1. A compound of Formula (I):
and stereoisomers, solvates, hydrates, tautomers, prodrugs, salts, pharmaceutically acceptable salts, and mixtures thereof, wherein:
Ra and Rb are independently a hydroxyl or a group that can be hydrolyzed to hydroxyl, or Ra and Rb together with the boron atom to which they are attached form a cyclic group which can be hydrolyzed to a B(OH)2 group;
R1, R1a, R2 and R2a are independently H or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl group, wherein any carbon atom can be substituted with J;
D is CH2, CH or N;
when D is CH2, then W, V, K and T are absent;
when D is CH, then W is C(R6)2, O, S, or NR7, and V, K, and T are as defined below;
when D is N then W, V and K are bonds, the bonds taken together forming a single bond, T is as defined below, such that T is bonded directly to D;
wherein R6 is independently at each occurrence hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl group is substituted with 0-3 J groups;
R7 is independently at each occurrence hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aralkanoyl, heteroaralkanoyl, C(O)R8, SO2R8 or carboxamido, wherein any alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aralkanoyl, or heteroaralkanoyl is substituted with 0-3 J groups;
R8 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
V is a bond, C(R10)2, C(O), S(O), or S(O)2;
K is a bond, O, S, C(O), S(O), S(O)2, S(O)(NR10), or N(R10);
except when V and K are both bonds, the bonds taken together form a single bond;
R10 is independently at each occurrence hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; wherein any R10 group except hydrogen is substituted with 0-3 J groups;
T is R11, alkyl-R11, alkenyl-R11, alkynyl-R11, OR11, N(R11)2, C(O)R11, or C(\u2550NOalkyl)-R11;
R11 is independently hydrogen, alkyl, aryl, aralkyl, alkoxy, aryloxy, alkylamino, arylamino, cycloalkyl, cycloalkylidenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkylidenyl, heteroaryl, or heteroarylalkyl, wherein any R11 group except hydrogen is substituted with 0-3 J groups, or a first R11 and a second R11 together with a nitrogen atom to which they are bound form a mono- or bicyclic ring system substituted with 0-3 J groups;
J is halogen, OR\u2032, OC(O)N(R\u2032)2, CN, CF3, OCF3, R\u2032, O, S, C(O), S(O), methylenedioxy, ethylenedioxy, N(R\u2032)2, SR\u2032, SOR\u2032, SO2R\u2032, SO2N(R\u2032)2, SO3R\u2032, C(O)R\u2032, C(O)C(O)R\u2032, C(O)CH2C(O)R\u2032, C(S)R\u2032, C(O)OR\u2032, OC(O)R\u2032, C(O)N(R\u2032)2, OC(O)N(R\u2032)2, C(S)N(R\u2032)2, (CH2)0-2NHC(O)R\u2032, N(R\u2032)N(R\u2032)C(O)R\u2032, N(R\u2032)N(R\u2032)C(O)OR\u2032, N(R\u2032)N(R\u2032)CON(R\u2032)2, N(R\u2032)SO2R\u2032, N(R\u2032)SO2N(R\u2032)2, N(R\u2032)C(O)OR\u2032, N(R\u2032)C(O)R\u2032, N(R\u2032)C(S)R\u2032, N(R\u2032)C(O)N(R\u2032)2, N(R\u2032)C(S)N(R\u2032)2, N(COR\u2032)COR\u2032, N(OR\u2032)R\u2032, C(\u2550NH)N(R\u2032)2, C(O)N(OR\u2032)R\u2032, or C(\u2550NOR\u2032)R\u2032 wherein;
each R\u2032 is independently at each occurrence hydrogen, (C1-C12)-alkyl, (C3-C10)-cycloalkyl or (C3-C10)-cycloalkenyl, (C3-C10)cycloalkyl or (C3-C10)-cycloalkenyl-(C1-C12)-alkyl, (C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)-alkyl, (C3-C10)-heterocyclyl, (C3-C10)-heterocyclyl-(C1-C12)-alkyl, (C5-C10)-heteroaryl, or (C5-C10)-heteroaryl-(C1-C12)-alkyl, wherein R\u2032 is substituted with 0-3 substituents selected independently from J; or, two R\u2032 groups together with a nitrogen atom to which both R\u2032 groups are attached or with two adjacent nitrogen atoms to which each R\u2032 group is respectively attached form a mono- or bicyclic ring system;
A is a connecting segment comprising a chain of about 6 to about 17 carbon atoms comprising 0 or 1 double bond, wherein any chain carbon atom can bear a C1-C6 alkyl group, the chain further comprising 0-2 heteroatoms independently selected from O, S, S(O), S(O)2, and NR7, the chain further comprising 0-3 J groups;
when W is C(R6)2, a bond, or absent:
X is a bond, O, S, C(R6)2 or N(R7);
Y is a bond, C(R6)2, C(O), C(O)C(O), S(O), S(O)2, or S(O)(NR7);
except when X and Y are both bonds, the bonds taken together form a single bond;
Z is
a) hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, OR9 , or N(R9)2, wherein any carbon atom is unsubstituted or is substituted with J, and wherein R9 is independently at each occurrence hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroarylalkyl, or two R9 groups which are bound to a nitrogen atom can form together with the nitrogen atom a 5-11 membered mono- or bicyclic heterocyclic ring system substituted with 0-3 J groups;
b) a substituted aryl or heteroaryl group; wherein any aryl or heteroaryl is substituted with 1-3 J groups;
c) a group of the formula:
wherein R12, R13, R14, R15, R18, and R19 are independently H, F, or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl group; or R12 and R13 or R41 and R15 or R18 and R19, together with the carbon to which they are attached, can form a C3-6 cycloalkyl group;
R16 and R17 are independently H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl group; or R16 and R17 together with the atoms to which they are attached can form a fused substituted or unsubstituted aryl or heteroaryl group;
p is 0 or 1; and
q is 0 or 1;
d) a group of the formula:
wherein R12, R13, R14, and R15 are independently H, F, or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl group; or R12 and R13 or R14 and R15, together with the carbon to which they are attached, can form a C3-6 cycloalkyl group;
wherein R20, R21, R22, R23 are independently H, F, Cl, Br, I, CN, CF3, OR24, O\u2014(CH2)r\u2014NR25R26, O\u2014(CH2)r\u2014OC(O)NR25R26, O\u2014(CH2)r\u2014NR25C(O)R26, (CH2)r\u2014OR24, OCF3, NR25R26, (CH2)r\u2014NR25R26, SR24, (CH2)r\u2014SR24, C(O)R24, C(O)OR24, NR27C(O)R24, C(O)NR25R26, NR27C(O)NR25R26, OC(O)NR25R26, NR27C(O)OR24, NR27SO2R24, SO2NR25R26, or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl group, wherein r is 1, 2, 3, 4, 5, or 6; and
each R24, R25, R26, and R27 is independently H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, aryl, aralkyl, arylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl group; or, when R25 and R26 are both bound to a nitrogen atom, R25 and R26 together with the nitrogen atom to which they are attached can form a 3-7 membered heterocyclic ring;
e) a group of the formula
wherein R12, R13, R14, R15, R22 and R23 are as defined above; or
f) a group of the formula
wherein R12, R13, R14, R15, R20, R22 and R23 are as defined above;
wherein a wavy line signifies a point of attachment; or when W is NR7, O, or S:
X is O, CH2, or NH;
Y is C(R6)2 or absent;
Z is a substituted alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, heteroaryl, or heteroarylalkyl; wherein any alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, heteroaryl, or heteroarylalkyl is substituted with 1-3 J groups, provided that K and V are both bonds, taken together forming a single bond such that T is bonded directly to W, T is not C(O)R11; or
X is O;
Y is C(O); and
Z is:
aa) a group of the formula
wherein R12, R13, R14, R15, R20, R21, R22 and R23 are as defined above; or
bb) a group of the formula
wherein R12, R13, R14, R15, R21, R22 and R23 are as defined above; or
cc) a group of the formula
wherein R12, R13, R14, R15, R20, R22 and R23 are as defined above;
wherein a wavy line signifies a point of attachment.
2. The compound of claim 1, wherein X is O.
3. The compound of claim 1, wherein Y is C(O).
4. The compound of claim 1, wherein Y is CH2.
5. The compound of claim 1, wherein Z is a group of the formula:
6. The compound of claim 5, wherein R12, R13, R14, R15, R20, R21, R22 and R23 are hydrogen.
7. The compound of claim 5 wherein R20 is F.
8. The compound of claim 1, wherein Ra and Rb are OH or a salt thereof.
9. The compound of claim 1, wherein W is NR7.
10. The compound of claim 1, wherein V is C(O).
11. The compound of claim 1, wherein K is O.
12. The compound of claim 1, wherein R11 is alkyl or cycloalkyl.
13. The compound of claim 1, wherein Z is:
wherein a wavy line signifies a point of attachment, wherein any carbon atom of Z can be substituted with J, wherein Ar is substituted or unsubstituted aryl and HetAr is substituted or unsubstituted hetero aryl.
14. The compound of claim 1 wherein D is CH.
15. The compound of claim 1 wherein D is N.
16. The compound of claim 15 wherein T is H, (C1-C6)alkyl, aryl, or aralkyl, wherein any alkyl, aryl, or aralkyl is substituted with 0-3 J groups.
17. The compound of claim 1 wherein D is CH2.
18. The compound of claim 1 wherein the relative stereochemistry of the compound of Formula (I) is a compound of Formula (IA):
19. The compound of claim 1, wherein R11 is alkyl or cycloalkyl.
20. The compound of claim 1, wherein R11 is t-butyl, neopentyl, or cyclopentyl.
21. The compound of claim 1, comprising:
22. A pharmaceutical composition comprising a compound of claim 1 and a suitable excipient.
23. A pharmaceutical combination comprising a compound of claim 1 in a therapeutically effective dose and a second medicament in a therapeutically effective dose.
24. A pharmaceutical composition comprising the combination of claim 23 and a suitable excipient.
25. A method of treatment of a malcondition in a patient in need thereof, wherein inhibition of a hepatitis C viral protease is medically indicated, comprising administering to the patient the compound of claim 1 or the composition of claim 22 in a therapeutically effective amount.
26. A method of treatment of a malcondition in a patient, the malcondition comprising a hepatitis C viral infection, comprising administering to the patient a compound of claim 1 in a therapeutically effective amount.
27. A method of treatment of a malcondition in a patient, the malcondition comprising a hepatitis C viral infection, comprising administering to the patient the pharmaceutical combination of claim 23 or the composition of claim 24 in a therapeutically effective amount.
28. A method of preparing a compound of Formula (I) of claim 1, wherein A comprises a linear alkyl chain comprising a single double bond, comprising contacting a compound of formula (II):
wherein x is 1 to about 7;
and a compound of Formula (III):
under conditions suitable to bring about formation of an amide bond;
to provide a compound of Formula (IV):
then,
contacting the compound of Formula (IV) with a Ring-Closure-Metathesis (RCM) catalyst to provide a compound of Formula (I) comprising a newly formed ethylenic bond, comprising:
wherein the ethylenic bond can be cis or trans.
29. The method of claim 28 wherein the Ring-Closure-Metathesis catalyst is a Grubbs-Hoveyda 1st generation catalyst.
30. The method of claim 28 further comprising contacting a compound of Formula (I) comprising:
and hydrogen gas in the presence of a hydrogenation catalyst to provide a compound of Formula (I), wherein A comprises a linear alkyl chain with zero double bonds, comprising:
31. The method of claim 28 wherein the compound of Formula (II) is:
32. A method of preparing a compound of Formula (II) of claim 28:
comprising contacting a compound of Formula (V):
with an carbanion of dichloromethane to provide a compound of Formula (VI):
then,
contacting the compound of Formula (VI) and lithium hexamethyldisilazide, followed by aqueous hydrochloric acid, to provide the compound of Formula (II).
33. The method of claim 32 wherein the compound of Formula (V) is:
34. The method of claim 32 wherein the compound of Formula (VI) is:
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 vehicle air conditioning system, comprising:
a low pressure section including an air conditioning evaporator, the low pressure section having a prescribed operating range bounded by at least a first fixed operation threshold;
a compressor in fluid communication with the air conditioning evaporator;
a sensor arranged to detect an operating condition of the low pressure section; and
a controller operably connected to the sensor and the compressor, the controller initially controlling operation of the compressor to switch from one of inactive and active states to the other in response to detecting that the operating condition is equal to or surpasses the first operation threshold,
the controller further determining a first time delay corresponding to a time occurring between initiating the switch from the one of the inactive and active states to the other of the compressor and an actual change in the operating condition due to the switch from the one of the inactive and active states to the other of the compressor; and
the controller further subsequently defining a first limit that is offset from the first operation threshold such that the controller controls the operation of the compressor to subsequently switch from the one of inactive and active states to the other in response to detecting that the operating condition is equal to or surpasses the first limit, the controller being further configured to repeatedly re-adjust the first limit in response to re-determining the first time delay.
2. The vehicle air conditioning system according to claim 1, wherein
the controller defines the first limit so as to compensate for the first time delay in order to have the actual change in the state of the compressor occur at a time with the operating condition being closer to the first operation threshold than the first limit.
3. The vehicle air conditioning system according to claim 1, wherein
the controller determines the first time delay corresponding to a time occurring between initiating the switch from the inactive state of the compressor to the active state of the compressor.
4. The vehicle air conditioning system according to claim 1, wherein
the controller determines the first time delay corresponding to a time occurring between initiating the switch from the active state of the compressor to the inactive state of the compressor.
5. The vehicle air conditioning system according to claim 4, wherein
the controller determines a second time delay corresponding to a time occurring between initiating the switch from the inactive state of the compressor to the active state of the compressor and
the controller further subsequently defining a second limit that is offset from a second operation threshold such that the controller controls the operation of the compressor to subsequently switch from the inactive state of the compressor to the active state of the compressor in response to detecting that the operating condition is equal to or surpasses the second limit.
6. The vehicle air conditioning system according to claim 1, wherein
the operating condition detected by the sensor is a refrigerant pressure level measured at the low pressure section of the vehicle air conditioning system proximate the evaporator and the prescribed operating range is defined between an upper pressure threshold and a lower pressure threshold, with one of the upper pressure threshold and the lower pressure threshold defining the first operation threshold.
7. The vehicle air conditioning system according to claim 6, wherein
the controller is configured to repeatedly re-adjust the first limit by incrementally changing a pressure value of the first limit in response to re-determining the first time delay.
8. The vehicle air conditioning system according to claim 1, wherein
the operating condition detected by the sensor is a temperature level measured at one of the following: air downstream from the evaporator, surface temperature of the evaporator, and refrigerant temperature within the evaporator, and
the prescribed operating range is defined between an upper temperature threshold and a lower temperature threshold, with one of the upper temperature threshold and the lower temperature threshold defining the first operation threshold.
9. The vehicle air conditioning system according to claim 8, wherein
the controller is configured to repeatedly re-adjust the first limit by incrementally changing a temperature value of the first limit in response to re-determining the first time delay.
10. A method of controlling a vehicle air conditioning system comprising:
setting a first operation threshold for a prescribed operating range of an air conditioning evaporator;
detecting an operating condition of the air conditioning evaporator;
initially controlling operation of a compressor to switch from one of inactive and active states to the other in response to detecting that the operating condition is equal to or surpassing the first operation threshold;
determining a first time delay corresponding to a time occurring between initiating the switch from the one of the inactive and active states to the other of the compressor and an actual change in the operating condition due to the switch from the one of the inactive and active states to the other of the compressor;
setting a first limit to compensate for the first time delay that was detected; and
subsequently controlling the operation of the compressor to switch from the one of inactive and active states to the other in response to detecting that the operating condition is equal to or surpasses the first limit.
11. The method of controlling a vehicle air conditioning system according to claim 10, wherein
the setting of the first limit is performed so as to compensate for the first time delay in order to have the actual change in the state of the compressor occur at a time with the operating condition is closer to the first operation threshold than the first limit.
12. The method of controlling a vehicle air conditioning system according to claim 10, wherein
the determining of the first time delay is performed corresponding to a time occurring between initiating the switch from the inactive state of the compressor to the active state of the compressor.
13. The method of controlling a vehicle air conditioning system according to claim 10, wherein
the determining of the first time delay is performed corresponding to a time occurring between initiating the switch from the active state of the compressor to the inactive state of the compressor.
14. The method of controlling a vehicle air conditioning system according to claim 13, further comprising
determining a second time delay corresponding to a time occurring between initiating the switch from the inactive state of the compressor to the active state of the compressor;
setting a second limit to compensate for the second time delay that was detected; and
subsequently controlling the operation of the compressor to switch from the inactive state of the compressor to the active state of the compressor in response to detecting that the operating condition is equal to or surpasses the second limit.
15. The method of controlling a vehicle air conditioning system according to claim 10, wherein
the detecting of the operating condition is performed with the sensor detecting a refrigerant pressure level measured at the low pressure section of the vehicle air conditioning system proximate the evaporator, and the prescribed operating range is set between an upper pressure threshold and a lower pressure threshold, with one of the upper pressure threshold and the lower pressure threshold defining the first operation threshold.
16. The method of controlling a vehicle air conditioning system according to claim 10, wherein
the detecting of the operating condition is performed with the sensor detecting a temperature level measured at one of the following: air downstream from the evaporator, surface temperature of the evaporator, and refrigerant temperature within the evaporator; and
the prescribed operating range is set between an upper temperature threshold and a lower temperature threshold, with one of the upper temperature threshold and the lower temperature threshold defining the first operation threshold.
17. The method according to claim 10, wherein
the setting of the first limit includes repeatedly re-adjusting the first limit in response to re-determining the first time delay.
18. A method of controlling a vehicle air conditioning system, comprising:
setting at least one of an activation threshold for an air conditioning evaporator and a deactivation threshold for the air conditioning evaporator;
detecting changes in an operating condition of the air conditioning evaporator;
activating a compressor to compress refrigerant in response to detecting that the operating condition is equal to or greater than the activation threshold;
deactivating the compressor to cease compressing refrigerant in response to detecting that the operating condition is equal to or less than the lower threshold;
determining at least one of the following:
a first time delay between the requesting of the activation of the compressor and an actual activation of the compressor; and
a second time delay between the requesting of the deactivation of the compressor and the actual deactivation of the compressor; and
setting a corresponding one of:
a first upper limit in response to determination of the first time delay to compensate for the detected first time delay such that the compressor subsequently begins compressing refrigerant with the detected changes in the operating condition being closer to the activation threshold than the first upper limit, and
a second lower limit in response to determination of the second time delay to compensate for the detected second time delay such that the compressor ceases compressing refrigerant with the detected changes in the operating condition being closer to the deactivation threshold than the second lower limit.
19. The method according to claim 18, wherein
the determining of at least one of the first and second time delays is performed such that both the first time delay and the second time delay are determined, and both the first limit and the second limit are re-adjusted to compensate for the determined first and second time delays.
20. The method according to claim 18, wherein
the detecting changes in the operating condition is performed such that the operating condition is a temperature detected proximate an evaporator of the vehicle air conditioning system.
21. The method according to claim 18, wherein
the detecting changes in the operating condition is performed such that the operating condition is a refrigerant pressure detected in a low pressure section of the vehicle air conditioning system proximate an evaporator.
22. The method according to claim 18, wherein
the setting of the first upper limit and the second lower limit includes repeatedly re-adjusting the first upper limit and the second lower limit in response to re-determining a corresponding one of the first time delay and the second time delay.