1. A method of providing security using a computer, comprising:
determining whether an application identified at a client appears on a white list of legitimate applications;
responsive to a determination that the application does not appear on the white list, monitoring execution of the application using a restrictive set of signatures;
responsive to a determination that the application does appear on the white list:
identifying a behavioral reputation of the application describing legitimate characteristics the application possesses;
excluding the legitimate characteristics described by the behavioral reputation from a set of signatures to produce a relaxed set of signatures; and
monitoring execution of the application using the relaxed set of signatures; and
evaluating whether the application is malicious responsive to the monitoring.
2. The method of claim 1, wherein the behavioral reputation of the application is specified by the white list.
3. The method of claim 1, wherein evaluating whether the application is malicious comprises:
identifying characteristics possessed by the application;
designating as suspicious any of the identified characteristics that appear in the set of signatures used in monitoring the application; and
evaluating whether the application is malicious responsive to any characteristics designated as suspicious.
4. The method of claim 1, wherein evaluating whether the application is malicious comprises:
identifying behaviors performed by the application during execution;
designating as suspicious any of the identified behaviors that appear in the set of signatures used in monitoring the execution of the application; and
evaluating whether the application is malicious responsive to any behaviors designated as suspicious.
5. The method of claim 1, wherein the relaxed signatures are a subset of the restrictive signatures.
6. The method of claim 1, further comprising:
determining a hygiene score for the client, the hygiene score representing an assessment of the trustworthiness of the client; and
reporting monitored characteristics of the application and the hygiene score to a server connected to the client via a network;
wherein the server is adapted to create the white list responsive to the hygiene score and the monitored characteristics and to provide the white list to the client.
7. A non-transitory computer-readable storage medium storing executable computer program instructions for providing security to a computer, the instructions comprising instructions for:
determining whether an application identified at a client appears on a white list of legitimate applications;
responsive to a determination that the application does not appear on the white list, monitoring execution of the application using a restrictive set of signatures;
responsive to a determination that the application does appear on the white list:
identifying a behavioral reputation of the application describing legitimate characteristics the application possesses;
excluding the legitimate characteristics described by the behavioral reputation from a set of signatures to produce a relaxed set of signatures; and
monitoring execution of the application using the relaxed set of signatures; and
evaluating whether the application is malicious responsive to the monitoring.
8. The non-transitory computer-readable storage medium of claim 7, wherein the behavioral reputation for the application is specified by the white list.
9. The non-transitory computer-readable storage medium of claim 7, wherein evaluating whether the application is malicious comprises:
identifying characteristics possessed by the application;
designating as suspicious any of the identified characteristics that appear in the set of signatures used in monitoring the application; and
evaluating whether the application is malicious responsive to any characteristics designated as suspicious.
10. The non-transitory computer-readable storage medium of claim 7, wherein evaluating whether the application is malicious comprises:
identifying behaviors performed by the application during execution;
designating as suspicious any of the identified behaviors that appear in the set of signatures used in monitoring the execution of the application; and
evaluating whether the application is malicious responsive to any behaviors designated as suspicious.
11. The non-transitory computer-readable storage medium of claim 7, wherein the relaxed signatures are a subset of the restrictive signatures.
12. The non-transitory computer-readable storage medium of claim 7, further comprising instructions for:
determining a hygiene score for the client, the hygiene score representing an assessment of the trustworthiness of the client; and
reporting monitored characteristics of the application and the hygiene score to a server connected to the client via a network;
wherein the server is adapted to create the white list responsive to the hygiene score and the monitored characteristics and to provide the white list to the client.
13. A computer system for providing security, comprising:
a non-transitory computer-readable storage medium storing executable computer program instructions comprising:
an interface module for receiving reports from clients, the reports comprising identifiers of applications and descriptions of execution characteristics possessed by the applications at the clients;
a behavioral reputation generation module for generating behavioral reputations for the applications responsive to the received reports, the behavioral reputations describing legitimate execution characteristics possessed at clients by the applications;
a white list generation module for generating a white list responsive to the behavioral reputations, the white list describing legitimate execution characteristics of the applications; and
a distribution module for providing the white list to the clients, wherein a client is adapted to:
determine whether an application identified at the client appears on the white list;
responsive to a determination that the application does not appear on the white list, monitor execution of the application using a restrictive set of signatures;
responsive to a determination that the application does appear on the white list:
identify a behavioral reputation of the application describing legitimate execution characteristics of the application;
exclude the legitimate execution characteristics described by the behavioral reputation from a set of signatures to produce a relaxed set of signatures;
monitor execution of the application using the relaxed set of signatures; and
evaluate whether the application is malicious responsive to the monitoring; and
a processor for executing the computer program instructions.
14. The computer system of claim 13, wherein the reports comprise descriptions of behaviors performed by the applications at the clients and the characteristics described by the behavioral reputations comprise legitimate behaviors performed by the applications at clients.
15. The computer system of claim 13, wherein the reports further comprise hygiene scores describing hygienes of the clients and wherein the behavioral reputation generation module is further adapted to:
identify reports from clients having good hygiene, wherein the behavioral reputations for the applications are generated responsive to the reports received from clients having good hygiene and the behavioral reputations describe characteristics possessed by the applications at clients having good hygiene.
16. The computer system of claim 13, wherein the reports further comprise hygiene scores describing hygienes of the clients and further comprising:
a reputation generation module for generating application reputations for the applications responsive to the hygiene scores of clients from which reports are received, the application reputations describing trustworthiness of the applications;
wherein the white list generation module generates the white list responsive to the reputations for the applications.
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 compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
Z1 is nitrogen or CR1;
Z2 is nitrogen or CR2;
Z3 is nitrogen or CR3;
Z4 is nitrogen or CR4;
provided that no more than two of Z1, Z2, Z3, and Z4 are nitrogen;
R1, R2, R3, and R4 are independently selected from
i) hydrogen, halogen, hydroxy, nitro, cyano, amino, haloalkyl, and haloalkoxy,
ii) alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, (cycloalkyl)alkyl, \u2014NH(R10), -N(R10)(R11) hydroxyalkyl, aminoalkyl, (R10)NHalkyl-, (R10)(R11)Nalkyl-, alkanoyl, alkoxycarbonyl, (heterocycloalkyl)alkyl, alkylsulfonyl, alkylthio, mono- or dialkylaminocarbonyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 of R20,
wherein R10 and R11 are independently selected at each occurrence from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, alkanoyl, and mono and dialkylaminoalkyl; and
iii) a group of the formula:
where G is a bond, alkyl, \u2014O\u2014, \u2014C(O)\u2014, or \u2014CH2C(\u2550O)\u2014, and
RA is a saturated, partially unsaturated, or aromatic carbocycle, consisting of 1 ring or 2 fused, pendant, or spiro rings, each ring containing 0, 1, or 2 heteroatoms independently chosen from N, S, and O, said saturated, partially unsaturated, or aromatic carbocycle is optionally substituted with 1, 2, 3, or 4 of R20,
iv) a group of the formula
where J is N, CH, or C-alkyl, and
RB and RC are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, aryl, arylalkyl, alkanoyl, heteroaryl, and mono and dialkylaminoalkyl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl;
RB and RC and the atom to which they are attached form a 4- to 10-membered monocyclic or bicyclic ring, which may contain:
a) one or more double bonds,
b) one or more of oxo, O, S, SO, SO2, or N\u2014RD wherein RD is hydrogen, Ar1, alkyl, cycloalkyl, heterocycloalkyl, or Ar1alkyl; wherein Ar1 is aryl or heteroaryl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl, andor
c) one or more substituents R20;
v) \u2014OC(\u2550O)RE, \u2014C(\u2550O)ORE, \u2014C(\u2550O)NH2, \u2014C(\u2550O)NHRE, \u2014C(\u2550O)NRERF, S(O)nRE, \u2014S(O)nNH2, \u2014S(O)nNHRE, \u2014S(O)nNRERF, \u2014NHC(\u2550O)RE, \u2014C(\u2550NRE)RF, \u2014HC\u2550N\u2014OH, \u2014HC\u2550N(alkoxy), \u2014HC\u2550N(alkyl), \u2014NREC(\u2550O)RF, NHS(O)mRE, and \u2014NRES(O)mRF, where m is 0, 1 or 2, and
RE and RF are independently selected at each occurrence from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, mono- or dialkylamino, aryl, or heteroaryl each of which is optionally substituted by 1, 2, or 3 of R20;
R20 is independently selected at each occurrence from the group consisting of: halogen; hydroxy; nitro; cyano; amino; alkyl; alkoxy optionally substituted with amino or mono- or dialkylamino; cycloalkyl; cycloalkylalkyl; cycloalkylalkoxy; alkenyl; alkynyl; haloalkyl; oxo; haloalkoxy; mono- and dialkylamino; aminoalkyl; and mono- and dialkylaminoalkyl;
R30 is independently selected at each occurrence from halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, oxo, mono- and dialkylamino, aminoalkyl, and mono- and dialkylaminoalkyl;
R5 represents hydrogen or haloalkyl; or
R5 represents alkyl, cycloalkyl, or (cycloalkyl)alkyl, each of which may contain one or more double or triple bonds, and each of which is optionally substituted with 1, 2, or 3 of R30, or
R5 represents aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of haloalkyl, amino, \u2014NH(R10), \u2014N(R10)(R11), carboxamido, (R10)NHcarbonyl, (R10)(R11)Ncarbonyl, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, aminoalkyl, and mono- and dialkylaminoalkyl;
Q represents \u2014C(R6)(R7) or oxygen,
with the proviso that Q is not oxygen when X2 is nitrogen;
R5 and R7 independently represent hydrogen, fluorine, or alkyl;
the group:
represents a 5 to 7 membered heteroaryl or heterocycloalkyl ring containing up to 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen, said 5 to 7 membered heteroaryl or heterocycloalkyl ring is substituted at each carbon atom by R, and substituted at each nitrogen atom available for substitution by R\u2032, wherein
R is independently chosen at each occurrence from hydrogen, halogen, amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, haloalkoxy, carboxamido, and 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, alkyl, and alkoxy;
R\u2032 is independently chosen at each occurrence from alkyl, hydrogen, cycloalkyl, cycloalkyl(alkyl), and 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which 3- to 7-membered carbocyclic or heterocyclic groups are optionally substituted with one or more substituents independently selected from halogen, oxo, hydroxy, alkyl, and alkoxy;
X1 and X2 independently represent nitrogen, carbon or CH;
Y is nitrogen, oxygen, carbon, \u2014CH\u2014, \u2014CH2\u2014, or absent; and
W represents aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with up to 4 groups independently selected from R30, \u2014CO2H, \u2014C(\u2550O)ORE, C(\u2550O)NHRE, \u2014C(\u2550O)NRERF, \u2014C(O)RE, and \u2014S(O)mRE, \u2014ORE, where R30 and RE are as defined above and m is 0, 1, or 2.
2-164. (canceled)
165. A pharmaceutical composition comprising a compound or salt according to claim 1 combined with at least one pharmaceutically acceptable carrier or excipient.
166. A method for altering the signal-transducing activity of a GABAA receptor, said method comprising contacting a cell expressing such a receptor with an amount of a compound or salt according to claim 1 sufficient to detectably alter the electrophysiology of the cell, wherein a detectable alteration of the electrophysiology of the cell indicates an alteration of the signal-transducing activity of GABAA receptors.
167. A method for altering the signal-transducing activity of a GABAA receptor, said method comprising contacting a cell expressing such receptors with an amount of a compound or salt according to claim 1 to detectably alter the chloride conductance in vitro of cell expressing GABAA receptors.
168. The method of claim 167 wherein the cell is recombinantly expresses a heterologous GABAA receptor and the alteration of the electrophysiology of the cell is detected by intracellular recording or patch clamp recording.
169. The method of claim 167 wherein the cell is a neuronal cell that is contacted in vivo in an animal, the cell is contacted with the compound or salt dissolved in a body fluid, and the alteration in the electrophysiology of the cell is detected as a change in the animal’s behavior.
170. (canceled)
171. A method for altering the signal-transducing activity of a GABAA receptor, the method comprising exposing a cell expressing the GABAA receptor to an amount of a compound or salt according to claim 1 sufficient to inhibit RO15-1788 binding in vitro to cells expressing a human GABAA receptor.
172. A method for the treatment of anxiety, depression, a sleep disorder, schizophrenia, attention deficit-hyperactivity disorder, or for the enhancement of memory, comprising administering an effective amount of a compound or salt of claim 1 to a patient.
173. A method for demonstrating the presence of a GABAA receptor in a cell or tissue sample, said method comprising:
contacting a cell or tissue sample with a labeled compound or salt according to claim 1;
washing the cell or tissue sample to remove unbound labeled compound or salt; and
detecting the presence of labeled compound or salt in the cell or tissue sample.
174. The method of claim 173 in which the cell or tissue sample is a tissue section.
175. The method of claim 173 in which the labeled compound or salt contains a radioactive label or a directly or indirectly luminescent label.
176. The method of claim 173 in which the cell or tissue sample is a tissue section, labeled compound or salt contains a radioactive label or a directly or indirectly luminescent label, and the labeled compound or salt is detected autoradiographically to generate an autoradiogram.
177. A method for demonstrating the presence of a GABAA receptor in a tissue section comprising:
contacting the tissue section with a radiolabeled or luminescently labeled compound or salt according to claim 1 to yield a contacted tissue section;
washing the tissue section to remove unbound labeled compound or salt;
detecting the labeled compound or salt in the tissue section; and
comparing the exposure density of the tissue section with the exposure density of a second tissue section that has not been contacted with a compound or salt according to claim 1.
178-182. (canceled)
183. A process for preparing a compound of claim 1, where the compound of claim 1 has the formula
comprising reacting a compound of Formula B
with a compound of Formula C
wherein:
Z1 is nitrogen or CR2;
Z2 is nitrogen or CR2;
Z3 is nitrogen or CR3;
Z4 is nitrogen or CR4;
provided that no more than two of Z2, Z2, Z3, and Z4 are nitrogen;
R2, R2, R3, and R4 are independently selected from
i) hydrogen, halogen, hydroxy, nitro, cyano, amino, haloalkyl, and haloalkoxy,
ii) alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, (cycloalkyl)alkyl, \u2014NH(R10), \u2014N(R10)(R11), hydroxyalkyl, aminoalkyl, (R10)NHalkyl, (R10)(R11)Nalkyl, alkanoyl, alkoxycarbonyl, (heterocycloalkyl)alkyl, alkylsulfonyl, alkylthio, mono- or dialkylaminocarbonyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 of R20,
wherein R10 and R11 are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, alkanoyl, and mono and dialkylaminoalkyl; and
iii) a group of the formula:
where G is a bond, alkyl, \u2014O\u2014, \u2014C(\u2550O)\u2014, or \u2014CH2C(\u2550O)\u2014, and
RA is a saturated, partially unsaturated, or aromatic carbocycle, consisting of 1 ring or 2 fused, pendant, or spiro rings, each ring containing 0, 1, or 2 heteroatoms independently chosen from N, S, and O, said saturated, partially unsaturated, or aromatic carbocycle is optionally substituted with 1, 2, 3, or 4 of R20, and
iv) a group of the formula
where J is N, CH, or C-alkyl, and
RB and RC are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, aryl, arylalkyl, alkanoyl, heteroaryl, and mono and dialkylaminoalkyl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl;
RB and RC and the atom to which they are attached form a 4- to 10-membered monocyclic or bicyclic ring, which may contain:
a) one or more double bonds,
b) one or more of oxo, O, S, SO, SO2, or N\u2014RD wherein RD is hydrogen, Ar1, alkyl, cycloalkyl, heterocycloalkyl, or Ar1alkyl; wherein Ar1 is aryl or heteroaryl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl, andor
c) one or more substituents R20;
v) \u2014OC(\u2550O)RE, \u2014C(\u2550O)ORE, \u2014C(\u2550O)NH2, \u2014C(\u2550O)NHRE, \u2014C(\u2550O)NRERF, S(O)nRE, \u2014S(O)nNH2, \u2014S(O)nNHRE, \u2014S(O)nNRERF, \u2014NHC(\u2550O)RE, \u2014C(\u2550NRE)RF, \u2014HC\u2550N\u2014OH, \u2014HC\u2550N(alkoxy), \u2014HC\u2550N(alkyl), \u2014NREC(\u2550O)RF, \u2014NHS(O)mRE, and \u2014NRES(O)mRF, where m is 0, 1 or 2, and
RE and RF are independently selected at each occurrence from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, mono- or dialkylamino, aryl, or heteroaryl each of which is optionally substituted by 1, 2, or 3 of R30;
R20 is independently selected at each occurrence from the group consisting of: halogen; hydroxy; nitro; cyano; amino; alkyl; alkoxy optionally substituted with amino or mono- or dialkylamino; cycloalkyl; cycloalkylalkyl; cycloalkylalkoxy; alkenyl; alkynyl; haloalkyl; oxo; haloalkoxy; mono- and dialkylamino; aminoalkyl; and mono- and dialkylaminoalkyl;
R30 is independently selected at each occurrence from halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, oxo, mono- and dialkylamino, aminoalkyl, and mono- and dialkylaminoalkyl;
R5 represents hydrogen or haloalkyl; or
R5 represents alkyl, cycloalkyl, or (cycloalkyl)alkyl, each of which may contain one or more double or triple bonds, and each of which is optionally substituted with 1, 2, or 3 of R30, or
R5 represents aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of haloalkyl, amino, \u2014NH(R10), \u2014N(R10)(R11), carboxamido, (R10)NHcarbonyl, (R10)(R11)Ncarbonyl, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, aminoalkyl, and mono- and dialkylaminoalkyl;
R6 and R7 independently represent hydrogen, fluorine, or alkyl;
R is independently chosen at each occurrence from hydrogen, halogen, amino, C2-C6alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, C2-C6alkoxy, (C3-C8) cycloalkyl, (C2-C8cycloalkyl)(C1-C4)alkyl, halo(C2-C6)alkyl, haloalkoxy, carboxamido, and 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, C2-4alkyl, and \u2014O(C2-4alkyl); and
W represents aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with up to 4 groups independently selected from R30, \u2014CO2H, \u2014C(\u2550O)ORE, \u2014C(\u2550O)NHRE, \u2014C(\u2550O)NRERF, \u2014C(O)RE, and \u2014S(O)mRE, \u2014ORE, where R30 and RE are as defined above and m is 0, 1, or 2.
184-210. (canceled)
211. A compound of the formula:
wherein
Hal represents a halogen; and
Z2 is nitrogen or CR1;
Z2 is nitrogen or CR2;
Z3 is nitrogen or CR3;
Z4 is nitrogen or CR4;
provided that no more than two of Z1, Z2, Z3, and Z4 are nitrogen;
R1, R2, R3, and R4 are independently selected from
i) hydrogen, halogen, hydroxy, nitro, cyano, amino, haloalkyl, and haloalkoxy,
ii) alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, (cycloalkyl)alkyl, \u2014NH(R10), \u2014N(R10)(R11), hydroxyalkyl, aminoalkyl, (R10)NHalkyl-, (R10)(R11)Nalkyl-, alkanoyl, alkoxycarbonyl, (heterocycloalkyl)alkyl, alkylsulfonyl, alkylthio, mono- or dialkylaminocarbonyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 of R20,
wherein R10 and R11 are independently selected at each occurrence from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, alkanoyl, and mono and dialkylaminoalkyl; and
iii) a group of the formula:
where G is a bond, alkyl, \u2014O\u2014, \u2014C(\u2550O)\u2014, or \u2014CH2C(\u2550O)\u2014, and
RA is a saturated, partially unsaturated, or aromatic carbocycle, consisting of 1 ring or 2 fused, pendant, or spiro rings, each ring containing 0, 1, or 2 heteroatoms independently chosen from N, S, and O, said saturated, partially unsaturated, or aromatic carbocycle is optionally substituted with 1, 2, 3, or 4 of R20,
iv) a group of the formula
where J is N, CH, or C-alkyl, and
RB and RC are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, aryl, arylalkyl, alkanoyl, heteroaryl, and mono and dialkylaminoalkyl,
each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl;
RB and RC and the atom to which they are attached form a 4- to 10-membered monocyclic or bicyclic ring, which may contain:
a) one or more double bonds,
b) one or more of oxo, O, S, SO, SO2, or N\u2014RD wherein RD is hydrogen, Ar1, alkyl, cycloalkyl, heterocycloalkyl, or Ar1alkyl; wherein Ar1 is aryl or heteroaryl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl, andor
c) one or more substituents R20;
v) \u2014OC(\u2550O)RE, \u2014C(\u2550O)ORE, \u2014C(\u2550O)NH2, \u2014C(\u2550O)NHRE, \u2014C(\u2550O)NRERF, \u2014S(O)nRE, \u2014S(O)nNH2, \u2014S(O)nNHRE, \u2014S(O)nNRERF, \u2014NHC(\u2550O)RE, \u2014C(\u2550NRE)RF, \u2014HC\u2550N\u2014OH, \u2014HC\u2550N(alkoxy), \u2014HC\u2550N(alkyl), \u2014NREC(\u2550O)RF, \u2014NHS(O)mRE, and \u2014NRES(O)mRF, where m is 0, 1 or 2, and
RE and RF are independently selected at each occurrence from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, mono- or dialkylamino, aryl, or heteroaryl each of which is optionally substituted by 1, 2, or 3 of R30;
R20 is independently selected at each occurrence from the group consisting of: halogen; hydroxy; nitro; cyano; amino; alkyl; alkoxy optionally substituted with amino or mono- or dialkylamino; cycloalkyl; cycloalkylalkyl; cycloalkylalkoxy; alkenyl; alkynyl; haloalkyl; oxo; haloalkoxy; mono- and dialkylamino; aminoalkyl; and mono- and dialkylaminoalkyl;
R30 is independently selected at each occurrence from halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, oxo, mono- and dialkylamino, aminoalkyl, and mono- and dialkylaminoalkyl; and
R5 represents hydrogen or haloalkyl; or
R5 represents alkyl, cycloalkyl, or (cycloalkyl)alkyl, each of which may contain one or more double or triple bonds, and each of which is optionally substituted with 1, 2, or 3 of R30, or
R5 represents aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of haloalkyl, amino, \u2014NH(R10), \u2014N(R10)(R11), carboxamido, (R10)NHcarbonyl, (R10)(R11)Ncarbonyl, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, aminoalkyl, and mono- and dialkylaminoalkyl.
212. A compound of the formula:
wherein
PROT represents a nitrogen protecting group; and
Z1 is nitrogen or CR2;
Z2 is nitrogen or CR2;
Z3 is nitrogen or CR3;
Z4 is nitrogen or CR4;
provided that no more than two of Z1, Z2, Z3, and Z4 are nitrogen;
R1, R2, R3, and R4 are independently selected from
i) hydrogen, halogen, hydroxy, nitro, cyano, amino, haloalkyl, and haloalkoxy,
ii) alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, (cycloalkyl)alkyl, \u2014NH(R10), \u2014N(R10)(R11), hydroxyalkyl, aminoalkyl, (R10)NHalkyl-, (R10)(R11)Nalkyl-, alkanoyl, alkoxycarbonyl, (heterocycloalkyl)alkyl, alkylsulfonyl, alkylthio, mono- or dialkylaminocarbonyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 of R20,
wherein R10 and R11 are independently selected at each occurrence from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, alkanoyl, and mono and dialkylaminoalkyl; and
iii) a group of the formula:
where G is a bond, alkyl, \u2014O\u2014, \u2014C(\u2550O)\u2014, or \u2014CH2C(\u2550O)\u2014, and
RA is a saturated, partially unsaturated, or aromatic carbocycle, consisting of 1 ring or 2 fused, pendant, or spiro rings, each ring containing 0, 1, or 2 heteroatoms independently chosen from N, S, and O, said saturated, partially unsaturated, or aromatic carbocycle is optionally substituted with 1, 2, 3, or 4 of R20,
iv) a group of the formula
where J is N, CH, or C-alkyl, and
RB and RC are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, aryl, arylalkyl, alkanoyl, heteroaryl, and mono and dialkylaminoalkyl,
each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl;
RB and RC and the atom to which they are attached form a 4- to 10-membered monocyclic or bicyclic ring, which may contain:
a) one or more double bonds,
b) one or more of oxo, O, S, SO, SO2, or N\u2014RD wherein RD is hydrogen, Ar1 alkyl, cycloalkyl, heterocycloalkyl, or Ar1alkyl; wherein Ar1 is aryl or heteroaryl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl, andor
c) one or more substituents R20;
v) \u2014OC(\u2550O)RE, \u2014C(\u2550O)ORE, \u2014C(\u2550O)NH2, \u2014C(\u2550O)NHRE, \u2014C(\u2550O)NRERF, \u2014S(O)nRE, \u2014S(O)nNH2, \u2014S(O)nNHRE, \u2014S(O)nNRERF, \u2014NHC(\u2550O)RE, \u2014C(\u2550NRE)RF, \u2014HC\u2550N\u2014OH, \u2014HC\u2550N(alkoxy), \u2014HC\u2550N(alkyl), \u2014NREC(\u2550O)RF, \u2014NHS(O)mRE, and \u2014NRES(O)mRF, where m is 0, 1 or 2, and
RE and RF are independently selected at each occurrence from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, mono- or dialkylamino, aryl, or heteroaryl each of which is optionally substituted by 1, 2, or 3 of R30;
R20 is independently selected at each occurrence from the group consisting of: halogen; hydroxy; nitro; cyano; amino; alkyl; alkoxy optionally substituted with amino or mono- or dialkylamino; cycloalkyl; cycloalkylalkyl; cycloalkylalkoxy; alkenyl; alkynyl; haloalkyl; oxo; haloalkoxy; mono- and dialkylamino; aminoalkyl; and mono- and dialkylaminoalkyl;
R30 is independently selected at each occurrence from halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, oxo, mono- and dialkylamino, aminoalkyl, and mono- and dialkylaminoalkyl; and
R5 represents hydrogen or haloalkyl; or
R5 represents alkyl, cycloalkyl, or (cycloalkyl)alkyl, each of which may contain one or more double or triple bonds, and each of which is optionally substituted with 1, 2, or 3 of R30, or
R5 represents aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of haloalkyl, amino, \u2014NH(R10), \u2014N(R10)(R11), carboxamido, (R10)NHcarbonyl, (R10)(R11)Ncarbonyl, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, aminoalkyl, and mono- and dialkylaminoalkyl.
213. A compound according to claim 212 wherein PROT is butoxycarbonyl.
214. A compound of the formula:
wherein
RH represents a halogen or hydrogen;
Z1 is nitrogen or CR1;
Z2 is nitrogen or CR2;
Z3 is nitrogen or CR3;
Z4 is nitrogen or CR4;
provided that no more than two of Z1, Z2, Z3, and Z4 are nitrogen;
R1, R2, R3, and R4 are independently selected from
i) hydrogen, halogen, hydroxy, nitro, cyano, amino, haloalkyl, and haloalkoxy,
ii) alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, (cycloalkyl)alkyl, \u2014NH(R10), \u2014N(R10)(R11), hydroxyalkyl, aminoalkyl, (R10)NHalkyl-, (R10)(Rn)Nalkyl-, alkanoyl, alkoxycarbonyl, (heterocycloalkyl)alkyl, alkylsulfonyl, alkylthio, mono- or dialkylaminocarbonyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 of R20,
wherein R10 and R11 are independently selected at each occurrence from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, alkanoyl, and mono and dialkylaminoalkyl; and
iii) a group of the formula:
where G is a bond, alkyl, \u2014O\u2014, \u2014C(\u2550O)\u2014, or \u2014CH2C(\u2550O)\u2014, and
RA is a saturated, partially unsaturated, or aromatic carbocycle, consisting of 1 ring or 2 fused, pendant, or spiro rings, each ring containing 0, 1, or 2 heteroatoms independently chosen from N, S, and O, said saturated, partially unsaturated, or aromatic carbocycle is optionally substituted with 1, 2, 3, or 4 of R20,
iv) a group of the formula
where J is N, CH, or C-alkyl, and
RB and RC are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, aryl, arylalkyl, alkanoyl, heteroaryl, and mono and dialkylaminoalkyl,
each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl;
RE, and Rc and the atom to which they are attached form a 4- to 10-membered monocyclic or bicyclic ring, which may contain:
a) one or more double bonds,
b) one or more of oxo, O, S, SO, SO2, or N\u2014RD wherein RD is hydrogen, Ar1, alkyl, cycloalkyl, heterocycloalkyl, or Ar1alkyl; wherein Ar1 is aryl or heteroaryl, each of which is optionally substituted by 1 or 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, alkoxy, and alkyl, andor
c) one or more substituents R20;
v) \u2014OC(\u2550O)RE, \u2014C(\u2550O)ORE, \u2014C(\u2550O)NH2, \u2014C(\u2550O)NHRE, \u2014C(\u2550O)NRERF, \u2014S(O)nRE, \u2014S(O)nNH2, \u2014S(O)nNHRE, \u2014S(O)nNRERF, \u2014NHC(\u2550O)RE, \u2014C(\u2550NRE)RF, \u2014HC\u2550N\u2014OH, \u2014HC\u2550N(alkoxy), \u2014HC\u2550N(alkyl), \u2014NREC(\u2550O)RF, \u2014NHS(O)mRE, and \u2014NRES(O)mRF, where m is 0, 1 or 2, and
RE and RF are independently selected at each occurrence from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, mono- or dialkylamino, aryl, or heteroaryl each of which is optionally substituted by 1, 2, or 3 of R30;
R20 is independently selected at each occurrence from the group consisting of: halogen; hydroxy; nitro; cyano; amino; alkyl; alkoxy optionally substituted with amino or mono- or dialkylamino; cycloalkyl; cycloalkylalkyl; cycloalkylalkoxy; alkenyl; alkynyl; haloalkyl; oxo; haloalkoxy; mono- and dialkylamino; aminoalkyl; and mono- and dialkylaminoalkyl;
R30 is independently selected at each occurrence from halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, oxo, mono- and dialkylamino, aminoalkyl, and mono- and dialkylaminoalkyl;
R5 represents hydrogen or haloalkyl; or
R5 represents alkyl, cycloalkyl, or (cycloalkyl)alkyl, each of which may contain one or more double or triple bonds, and each of which is optionally substituted with 1, 2, or 3 of R30, or
R5 represents aryl, arylalkyl, heteroaryl, or heteroarylalkyl each of which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of haloalkyl, amino, \u2014NH(R10), \u2014N(R10)(R11), carboxamido, (R10)NHcarbonyl, (R10)(R11)Ncarbonyl, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy optionally substituted with amino or mono- or dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, aminoalkyl, and mono- and dialkylaminoalkyl; and
W represents aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with up to 4 groups independently selected from R30, \u2014CO2H, \u2014C(\u2550O)ORE, \u2014C(\u2550O)NHRE, \u2014C(\u2550O)NRERF, \u2014C(O)RE, and \u2014S(O)mRE, \u2014ORE, where R30 and RE are as defined above; and m is 0, 1, or 2.
215. A compound according to claim 214 wherein RH is hydrogen.
216. A compound according to claim 214 wherein RH is halogen.