1. A compound of formula I or Ia:
wherein:
represents the presence of a single bond or double bond;
R1, R2, R3, R6, R7, R8, and R11 are each independently H or C1-10alkyl;
R4 and R9 are each independently H or acid labile protecting group;
R5 is C2-6monoalkenyl or C4-6alkadienyl;
R10 is H, C(\u2550O)NR13R14, or oxidatively labile hydroxyl protecting group;
Q is \u2014O\u2014;
Z is \u2014CH\u2014 or \u2014CH2\u2014, provided that when represents a double bond, then Z is \u2014CH\u2014;
R12 is H, alkyl, or acid labile amino protecting group;
R13 and R14 are each independently H, C1-10alkyl, C2-6alkenyl, C2-6alkynyl, ORc, C(\u2550O)Rb, S(O)pRb, (CH2)rC3-12carbocycle, or (CH2)rheterocycle having 5 to 12 ring atoms; or R13 and R14 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle containing 0-3 additional heteroatoms selected from O, S, and N;
Rb and Rc are each independently H, C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, or (CH2)rphenyl;
p is 1 or 2; and
each r is independently 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt thereof.
2. The compound or its pharmaceutically acceptable salt of claim 1 having formula I.
3. The compound or its pharmaceutically acceptable salt of claim 2, wherein R1, R2, R3, R6, R7, R8, and R11 are each independently H or C1-3alkyl.
4. The compound or its pharmaceutically acceptable salt of claim 2, wherein R1, R2, R3, R6, R7, R8, and R11 are each independently H or methyl.
5. The compound or its pharmaceutically acceptable salt of claim 2, wherein at least one of R4 and R9 is H.
6. The compound or its pharmaceutically acceptable salt of claim 5, wherein R4 and R9 are each H.
7. The compound or its pharmaceutically acceptable salt of claim 2, wherein R5 is C2-4-monoalkenyl or 1,3-butadien-1-yl.
8. The compound or its pharmaceutically acceptable salt of claim 2, wherein R5 is
9. The compound or its pharmaceutically acceptable salt of claim 2, wherein R10 is \u2014C(\u2550O)NR13R14 or oxidatively labile hydroxyl protecting group.
10. The compound or its pharmaceutically acceptable salt of claim 2 or, wherein R10 is \u2014C(\u2550O)NR13R14.
11. The compound or its pharmaceutically acceptable salt of claim 1, wherein represents the presence of a carbon-carbon double bond.
12. The compound or its pharmaceutically acceptable salt of claim 10, wherein at least one of R13 and R14 is H.
13. The compound or its pharmaceutically acceptable salt of claim 10, wherein R13 and R14 are each H.
14. The compound or its pharmaceutically acceptable salt of claim 4, wherein R4 and R9 are each H.
15. The compound or its pharmaceutically acceptable salt of claim 1, having the structure:
16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
17. A method for stabilizing microtubules, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to claim 15 or a pharmaceutically acceptable salt thereof.
19. A method for stabilizing microtubules, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 15 or a pharmaceutically acceptable salt thereof.
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 of inhibiting the activity of a serine protease comprising the step of contacting said serine protease with a compound of formula (I)
or a pharmaceutically acceptable salt thereof wherein:
Each A is \u2014(CX1X2)a\u2014;
Each B is \u2014(CX1X2)b\u2014;
Each X1 is independently hydrogen, halo, amino, sulfanyl, optionally substituted (C1-4)-aliphatic, optionally substituted aryl, or \u2014O\u2014X1A;
Each X2 is independently hydrogen, halo, amino, sulfanyl, optionally substituted (C1-4)-aliphatic, optionally substituted aryl, or \u2014O\u2014X1B;
X1A and X1B are each independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
Or, X1 and X2 together form an oxo group;
Each R1 is
wherein T is a bond, \u2014C(O)\u2014, \u2014OC(O)\u2014, \u2014NHC(O)\u2014, \u2014S(O)2N(H)\u2014, \u2014C(O)C(O)\u2014 or \u2014SO2\u2014; each R is independently hydrogen, amino, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; each R8 and R\u20328 is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; and each R9 is independently hydrogen, an optionally substituted aliphatic, an optionally substituted heteroaryl, an optionally substituted phenyl, or R8 and R9, bound on adjacent atoms, taken together with the atoms to which they are attached form a 5 to 7 membered, optionally substituted monocyclic heterocycloaliphatic, or a 6 to 12 membered, optionally substituted bicyclic heterocycloaliphatic; or R8 and R\u20328, taken together with the atoms to which they are attached form an optionally substituted cycloaliphatic or an optionally substituted heterocycloaliphatic;
Each R2 is \u2014ZBR5, wherein each ZB is independently a bond or an optionally substituted branched or straight C1-12 aliphatic chain wherein up to three carbon units of ZB are optionally and independently replaced by \u2014C(O)\u2014, \u2014C(S)\u2014, \u2014C(O)NRB\u2014, \u2014C(O)NRBNRB\u2014, \u2014C(O)O\u2014, \u2014NRBC(O)O\u2014, \u2014NRBC(O)NRB\u2014, \u2014NRBNRB\u2014, \u2014S\u2014, \u2014SO\u2014, \u2014SO2\u2014, \u2014NRB\u2014, \u2014SO2NRB\u2014, or \u2014NRBSO2NRB\u2014, provided that SO, SO2, or \u2014SO2NRB\u2014 is not directly bound to the carbonyl of formula I;
Each R5 is independently RB, halo, \u2014OH, \u2014CN, \u2014NO2, \u2014NH2, or \u2014OCF3;
Each RB is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
Or R1 and R2, together with the atoms to which they are attached, form an optionally substituted heterocycloaliphatic ring;
Each R3 is an optionally substituted aliphatic, amino, sulfonyl, sulfanyl, sulfinyl, sulfonamide, sulfamide, sulfo, \u2014O\u2014R3A, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
Each R3A is independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
Each Y and Y\u2032 is independently \u2014ZDR7, wherein each ZD is independently a bond or an optionally substituted straight or branched C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by \u2014C(O)\u2014, \u2014C(S)\u2014, \u2014C(O)NRD\u2014, \u2014C(O)NRDNRD\u2014, \u2014C(O)O\u2014, \u2014NRDC(O)O\u2014, \u2014O\u2014, \u2014NRDC(O)NRD\u2014, \u2014NRDNRD\u2014, \u2014S\u2014, \u2014SO\u2014, \u2014SO2\u2014, \u2014NRD\u2014, \u2014SO2NRD\u2014, \u2014NRDSO2\u2014, or \u2014NRDSO2NRD\u2014, or Y and Y\u2032 together form \u2550O or \u2550S;
Each R7 is independently RD, halo, \u2014OH, \u2014CN, \u2014NO2, \u2014NH2, or \u2014OCF3;
Each RD is independently hydrogen, or optionally substituted aryl; and
Each of a and b is independently 0, 1, 2, or 3; provided that the sum of a and b is 2 or 3.
2. A method of inhibiting the activity of a serine protease comprising the step of contacting said serine protease with a compound selected from the group of compounds:
3. The method according to claim 1, wherein said serine protease is an HCV NS3 protease.
4. The method according to claim 2, wherein said serine protease is an HCV NS3 protease.
5. A method of treating an HCV infection in a patient comprising the step of administering to said patient a compound of formula (I)
or a pharmaceutically acceptable salt thereof wherein:
Each A is \u2014(CX1X2)a\u2014;
Each B is \u2014(CX1X2)b\u2014;
Each X1 is independently hydrogen, halo, amino, sulfanyl, optionally substituted (C1-4)-aliphatic, optionally substituted aryl, or \u2014O\u2014X1A;
Each X2 is independently hydrogen, halo, amino, sulfanyl, optionally substituted (C1-4)-aliphatic, optionally substituted aryl, or \u2014O\u2014X1B;
X1A and X1B are each independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
Or, X1 and X2 together form an oxo group;
Each R1 is
wherein T is a bond, \u2014C(O)\u2014, \u2014OC(O)\u2014, \u2014NHC(O)\u2014, \u2014S(O)2N(H)\u2014, \u2014C(O)C(O)\u2014 or \u2014SO2\u2014; each R is independently hydrogen, amino, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; each R8 and R\u20328 is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; and each R9 is independently hydrogen, an optionally substituted aliphatic, an optionally substituted heteroaryl, an optionally substituted phenyl, or R8 and R9, bound on adjacent atoms, taken together with the atoms to which they are attached form a 5 to 7 membered, optionally substituted monocyclic heterocycloaliphatic, or a 6 to 12 membered, optionally substituted bicyclic heterocycloaliphatic; or R8 and R\u20328, taken together with the atoms to which they are attached form an optionally substituted cycloaliphatic or an optionally substituted heterocycloaliphatic;
Each R2 is \u2014ZBR5, wherein each ZB is independently a bond or an optionally substituted branched or straight C1-12 aliphatic chain wherein up to three carbon units of ZB are optionally and independently replaced by \u2014C(O)\u2014, \u2014C(S)\u2014, \u2014C(O)NRB\u2014, \u2014C(O)NRBNRB\u2014, \u2014C(O)O\u2014, \u2014NRBC(O)O\u2014, \u2014NRBC(O)NRB\u2014, \u2014NRBNRB\u2014, \u2014S\u2014, \u2014SO\u2014, \u2014SO2\u2014, \u2014NRB\u2014, \u2014SO2NRB\u2014, or \u2014NRBSO2NRB\u2014, provided that SO, SO2, or \u2014SO2NRB\u2014 is not directly bound to the carbonyl of formula I;
Each R5 is independently RB, halo, \u2014OH, \u2014CN, \u2014NO2, \u2014NH2, or \u2014OCF3;
Each RB is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
Or R1 and R2, together with the atoms to which they are attached, form an optionally substituted heterocycloaliphatic ring;
Each R3 is an optionally substituted aliphatic, amino, sulfonyl, sulfanyl, sulfinyl, sulfonamide, sulfamide, sulfa, \u2014O\u2014R3A, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
Each R3A is independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
Each Y and Y\u2032 is independently \u2014ZDR7, wherein each ZD is independently a bond or an optionally substituted straight or branched C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by \u2014C(O)\u2014, \u2014C(S)\u2014, \u2014C(O)NRD\u2014, \u2014C(O)NRDNRD\u2014, \u2014C(O)O\u2014, \u2014NRDC(O)O\u2014, \u2014O\u2014, \u2014NRDC(O)NRD\u2014, \u2014NRDNRD\u2014, \u2014S\u2014, \u2014SO\u2014, \u2014SO2\u2014, \u2014NRD\u2014, \u2014SO2NRD\u2014, \u2014NRDSO2\u2014, or \u2014NRDSO2NRD\u2014, or Y and Y\u2032 together form \u2550O or \u2550S;
Each R7 is independently RD, halo, \u2014OH, \u2014CN, \u2014NO2, \u2014NH2, or \u2014OCF3;
Each RD is independently hydrogen, or optionally substituted aryl; and
Each of a and b is independently 0, 1, 2, or 3; provided that the sum of a and b is 2 or 3.
6. A method of treating an HCV infection in a patient comprising the step of administering to said patient a compound selected from the group of compounds:
7. The method according to claim 5, further comprising administering to said patient an agent selected from an immunomodulatory agent; an antiviral agent; an inhibitor of HCV protease; an inhibitor of another target in the HCV life cycle; or combinations thereof; wherein said agent is administered to said patient in the same dosage form as the serine protease inhibitor or as a separate dosage form.
8. The method according to claim 6, further comprising administering to said patient an agent selected from an immunomodulatory agent; an antiviral agent; an inhibitor of HCV protease; an inhibitor of another target in the HCV life cycle; or combinations thereof; wherein said agent is administered to said patient in the same dosage form as the serine protease inhibitor or as a separate dosage form.
9. The method according to claim 7, wherein said immunomodulatory agent is \u03b1-, \u03b2-, or \u03b3-interferon or thymosin; said antiviral agent is ribavarin or amantadine; or said inhibitor of another target in the HCV life cycle is an inhibitor of HCV helicase, polymerase, or metalloprotease.
10. The method according to claim 8, wherein said immunomodulatory agent is \u03b1-, \u03b2-, or \u03b3-interferon or thymosin; said antiviral agent is ribavarin or amantadine; or said inhibitor of another target in the HCV life cycle is an inhibitor of HCV helicase, polymerase, or metalloprotease.
11. A method of eliminating or reducing HCV contamination of a biological sample or medical or laboratory equipment, comprising the step of contacting said biological sample or medical or laboratory equipment with a compound of formula (I)
or a pharmaceutically acceptable salt thereof wherein:
Each A is \u2014(CX1X2)a\u2014;
Each B is \u2014(CX1X2)b\u2014;
Each X1 is independently hydrogen, halo, amino, sulfanyl, optionally substituted (C1-4)-aliphatic, optionally substituted aryl, or \u2014O\u2014X1A;
Each X2 is independently hydrogen, halo, amino, sulfanyl, optionally substituted (C1-4)-aliphatic, optionally substituted aryl, or \u2014O\u2014X1B;
X1A and X1B are each independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
Or, X1 and X2 together form an oxo group;
Each R1 is
wherein T is a bond, \u2014C(O)\u2014, \u2014OC(O)\u2014, \u2014NHC(O)\u2014, \u2014S(O)2N(H)\u2014, \u2014C(O)C(O)\u2014 or \u2014SO2\u2014; each R is independently hydrogen, amino, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; each R8 and R\u20328 is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; and each R9 is independently hydrogen, an optionally substituted aliphatic, an optionally substituted heteroaryl, an optionally substituted phenyl, or R8 and R9, bound on adjacent atoms, taken together with the atoms to which they are attached form a 5 to 7 membered, optionally substituted monocyclic heterocycloaliphatic, or a 6 to 12 membered, optionally substituted bicyclic heterocycloaliphatic; or R8 and R\u20328, taken together with the atoms to which they are attached form an optionally substituted cycloaliphatic or an optionally substituted heterocycloaliphatic;
Each R2 is \u2014ZBR5, wherein each ZB is independently a bond or an optionally substituted branched or straight C1-12 aliphatic chain wherein up to three carbon units of ZB are optionally and independently replaced by \u2014C(O)\u2014, \u2014C(S)\u2014, \u2014C(O)NRB\u2014, \u2014C(O)NRBNRB\u2014, \u2014C(O)O\u2014, \u2014NRBC(O)O\u2014, \u2014NRBC(O)NRB\u2014, \u2014NRBNRB\u2014, \u2014S\u2014, \u2014SO\u2014, \u2014SO2\u2014, \u2014NRB\u2014, \u2014SO2NRB\u2014, or \u2014NRBSO2NRB\u2014, provided that SO, SO2, or \u2014SO2NRB\u2014 is not directly bound to the carbonyl of formula I;
Each R5 is independently RB, halo, \u2014OH, \u2014CN, \u2014NO2, \u2014NH2, or \u2014OCF3;
Each RB is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
Or R1 and R2, together with the atoms to which they are attached, form an optionally substituted heterocycloaliphatic ring;
Each R3 is an optionally substituted aliphatic, amino, sulfonyl, sulfanyl, sulfinyl, sulfonamide, sulfamide, sulfo, \u2014O\u2014R3A, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
Each R3A is independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;
Each Y and Y\u2032 is independently \u2014ZDR7, wherein each ZD is independently a bond or an optionally substituted straight or branched C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by \u2014C(O)\u2014, \u2014C(S)\u2014, \u2014C(O)NRD\u2014, \u2014C(O)NRDNRD\u2014, \u2014C(O)O\u2014, \u2014NRDC(O)O\u2014, \u2014O\u2014, \u2014NRDC(O)NRD\u2014, \u2014NRDNRD\u2014, \u2014S\u2014, \u2014SO\u2014, \u2014SO2\u2014, \u2014NRD\u2014, \u2014SO2NRD\u2014, \u2014NRDSO2\u2014, or \u2014NRDSO2NRD\u2014, or Y and Y\u2032 together form \u2550O or \u2550S;
Each R7 is independently RD, halo, \u2014OH, \u2014CN, \u2014NO2, \u2014NH2, or \u2014OCF3;
Each RD is independently hydrogen, or optionally substituted aryl; and
Each of a and b is independently 0, 1, 2, or 3; provided that the sum of a and b is 2 or 3.
12. A method of eliminating or reducing HCV contamination of a biological sample or medical or laboratory equipment, comprising the step of contacting said biological sample or medical or laboratory equipment with a compound selected from the group of compounds: