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US 2019/0055277 A1Published application
Immune Modulatory Compositions
OwnerKumar Rajappaninventor
Life of this patent
Estimating the term…
Abstract
A class of phosphorus containing polycyclic compounds of general formula I, of general formula I′ or of general formula I″, wherein B1, B2, R1, R2, R1′, X1, X2, Y1, Y2, BL1, BL2, Z1, and Z2 are defined herein, that may be useful as modulators of type I interferon production, specifically as STING modulating agents, are provided. Also, provided are use of such compounds.
Claims23
A compound of formula I
- wherein, B1 and B2 are selected from a group consisting of
- Wherein, each R3, R4, R5, R8, R9, R10, R11 and R12 is selected from a group consisting of hydrogen, halogen, —NO2, —CN, R, —OR, —SR, —NHR, —N(R)2, —C(O)R, —CO2R, —C(O)C(O)R, —C(O)CH2C(O)R, —S(O)R, —S(O)2R, —C(O)N(R)2, —SO2N(R)2, —OC(O)R, —N(R)C(O)R, —N(R)C(═NR)N(R)2, —C(═NR)N(R)2, —C═NOR, —N(R)SO2N(R)2, —N(R)SO2R, —OC(O)N(R)2, and
- R6 is selected from a group consisting of NH2, NHR, OH, —OR, —SR, —N(R)2,
- R7 is selected from a group consisting of NH2, NHR, OH, OR, SH, SR, —N(R)2 when G is a C, and
- R7 is absent when G is N,
- Each R is independently selected from a group consisting of hydrogen, C1-6 aliphatic, phenyl, a 3-7 membered saturated, partially unsaturated carbocyclic ring,
- A, E and G are selected from a group consisting of N, C, CRa where Ra is independently a halogen or H,
- D is selected from a group consisting of N, CH, C—CN, C—NO2, CR, C—NH2, C—NHR, CN(R)2, CF, CI, C—CONH2, C—CONHR, C—CON(R)2, C—CSN(R)2, C—COOR, C—C(═NH)NH2, C—OH, C—OR, C—C1-4 alkylamino, C-di(C1-4 alkyl)amino, C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl);
- wherein alkyl is optionally substituted with one to three groups selected from a group consisting of halogen, amino, hydroxyl, carboxyl, or C1-3 alkoxy,
- D1 is selected from a group consisting of N, CH, C—CN, C—NO2, CR, C—NH2, C—NHR, CN(R)2, CF, CI, C—CONH2, C—CONHR, C—CON(R)2, C—CSN(R)2, C—COOR, C—C(═NH)NH2, C—OH, C—OR, C—C1-4 alkylamino, C-di(C1-4 alkyl)amino, C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl);
- wherein alkyl is optionally substituted with one to three groups independently selected from a group consisting of halogen, amino, hydroxyl, carboxyl, C1-3 alkoxy,
- J is selected from a group consisting of O, S, SO2, NH, NR,
- L is selected from a group consisting of C, N;
- wherein when L is N, R4 is absent and when L is C,
- R4 is as defined above,
- W is selected from a group consisting of O, S, NH,
- R1 and R2 are independently and optionally selected from a group consisting of hydrogen, halogen, —NO2, —CN, —OR, —SR, —NHR, —N(R)2, —C(O)R, —CO2R, —C(O)CH2C(O)R, —S(O)R, —S(O)2R, —C(O)N(R)2, —SO2N(R)2, —OC(O)R, —N(R)C(O)R, —N(R)N(R)2, —N(R)C(═NR)N(R)2, C(═NR)N(R)2, —C═NOR, —N(R)C(O)N(R)2, —N(R)SO2N(R)2, —N(R)SO2R, —OC(O)N(R)2, and optionally substituted C1-12 aliphatic or C1-4 alkoxy-C1-4 alkyl;
- R1 and R2 cannot be the same except for hydrogen,
- Either BL1 or BL2 is independently and optionally a bond connecting the two carbons attached to each of them,
- Either BL1 or BL2 are independently absent or both BL1 and BL2 may be absent such that no C—C bond exists,
- Both BL1 and BL2 cannot be a bond at the same time,
- Each R1′ is selected from a group consisting of hydrogen, halogen, N3, C(O)OH, CN, C(O)NH2, C(S)NH2, C(O)OR, R,
- X1 and X2 are selected from a group consisting of O, S, NH, NR, CH2, CHR, C(R)2, C═CH2, C═CF2,
- X3 is selected from a group consisting of O, NH, C═O, SO2, C═NH, NR,
- Y1 and Y2 are selected from a group consisting of O, S, NH, CH2, CF2 or CCl2
- Z1 and Z2 are selected from a group consisting of O−, S−, OH, SH, H, CH3, F, BH3−,
- Alternatively, Z1 and Z2 are selected from a group consisting of OL2, OCH2CH2L2, OCH2OC(O)L2, OCH2OC(O)NHL2, OCH2OC(O)N(L2)2, OCH2OC(O)OL2, OCH2OC(O)SL2, OCH2NHC(O)L2, OCH2SC(O)L2, OCH2(CH2)1-6OC(O)L2, OCH2(CH2)1-6SC(O)L2, OCH2(CH2)1-6NHC(O)L2, OCH2(CH2)1-6OC(O)OL2, OCH2(CH2)1-6SC(O)OL2, OCH2(CH2)1-6NHC(O)OL2, OCH2O(CO)C(CH3)3, OCH2O(CO)C(CH3)2CH2OL2, OCH2S(CO)C(CH3)2CH2OL2, OCH2CH2O(CO)C(CH3)3, OCH2CH2S(CO)C(CH3)3, OCH2 CH2 O(CO)C(CH3)2CH2OL2, OCH2 CH2 S(CO)C(CH3)2CH2OL2, OCH2CH2S—SCH2(CH2)0-6L2, OCH2CH2S—SCH2(CH2)0-6OL2, —O(CH2CH2O)2-20L2, —O(CH2CH2O)2-20 C(O)OL2, O(CH2CH2O)2-20 C(O)NHL2, —O(CH2CH2O)2-20 CH2CH2NHC(O)L2, —O(CH2CH2O)2-20 C(O)N(L2)2, —S(CH2CH2O)2-20L2, —S(CH2CH2O)2-20 C(O)OL2, —S(CH2CH2O)2-20 C(O)NHL2, S(CH2CH2O)2-20 C(O)N(L2)2,
- where L2 is independently selected from a group consisting of H, N3, C1-20 straight chain alkyl, a C1-20 straight chain alkenyl, C1-20 alkynyl, C3-6 cycloalkyl, C1-6 haloalkyl, a tert-butyl, a substituted tert-butyl, a glucuronide moiety, a tyrosine.
25 more elements
A compound of formula I′
- wherein:
- B1 and B2 are independently and optionally selected from a group consisting of:
- each R1 and R2 are independently and optionally selected from a group consisting of hydrogen, halogen, —NO2, —CN, —OR, —SR, —NHR, —N(R)2, —C(O)R, —CO2R, —C(O)CH2C(O)R, —S(O)R, —S(O)2R, —C(O)N(R)2, —SO2N(R)2, —OC(O)R, —N(R)C(O)R, —N(R)N(R)2, —N(R)C(═NR)N(R)2, —C(═NR)N(R)2, —C═NOR, —N(R)C(O)N(R)2, —N(R)SO2N(R)2, —N(R)SO2R, —OC(O)N(R)2, and optionally substituted with C1-12 aliphatic or C1-4 alkoxy-C1-4 alkyl,
- R1 and R2 cannot be the same except for hydrogen,
- BL2 is a bond connecting the two carbons attached to it or optionally not a bond,
- Each R1′ are independently and optionally selected from a group consisting of hydrogen, halogen, N3, C(O)OH, CN, C(O)NH2, C(S)NH2, C(O)OR, R,
- each R3, R4, R5, R8, R9, R10, R11 and R12 is independently and optionally selected from a group consisting of hydrogen, halogen, —NO2, —CN, R, —OR, —SR, —NHR, —N(R)2, —C(O)R, —CO2R, —C(O)C(O)R, —C(O)CH2C(O)R, —S(O)R, —S(O)2R, —C(O)N(R)2, —SO2N(R)2, —OC(O)R, —N(R)C(O)R, —N(R)C(═NR)N(R)2, —C(═NR)N(R)2, —C═NOR, —N(R)SO2N(R)2, —N(R)SO2R, —OC(O)N(R)2, C1-12 aliphatic, phenyl,
- R6 is independently selected from a group consisting of NH2, NHR, OH, —OR, —SR, —N(R)2,
- R7 is independently selected from a group consisting of halogen, NH2, NHR, OH, OR, SH, SR, —N(R)2 when G is a C, and R7 is absent when G is N,
- each R is independently selected from the group consisting of hydrogen, C1-6 aliphatic, phenyl,
- A, E and G are independently selected from a group consisting of N, C, CRa where Ra is independently halogen or H,
- D is independently selected from a group consisting of N, CH, C—CN, C—NO2, CR, C—NH2, C—NHR, CN(R)2, CF, CI, C—CONH2, C—CONHR, C—CON(R)2, C—CSN(R)2, C—COOR, C—C(═NH)NH2, C—OH, C—OR, C—C1-4 alkylamino, C-di(C1-4 alkyl)amino, C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl),
- D1 is independently selected from a group consisting of N, CH, C—CN, C—NO2, CR, C—NH2, C—NHR, CN(R)2, CF, CI, C—CONH2, C—CONHR, C—CON(R)2, C—CSN(R)2, C—COOR, C—C(═NH)NH2, C—OH, C—OR, C—C1-4 alkylamino, C-di(C1-4 alkyl)amino, C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), C-(imidazol-2-yl);
- wherein alkyl is optionally substituted with one to three groups independently selected from a group consisting of halogen, amino, hydroxyl, carboxyl, or C1-3 alkoxy,
- J is independently selected from a group consisting of O, S, SO2, NH, NR,
- In structure II, L is independently C or N;
- wherein when L is N, R4 is absent and when L is C, R4 is as defined above,
- W is independently selected from a group consisting of O, S, NH,
- X1 and X2 are independently selected from a group consisting of O, S, NH, NR, CH2, CHR, C(R)2, C═CH2, C═CF2,
- X3 is selected from a group consisting of O, NH, C═O, SO2, C═NH, NR,
- Y1 and Y2 are selected from a group consisting of O, S, NH, CH2, CF2, CCl2,
- Z1 and Z2 are independently selected from a group consisting of O−, S−, OH, SH, H, CH3, F, BH3−, alternatively, Z1 and Z2 are independently selected from a group consisting of OL2, OCH2CH2L2, OCH2OC(O)L2, OCH2OC(O)NHL2, OCH2OC(O)N(L2)2, OCH2OC(O)OL2, OCH2OC(O)SL2, OCH2NHC(O)L2, OCH2SC(O)L2, OCH2(CH2)1-6OC(O)L2, OCH2(CH2)1-6SC(O)L2, OCH2(CH2)1-6NHC(O)L2, OCH2(CH2)1-6OC(O)OL2, OCH2(CH2)1-6SC(O)OL2, OCH2(CH2)1-6NHC(O)OL2, OCH2O(CO)C(CH3)3, OCH2O(CO)C(CH3)2CH2OL2, OCH2S(CO)C(CH3)2CH2OL2, OCH2CH2O(CO)C(CH3)3, OCH2CH2S(CO)C(CH3)3, OCH2 CH2 O(CO)C(CH3)2CH2OL2, OCH2 CH2 S(CO)C(CH3)2CH2OL2, OCH2CH2S—SCH2(CH2)0-6L2, OCH2CH2S—SCH2(CH2)0-6OL2, —O(CH2CH2O)2-20L2, —O(CH2CH2O)2-20 C(O)OL2, O(CH2CH2O)2-20 C(O)NHL2, —O(CH2CH2O)2-20 CH2CH2NHC(O)L2, —O(CH2CH2O)2-20 C(O)N(L2)2, —S(CH2CH2O)2-20L2, —S(CH2CH2O)2-20 C(O)OL2, —S(CH2CH2O)2-20 C(O)NHL2, S(CH2CH2O)2-20 C(O)N(L2)2,
- where L2 is independently and optionally selected from a group consisting of H, N3, C1-20 straight chain alkyl, a C1-20 straight chain alkenyl, C1-20 alkynyl, C3-6 cycloalkyl, C1-6 haloalkyl, a tert-butyl, a substituted tert-butyl, a tyrosine.
20 more elements
A compound of formula I″
- wherein:
- B1 and B2 are independently and optionally selected from a group consisting of:
- each R1 and R2 are independently and optionally selected from a group consisting of hydrogen, halogen, —NO2, —CN, —OR, —SR, —NHR, —N(R)2, —C(O)R, —CO2R, —C(O)CH2C(O)R, —S(O)R, —S(O)2R, —C(O)N(R)2, —SO2N(R)2, —OC(O)R, —N(R)C(O)R, —N(R)N(R)2, —N(R)C(═NR)N(R)2, —C(═NR)N(R)2, —C═NOR, —N(R)C(O)N(R)2, —N(R)SO2N(R)2, —N(R)SO2R, —OC(O)N(R)2, optionally substituted C1-12 aliphatic, C1-4 alkoxy-C1-4 alkyl,
- R1 and R2 cannot be the same except for hydrogen,
- BL2 is a bond connecting the two carbons attached to it or optionally not a bond,
- Each R1′ are independently and optionally selected from a group consisting of hydrogen, halogen, N3, C(O)OH, CN, C(O)NH2, C(S)NH2, C(O)OR, R,
- Each R3, R4, R5, R8, R9, R10, R11 and R12 is independently and optionally selected from a group consisting of hydrogen, halogen, —NO2, —CN, R, —OR, —SR, —NHR, —N(R)2, —C(O)R, —CO2R, —C(O)C(O)R, —C(O)CH2C(O)R, —S(O)R, —S(O)2R, —C(O)N(R)2, —SO2N(R)2, —OC(O)R, —N(R)C(O)R, —N(R)C(═NR)N(R)2, —C(═NR)N(R)2, —C═NOR, —N(R)SO2N(R)2, —N(R)SO2R, —OC(O)N(R)2, C1-12 aliphatic, phenyl,
- R6 is selected from a group consisting of NH2, NHR, OH, —OR, —SR, —N(R)2,
- R7 is selected from a group consisting of halogen, NH2, NHR, OH, OR, SH, SR, —N(R)2 when G is a C, and R7 is absent when G is N,
- each R is independently selected from a group consisting of hydrogen, an optionally substituted group selected from C1-6 aliphatic, phenyl,
- A, E and G are independently selected from a group consisting of N, C, CRa where Ra is independently halogen or H,
- D is selected from a group consisting of N, CH, C—CN, C—NO2, CR, C—NH2, C—NHR, CN(R)2, CF, CI, C—CONH2, C—CONHR, C—CON(R)2, C—CSN(R)2, C—COOR, C—C(═NH)NH2, C—OH, C—OR, C—C1-4 alkylamino, C-di(C1-4 alkyl)amino, C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), C-(imidazol-2-yl);
- wherein alkyl is optionally substituted with one to three groups selected from a group consisting of halogen, amino, hydroxyl, carboxyl, C1-3 alkoxy,
- D1 is selected from a group consisting of N, CH, C—CN, C—NO2, CR, C—NH2, C—NHR, CN(R)2, CF, CI, C—CONH2, C—CONHR, C—CON(R)2, C—CSN(R)2, C—COOR, C—C(═NH)NH2, C—OH, C—OR, C—C1-4 alkylamino, C-di(C1-4 alkyl)amino, C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl);
- wherein alkyl is optionally substituted with one to three groups selected from a group consisting of halogen, amino, hydroxyl, carboxyl, C1-3 alkoxy,
- J is selected from a group consisting of O, S, SO2, NH or NR,
- in structure II, L is selected from a group consisting of C, N;
- wherein when L is N, R4 is absent and when L is C, R4 is as defined above,
- W is selected from a group consisting of O, S or NH,
- X1 and X2 are selected from a group consisting of O, S, NH, NR, CH2, CHR, C(R)2, C═CH2, or C═CF2,
- X3 is selected from a group consisting of O, NH, C═O, SO2, C═NH, NR
- Y1 and Y2 are selected from a group consisting of O, S, NH, CH2, CF2, CCl2,
- Z1 and Z2 are selected from a group consisting of O−, S−, OH, SH, H, CH3, F, BH3−,
- Alternatively, Z1 and Z2 are selected from a group consisting of OL2, OCH2CH2L2, OCH2OC(O)L2, OCH2OC(O)NHL2, OCH2OC(O)N(L2)2, OCH2OC(O)OL2, OCH2OC(O)SL2, OCH2NHC(O)L2, OCH2SC(O)L2, OCH2(CH2)1-6OC(O)L2, OCH2(CH2)1-6SC(O)L2, OCH2(CH2)1-6NHC(O)L2, OCH2(CH2)1-6OC(O)OL2, OCH2(CH2)1-6SC(O)OL2, OCH2(CH2)1-6NHC(O)OL2, OCH2O(CO)C(CH3)3, OCH2O(CO)C(CH3)2CH2OL2, OCH2S(CO)C(CH3)2CH2OL2, OCH2CH2O(CO)C(CH3)3, OCH2CH2S(CO)C(CH3)3, OCH2 CH2 O(CO)C(CH3)2CH2OL2, OCH2 CH2 S(CO)C(CH3)2CH2OL2, OCH2CH2S—SCH2(CH2)0-6L2, OCH2CH2S—SCH2(CH2)0-6OL2, —O(CH2CH2O)2-20L2, —O(CH2CH2O)2-20 C(O)OL2, O(CH2CH2O)2-20 C(O)NHL2, —O(CH2CH2O)2-20 CH2CH2NHC(O)L2, —O(CH2CH2O)2-20 C(O)N(L2)2, —S(CH2CH2O)2-20L2, —S(CH2CH2O)2-20 C(O)OL2, —S(CH2CH2O)2-20 C(O)NHL2, S(CH2CH2O)2-20 C(O)N(L2)2,
- where L2 is selected from a group consisting of H, N3, C1-20 straight chain alkyl, a C1-20 straight chain alkenyl, C1-20 alkynyl, C3-6 cycloalkyl, C1-6 haloalkyl, a tert-butyl, a substituted tert-butyl, a tyrosine.
22 more elements
Dependencies are inferred from the claim text.