R2 is H or C1-C3alkyl.
- 6. The compound according to claim 2 wherein R4 and R5 are each independently H or a C1-C3alkyl, phenyl or benzyl group each optionally substituted with one or two hydroxy groups or R4 and R5 may be taken together with the atom to which they are attached to form a pyrrolidinyl or morpholinyl ring each optionally substituted with one carboxy group.
- 7. The compound according to claim 5 wherein R6 is phenyl optionally substituted in the 3-position with CF3.
- 8. The compound according to claim 7 wherein R1 is H.
- 9. The compound according to claim 7 wherein R1 is H, the compound according to claim 1 selected from the group consisting of:N-(4-hydroxyphenyl)-3-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide; N-(2,2-dimethoxyethyl)-N-methyl-3-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide; 6-methyl-2-[3-(1-pyrrolidinylcarbonyl)phenyl]-4-[3-(trifluoromethyl)phenyl]-1,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-3(2H)-one; (2R)-1-[3-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]-pyridin-2(1H)-yl)benzoyl]-2-pyrrolidinecarboxylic acid; N-(3,4-dihydroxybenzyl)-3-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide; N-(2-hydroxypropyl)-3-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide; 1-{2-chloro-5-[6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3′,4′-d]pyridin-2(1H)-yl]benzoyl}-D-proline; 2-(4-chloro-3-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]carbonyl}phenyl)-6-methyl-4-[3(trifluoromethyl)phenyl]-1,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-3(2H)-one; N-(4-hydroxyphenyl-4-{6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3′,4′-d]pyridin-2(1H)-yl}benzamide; N-(2-hydroxyphenyl)-4-{6-methyl-3-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3′,4′-d]pyridin-2(1H)-yl}benzamide; 6-methyl-2-[4-(4-morpholinylcarbonyl)phenyl]-4-[3-(trifluoromethyl)phenyl]-1,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-3(2H)-one; N-[4-(2-hydroxyethyl)phenyl]-4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide; N-[3-(1-hydroxyethyl)phenyl]-4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide; N-[3-(hydroxymethyl)pheny]-4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide; N-(5-hydroxypentyl)-4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzenesulfonamide; N-benzyl-4-[6-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,6-dihydro-1H-1,2,5,6,7-pentaaza-as-indacen-2-yl]-benzenesulfonamide; N-(2-hydroxyethyl)-4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzenesulfonamide; methyl ({[4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)pheny]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)phenyl]sulfonyl}amino)acetate; N-cyclopropylmethyl-4-[6-methyl-3-oxo-4-(3-trfluoromethyl-phenyl)-3,6-dihydro-1H-1,2,5,6,7-pentaaza-as-indacen-2-yl]-benzenesulfonamide; ({[4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)phenyl]sulfonyl}amino)acetic acid; the stereoisomers thereof; andthe pharmaceutically acceptable salts thereof.
- 10. A method for the treatment of an immune disorder related to or affected by the immune regulatory protein B7-1 which comprises providing a patient in need thereof an immunotherapeutically effective amount of a compound of formula I whereinX is CO or SO2; R1 and R2 are each independently H, C1-C10alkyl optionally substituted with one or more halogen, hydroxy, C1-C4alkoxy, CO2R8, CONR9R10, C3-C7cycloalkyl or optionally substituted phenyl groups, or phenyl optionally substituted with one to three halogen, hydroxy, C1-C6haloalkyl, C1-C4alkoxy, CO2R11, NR12R13 or CN groups; R3 is H, F, Cl, Br or I; R4 and R5 are each independently H, NH2, CH2CH2OCH2CH2OCH2CH2NH2 or a C1-C6alkyl group optionally substituted with one or two CN, OR14, NR15R16, CO2R17 or C3-C7cycloalkyl group, phenyl optionally substituted with one or two halogen, CN, OR14, NR15R16, CO2R17, COR18, an optionally substituted C1-C6alkyl or an optionally substituted C2-C6alkenyl group, benzyl optionally substituted with one or two halogen, OR14, COR18, or a C1-C3alkyl group optionally substituted with one OR14 group, or pyridinyl optionally substituted with one or two halogen, OR14, NR15R16 or CO2R17 groups, or R4 and R5 may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one double bond, a benzofused ring or an additional heteroatom selected from O, NR19 or S; R6 is phenyl optionally substituted with one to three halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6alkylthio, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SOnR20, SO2NR21R22, CO2R23 or NR24R25 groups, cycloheteroalkyl optionally substituted with one or more halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6alkylthio, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SOnR20, SO2NR21,R22, CO2R23 or NR24R25 groups, or heteroaryl optionally substituted with one or more halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6alkylthio, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SOnR20, SO2NR21R22, CO2R23 or NR24R25 groups; R8, R11, R17, R18 and R23 are each independently H or a C1-C6alkyl, C3-C7 cycloalkyl, C1-C6haloalkyl, phenyl, C5-C7cycloheteroalkyl or heteroaryl group each optionally substituted; R9, R10, R12, R13, R15, R16, R21, R22, R24 and R25 are each independently H or a C1-C6alkyl, C3-C7cycloalkyl, C1-C6haloalkyl, phenyl, C5-C7cycloheteroalkyl or heteroaryl group each optionally substituted or each of R9 and R10 or R12 and R13 or R15 and R16 or R21 and R22 or R24 and R25 may be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing another heteroatom selected from O, N or S; n is 0 or an integer of 1 or 2; R14 is H, C1-C3alkyl or C1-C3haloalkyl; R19 is H or C1-C3alkyl; and R20 is a C1-C6alkyl, C3-C7cycloalkyl, C1-C6haloalkyl, phenyl, C5-C7cycloheteroalkyl or heteroaryl group each optionally substituted; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
- 11. The method according to claim 10 wherein said disorder is transplant rejection.
- 12. The method according to claim 10 wherein said disorder is an autoimmune disease.
- 13. The method according to claim 10 wherein said disorder is graft vs. host disease.
- 14. The method according to claim 12 wherein said disease is multiple sclerosis or rheumatoid arthritis.
- 15. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I whereinX is CO or SO2; R1 and R2 are each independently H, C1-C10alkyl optionally substituted with one or more halogen, hydroxy, C1-C4alkoxy, CO2R8, CONR9R10, C3-C7cycloalkyl or optionally substituted phenyl groups, or phenyl optionally substituted with one to three halogen, hydroxy, C1-C6haloalkyl, C1-C4alkoxy, CO2R11, NR12R13 or CN groups; R3 is H, F, Cl, Br or I; R4 and R5 are each independently H, NH2, CH2CH2OCH2CH2OCH2CH2NH2 or a C1-C6alkyl group optionally substituted with one or two CN, OR14, NR15R16, CO2R17 or C3-C7cycloalkyl group, phenyl optionally substituted with one or two halogen, CN, OR14, NR15R16, CO2R17, COR18, an optionally substituted C1-C6alkyl or an optionally substituted C2-C6alkenyl group, benzyl optionally substituted with one or two halogen, OR14, COR18, or a C1-C3alkyl group optionally substituted with one OR14 group, or pyridinyl optionally substituted with one or two halogen, OR14, NR15R18 or CO2R17 groups, or R4 and R5 may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one double bond, a benzofused ring or an additional heteroatom selected from O, NR19 or S; R6 is phenyl optionally substituted with one to three halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6alkylthio, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SOnR20, SO2NR21R22, CO2R23 or NR24R25 groups, cycloheteroalkyl optionally substituted with one or more halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6alkylthio, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SOnR20, SO2NR21,R22, CO2R23 or NR24R25 groups, or heteroaryl optionally substituted with one or more halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6alkylthio, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SOnR20, SO2NR21R22, CO2R23 or NR24R25 groups; R8, R11, R17, R18 and R23 are each independently H or a C1-C6alkyl, C3-C7 cycloalkyl, C1-C6haloalkyl, phenyl, C5-C7cycloheteroalkyl or heteroaryl group each optionally substituted; R9, R10, R12, R13, R15, R16, R21, R22, R24 and R25 are each independently H or a C1-C6alkyl, C3-C7cycloalkyl, C1-C6haloalkyl, phenyl, C5-C7cycloheteroalkyl or heteroaryl group each optionally substituted or each of R9 and R10 or R12 and R13 or R15 and R16 or R21 and R22 or R24 and R25 may be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing another heteroatom selected from O, N or S; n is 0 or an integer of 1 or 2; R14 is H, C1-C3alkyl or C1-C3haloalkyl; R19 is H or C1-C3alkyl; and R20 is a C1-C6alkyl, C3-C7cycloalkyl, C1-C6haloalkyl, phenyl, C5-C7cycloheteroalkyl or heteroaryl group each optionally substituted; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
- 16. The composition according to claim 15 having a formula I compound wherein X is CO.
- 17. The composition according to claim 16 having a formula I compound wherein R1 is H.
- 18. The composition according to claim 17 having a formula I compound wherein R2 is H or CH3.
- 19. The composition according to claim 18 having a formula I compound wherein R6 is phenyl optionally substituted in the 3-position with CF3.
- 20. A process for the preparation of a compound of formula Ia whereinR1 and R2 are each independently H, C1-C10alkyl optionally substituted with one or more halogen, hydroxy, C1-C4alkoxy, CO2R8, CONR9R10, C3-C7cycloalkyl or optionally substituted phenyl groups, or phenyl optionally substituted with one to three halogen, hydroxy, C1-C6haloalkyl, C1-C4alkoxy, CO2R11, NR12R13 or CN groups; R3 is H, F, Cl, Br or I; R4 and R5 are each independently H, NH2, CH2CH2OCH2CH2OCH2CH2NH2 or a C1-C6alkyl group optionally substituted with one or two CN, OR14, NR15R16, CO2R17 or C3-C7cycloalkyl group, phenyl optionally substituted with one or two halogen, CN, OR14, NR15R16, CO2R17, COR18, an optionally substituted C1-C6alkyl or an optionally substituted C2-C6alkenyl group, benzyl optionally substituted with one or two halogen, OR14, COR18, or a C1-C3alkyl group optionally substituted with one OR14 group, or pyridinyl optionally substituted with one or two halogen, OR14, NR15R16 or CO2R17 groups, or R4 and R5 may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one double bond, a benzofused ring or an additional heteroatom selected from O, NR19 or S; R6 is phenyl optionally substituted with one to three halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6alkylthio, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SOnR20, SO2NR21R22, CO2R23 or NR24R25 groups, cycloheteroalkyl optionally substituted with one or more halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6alkylthio, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SOnR20, SO2NR21,R22, CO2R23 or NR24R25 groups, or heteroaryl optionally substituted with one or more halogen, NO2, CN, hydroxy, C1-C6alkyl, C1-C6alkylthio, C1-C6haloalkyl, C1-C6alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SOnR20, SO2NR21R22, CO2R23 or NR24R25 groups; R8, R11, R17, R18 and R23 are each independently H or a C1-C6alkyl, C3-C7 cycloalkyl, C1-C6haloalkyl, phenyl, C5-C7cycloheteroalkyl or heteroaryl group each optionally substituted; R9, R10, R12, R13, R15, R16, R21, R22, R24 and R25 are each independently H or a C1-C6alkyl, C3-C7cycloalkyl, C1-C6haloalkyl, phenyl, C5-C7cycloheteroalkyl or heteroaryl group each optionally substituted or each of R9 and R10 or R12 and R13 or R15 and R16 or R21 and R22 or R24 and R25 may be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing another heteroatom selected from O, N or S; n is 0 or an integer of 1 or 2; R14 is H, C1-C3alkyl or C1-C3haloalkyl; R19 is H or C1-C3alkyl; and R20 is a C1-C6alkyl, C3-C7cycloalkyl, C1-C6haloalkyl, phenyl, C5-C7cycloheteroalkyl or heteroaryl group each optionally substituted which process comprises reacting a compound of formula II wherein R1, R2, R3 and R6 are defined hereinabove with an amine, HNR4R5, in the presence of an activating agent and a solvent.
Parent Case Info
This application claims priority from copending provisional application Ser. No. 60/399,146, filed Jul. 29, 2002, the entire disclosure of which is hereby incorporated by reference.
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Provisional Applications (1)
|
Number |
Date |
Country |
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60/399146 |
Jul 2002 |
US |