(S)-3-(2-(4-(benzyl)-3-oxopiperazin-1-yl)acetamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid derivatives and related compounds as caspase inhibitors for treating cardiovascular diseases

A compound of the following formula:

• or a pharmaceutically acceptable salt, solvate, tautomer or isomer thereof, wherein:
• Z is aryl, arylalkyl, heteroaryl or heteroarylalkyl, each of which is optionally substituted;
• Ar is phenyl, phenylalkyl, naphthyl, naphthylalkyl or heteroaryl, each of which is optionally substituted;
• X is a bond, SO2, SO, CO or optionally substituted lower alkylene;
• R1 is hydrogen, lower alkyl, cycloalkyl, (cycloalkyl)alkyl or optionally substituted phenylalkyl;
• R2 and R2′ are selected as follows:
• i) R2 and R2′ are each independently hydrogen, fluoro, —OH, —NH2, lower alkyl, lower alkoxy, lower alklylthio, mono-alkylamino or di-alkylamino, wherein the alkyl chain(s) of lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH2, lower alkoxy, halogen substituted lower alkoxy, lower alkylthio, halogen substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
• or
• ii) R2 and R2′ combine with the carbon to which they are attached to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl, wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH2, lower alkyl, halogen substituted lower alkyl, lower alkoxy, halogen substituted lower alkoxy, lower alkylthio, halogen substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
• R3, R3′, R4, R4′, R5, R5′, R6 and R6′ are selected as follows:
• i) R3, R3′, R4, R4′, R5, R5′, R6 and R6′ are each independently hydrogen, optionally substituted lower alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl;
• ii) R3, R3′ and R6, R6′ together form an optionally substituted aryl, optionally substituted heteroaryl ring, and R4, R4′, R5 and R5′ are each independently hydrogen, optionally substituted lower alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl;
• iii) R4, R4′ and R5, R5′ together form an optionally substituted aryl or optionally substituted heteroaryl ring, and R3, R3′, R6 and R6′ are each independently hydrogen, optionally substituted lower alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl, with the proviso that
• when R3, R3′ and R6, R6′ together form an aryl, substituted aryl, heteroaryl or substituted heteroaryl ring, R4, R4′ and R5, R5′ cannot together form an aryl, substituted aryl, heteroaryl or substituted heteroaryl ring and
• when R4, R4′ and R5, R5′ together form an aryl, substituted aryl, heteroaryl or substituted heteroaryl ring, R3, R3′ and R6, R6′ cannot together form an aryl, substituted aryl, heteroaryl or substituted heteroaryl ring;
• or
• iv) R3 and R3′ together, R4 and R4′ together, R5 and R5′ together or R6 and R6′ together is oxo, and all substituents for R3, R3′, R4, R4′, R5, R5′, R6 and R6′ other than the oxo being as defined in i), ii) and iii) above, with the proviso that:
• when R3 and R3′ together is oxo, none or one of R4 and R4′ together, R5 and R5′ together and R6 and R6′ together is oxo,
• when R4 and R4′ together is oxo, none or one of R3 and R3′ together, R5 and R5′ together and R6 and R6′ together is oxo,
• when R5 and R5′ together is oxo, none or one of R3 and R3′ together, R4 and R4′ together and R6 and R6′ together is oxo, and
• when R6 and R6′ together is oxo, none or one of R3 and R3′ together, R4 and R4′ together and R5 and R5′ together is oxo,
• wherein, unless specified otherwise, the substituents on cycloalkyl, aryl, heterocycloalkyl, and heteroaryl groups, when present are selected from one or more, substituents Q1, wherein each Q1 is independently selected from halogen, —OH, —NH2, —NO2, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH2, —C(S)—NH2, —S(O)2—NH2, —N(H)—C(O)—NH2, —N(H)—C(S)—NH2, —N(H)—S(O)2—NH2, —C(NH)—NH2, —O—Ro, —S—Ro, —O—C(O)—Ro, —O—C(S)—Ro, —C(O)—Ro, —C(S)—Ro, —C(O)—O—Ro, —C(S)—O—Ro, —S(O)—Ro, —S(O)2—Ro, —C(O)—N(H)—Ro, —C(S)—N(H)—Ro, —C(O)—N(Ro)—Ro), —C(S)—N(Ro—Ro, —S(O)2—N(H)—Ro), —S(O)2—N(Ro—Ro, —C(NH)—N(H)—Ro, —C(NH)N(Rp)Ro, —N(H)—C(O)—Ro, —N(H)—C(S)—Ro, —N(Ro)—C(O)—Ro, —N(Ro)—C(S)—Ro, —N(H)—S(O)2—Ro, —N(Ro)—S(O)2—Ro, —N(H)—C(O)—N(H)—Ro, —N(H)—C(S)—N(H)—Ro, —N(Ro)—C(O)—NH2, —N(Ro)—C(S)—NH2, —N(Ro)—C(O)—N(H)—Ro, —N(Ro)—C(S)—N(H)—Ro, —N(H)—C(O)—N(Ro)—Ro, —N(H)—C(S)—N(Ro)—Ro, —N(Ro)—C(O)—N(Ro)—Ro, —N(Ro)—C(S)—N(Ro)—Ro, —N(H)—S(O)2—N(H)—Ro, —N(Ro)—S(O)2—NH2, —N(Ro)—S(O)2—N(H)—Ro, —N(H)—S(O)2—N(Ro)—Ro, —N(Ro)—S(O)2—N(Ro)—Ro, —N(H)—Ro, —N(Ro)—Ro, —Rd, —Re, —Rf, and —Rg;
• unless specified otherwise, the substituents on alkyl, alkenyl and alkynyl groups, when present are selected from one or more substituents Q2, wherein each Q2 is independently selected from —F, —OH, —NH2, —NO2, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH2, —C(S)—NH2, —S(O)2—NH2, —N(H)—C(O)—NH2, —N(H)—C(S)—NH2, —N(H)—S(O)2—NH2, —C(NH), —NH2, —O—Ro, —S—Ro, —O—C(O)—Ro, —O—C(S)—Ro, —C(O)—Ro, —C(S)—Ro, —C(O)—O—Ro, —C(S)—O—Ro, —S(O)—Ro, —S(O)2—Ro, —C(O)—N(H)—Ro, —C(S)—N(H)—Ro, —C(O)—N(Ro)—Ro, —C(S)—N(Ro)—Ro, —S(O)2—N(H)—Ro, —S(O)2—N(Ro)—Ro, —C(NH)—N(H)—Ro, —C(NH)—N(Rp)—Rc, —N(H)—C(O)—Ro, —N(H)—C(S)—Ro, —N(Ro)—C(O)—Ro, —N(Ro)—C(S)—Ro, —N(H)—S(O)2—Ro, —N(Ro)—S(O)2—Ro, —N(H)—C(O)—N(H)—Ro, —N(H)—C(S)—N(H)—Ro, —N(Ro)—C(O)—NH2, —N(Ro)—C(S)—NH2, —N(Ro)—C(O)—N(H)—Ro, —N(Ro)—C(S)—N(H)—Ro, —N(H)—C(O)—N(Ro)—Ro, —N(H)—C(S)—N(Ro)—Ro, —N(Ro)—C(O)—N(Ro)—Ro, —N(Ro)—C(S)—N(Ro)—Ro, —N(H)—S(O)2—N(H)—Ro, —N(Ro)—S(O)2—NH2, —N(Ro)—S(O)2—N(H)—Ro, —N(H)—S(O)2—N(Ro)—Ro, —N(Ro)—S(O)2—N(Ro)—Ro, —N(H)—Ro, —N(Ro)—Ro, —Rd, —Re, and —Rg;
• each Ro, Rp, and Rc are independently selected from the group consisting of Rd, Re, Rf, and Rg, or Rp and Rc combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more, substituents selected from the group consisting of halogen, —NO2, —CN, —OH, —NH2, —O—Ru, —N(H)—Ru, —N(Ru)—Ru, —Rx, and —Ry;
• each Rd is independently lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH2, —NO2, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH2, —C(S)—NH2, —S(O)2—NH2, —N(H)—C(O)—NH2, —N(H)—C(S)—NH2, —N(H)—S(O)2—NH2, —C(NH)—NH2, —O—Rk, —S—Rk, —O—C(O)—Rk, —O—C(S)—Rk, —C(O)—Rk, —C(S)—Rk, —C(O)—O—Rk, —C(S)—O—Rk, —S(O)—Rk, —S(O)2—Rk, —C(O)—N(H)—Rk, —C(S)—N(H)—Rk, —C(O)—N(Rk)—Rk, —C(S)—N(Rk)—Rk, —S(O)2—N(H)—Rk, —S(O)2—N(Rk)—Rk, —C(NH)—N(H)—Rk, —C(NH)—N(Rm)—Rn, —N(H)—C(O)—Rk, —N(H)—C(S)—Rk, —N(Rk)—C(O)—Rk, —N(Rk)—C(S)—Rk, —N(H)—S(O)2—Rk, —N(Rk)—S(O)2—Rk, —N(H)—C(O)—N(H)—Rk, —N(H)—C(S)—N(H)—Rk, —N(Rk)—C(O)—NH2, —N(Rk)—C(S)—NH2, —N(Rk)—C(O)—N(H)—Rk, —N(Rk)—C(S)—N(H)—Rk, —N(H)—C(O)—N(Rk)—Rk, —N(H)—C(S)—N(Rk)—Rk, —N(Rk)C(O)N(Rk)Rk, —N(Rk)C(S)N(Rk)Rk, —N(H)—S(O)2—N(H)—Rk, —N(Rk)—S(O)2—NH2, —N(Rk)—S(O)2—N(H)—Rk, —N(H)—S(O)2—N(Rk)—Rk, —N(Rk)—S(O)2—N(Rk)—Rk, —N(H)—Rk, —N(Rk)—Rk, —Ri, and —Rj;
• each Re is independently lower alkenyl, wherein lower alkenyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH2, —NO2, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH2, —C(S)—NH2, —S(O)2—NH2, —N(H)—C(O)—NH2, —N(H)—C(S)—NH2, —N(H)—S(O)2—NH2, —C(NH)—NH2, —O—Rk, —S—Rk, —O—C(O)—Rk, —O—C(S)—Rk, —C(O)—Rk, —C(S)—Rk, —C(O)—O—Rk, —C(S)—O—Rk, —S(O)—Rk, —S(O)2—Rk, —C(O)—N(H)—Rk, —C(S)—N(H)—Rk, —C(O)—N(Rk)—Rk, —C(S)—N(Rk)—Rk, —S(O)2—N(H)—Rk, —S(O)2—N(Rk)—Rk, —C(NH)—N(H)—Rk, —C(NH)—N(Rm)—Rn, —N(H)—C(O)—Rk, —N(H)—C(S)—Rk, —N(Rk)—C(O)—Rk, —N(Rk)—C(S)—Rk, —N(H)—S(O)2—Rk, —N(Rk)—S(O)2—Rk, —N(H)—C(O)—N(H)—Rk, —N(H)—C(S)—N(H)—Rk, —N(Rk)—C(O)—NH2, —N(Rk)—C(S)—NH2, —N(Rk)—C(O)—N(H)—Rk, —N(Rk)—C(S)—N(H)—Rk, —N(H)—C(O)—N(Rk)—Rk, —N(H)—C(S)—N(Rk)—Rk, —N(Rk)C(O)N(Rk)Rk, —N(Rk)C(S)N(Rk)Rk, —N(H)—S(O)2—N(H)—Rk, —N(Rk)—S(O)2—NH2, —N(Rk)—S(O)2—N(H)—Rk, —N(H)—S(O)2—N(Rk)—Rk, —N(Rk)—S(O)2—N(Rk)—Rk, —N(H)—Rk, —N(Rk)—Rk, —Rh, and —Rj;
• each Rf is independently lower alkynyl, wherein lower alkynyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH2, —NO2, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH2, —C(S)—NH2, —S(O)2—NH2, —N(H)—C(O)—NH2, —N(H)—C(S)—NH2, —N(H)—S(O)2—NH2, —C(NH)—NH2, —O—Rk, —S—Rk, —O—C(O)—Rk, —O—C(S)—Rk, —C(O)—Rk, —C(S)—Rk, —C(O)—O—Rk, —C(S)—O—Rk, —S(O)—Rk, —S(O)2—Rk, —C(O)—N(H)—Rk, —C(S)—N(H)—Rk, —C(O)—N(Rk)—Rk, —C(S)—N(Rk)—Rk, —S(O)2—N(H)—Rk, —S(O)2—N(Rk)—Rk, —C(NH)—N(H)—Rk, —C(NH)—N(Rm)—Rn, —N(H)—C(O)—Rk, —N(H)—C(S)—Rk, —N(Rk)—C(O)—Rk, —N(Rk)—C(S)—Rk, —N(H)—S(O)2—Rk, —N(Rk)—S(O)2—Rk, —N(H)—C(O)—N(H)—Rk, —N(H)—C(S)—N(H)—Rk, —N(Rk)—C(O)—NH2, —N(Rk)—C(S)—NH2, —N(Rk)—C(O)—N(H)—Rk, —N(Rk)—C(S)—N(H)—Rk, —N(H)—C(O)—N(Rk)—Rk, —N(H)—C(S)—N(Rk)—Rk, —N(Rk)C(O)N(Rk)Rk, —N(Rk)C(S)N(Rk)Rk, —N(H)—S(O)2—N(H)—Rk, —N(Rk)—S(O)2—NH2, —N(Rk)—S(O)2—N(H)—Rk, —N(H)—S(O)2—N(Rk)—Rk, —N(Rk)—S(O)2—N(Rk)—Rk, —N(H)—Rk, —N(Rk)—Rk, —Rh, and —Rj;
• each Rg is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH2, —NO2, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH2, —C(S)—NH2, —S(O)2—NH2, —N(H)—C(O)—NH2, —N(H)—C(S)—NH2, —N(H)—S(O)2—NH2, —C(NH)—NH2, —O—Rk, —O—C(O)—Rk, —O—C(S)—Rk, —C(O)—Rk, —C(S)—Rk, —C(O)—O—Rk, —C(S)—O—Rk, —S(O)—Rk, —S(O)2—Rk, —C(O)—N(H)—Rk, —C(S)—N(H)—Rk, —C(O)—N(Rk)—Rk, —C(S)—N(Rk)—Rk, —S(O)2—N(H)—Rk, —S(O)2—N(Rk)—Rk, —C(NH)—N(H)—Rk, —C(NH)—N(Rm)—Rn, —N(H)—C(O)—Rk, —N(H)—C(S)—Rk, —N(Rk)—C(O)—Rk, —N(Rk)—C(S)—Rk, —N(H)—S(O)2—Rk, —N(Rk)—S(O)2—Rk, —N(H)—C(O)—N(H)—Rk, —N(H)—C(S)—N(H)—Rk, —N(Rk)—C(O)—NH2, —N(Rk)—C(S)—NH2, —N(Rk)C(O)N(H)Rk, —N(Rk)C(S)N(H)Rk, —N(H)—C(O)—N(Rk)—Rk, —N(H)—C(S)—N(Rk)—Rk, —N(Rk)—C(O)—N(Rk)—Rk, —N(Rk)—C(S)—N(Rk)—Rk, —N(H)—S(O)2—N(H)—Rk, —N(Rk)—S(O)2—NH2, —N(Rk)—S(O)2—N(H)—Rk, —N(H)—S(O)2—N(Rk)—Rk, —N(Rk)—S(O)2—N(Rk)— Rk, —N(H)—Rk, —N(Rk)—Rk, —Rh, —Ri, and —Rj;
• Rk, Rm, and Rn are each independently selected from the group consisting of Rh, Ri, and Rj, or Rm and Rn combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —OH, —NH2, —O—Ru, —S—Ru, —N(H)—Ru, —NRuRu, —Rx, and —Ry;
• each Rh is independently lower alkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH2, —NO2, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH2, —C(S)—NH2, —S(O)2—NH2, —N(H)—C(O)—NH2, —N(H)—C(S)—NH2, —N(H)—S(O)2—NH2, —C(NH)—NH2, —O—Rf—S—Rf, —O—C(O)—Rr, —O—C(S)—Rr, —C(O)—Rr, —C(S)—Rr, —C(O)—O—Rr, —C(S)—O—Rr, —S(O)—Rr, —S(O)2—Rr, —C(O)—N(H)—Rr, —C(S)—N(H)—Rr, —C(O)—N(Rr)—Rr, —C(S)—N(Rr)—Rr, —S(O)2—N(H)—Rr, —S(O)2—N(Rr)—Rr, —C(NH)—N(H)—Rr, —C(NH)N(Rs)Rt, —N(H)—C(O)—Rr, —N(H)—C(S)—Rr, —N(Rr)—C(O)—Rr, —N(Rr)—C(S)—Rr, —N(H)—S(O)2—Rr, —N(Rr)—S(O)2—Rr, —N(H)—C(O)—N(H)—Rr, —N(H)—C(S)—N(H)—Rr, —N(Rr)—C(O)—NH2, —N(Rr)—C(S)—NH2, —N(Rr)—C(O)—N(H)—Rr, —N(Rr)—C(S)—N(H)—Rr, —N(H)—C(O)—N(Rr)—Rr, —N(H)—C(S)—N(Rr)—Rr, —N(Rr)—C(O)—N(Rr)—Rr, —N(Rr)—C(S)—N(Rr)—Rr, —N(H)—S(O)2—N(H)—Rr, —N(Rr)—S(O)2—NH2, —N(Rr)—S(O)2—N(H)—Rr, —N(H)—S(O)2—N(Rr)—Rr, —N(Rr)—S(O)2—N(Rr)—Rr, —N(H)—Rr, —N(Rr)—Rr, —Ri, and —Rj;
• each Ri is independently selected from the group consisting of lower alkenyl and lower alkynyl, wherein lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH2, —NO2, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH2, —C(S)—NH2, —S(O)2—NH2, —N(H)—C(O)—NH2, —N(H)—C(S)—NH2, —N(H)—S(O)2—NH2, —C(NH)—NH2, —O—Rr, —S—Rr, —O—C(O)—Rr, —O—C(S)—Rr, —C(O)—Rr, —C(S)—Rr, —C(O)—O—Rr, —C(S)—O—Rr, —S(O)—Rr, —S(O)2—Rr, —C(O)—N(H)—Rr, —C(S)—N(H)—Rr, —C(O)—N(Rr)—Rr, —C(S)—N(Rr)—Rr, —S(O)2—N(H)—Rr, —S(O)2—N(Rr)—Rr, —C(NH)—N(H)—Rr, —C(NH)—N(Rs)—Rt, —N(H)—C(O)—Rr, —N(H)—C(S)—Rr, —N(Rr)—C(O)—Rr, —N(Rr)—C(S)—Rr, —N(H)—S(O)2—Rr, —N(Rr)—S(O)2—Rr, —N(H)—C(O)—N(H)—Rr, —N(H)—C(S)—N(H)—Rr, —N(Rr)—C(O)—NH2, —N(Rr)—C(S)—NH2, —N(Rr)—C(O)—N(H)—Rr, —N(Rr)—C(S)—N(H)—Rr, —N(H)—C(O)—N(Rr)—Rr, —N(H)—C(S)—N(Rr)—Rr, —N(Rr)—C(O)—N(Rr)—Rr, —N(Rr)—C(S)—N(Rr)—Rr, —N(H)—S(O)2—N(H)—Rr, —N(Rr)—S(O)2—NH2, —N(Rr)—S(O)2—N(H)—Rr, —N(H)—S(O)2—N(Rr)—Rr, —N(Rr)—S(O)2—N(Rr)—Rr, —N(H)—Rr, —N(Rr)—Rr, and —Rj;
• each Rj is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH2, —NO2, —CN, —C(O)—OH, —C(S)—OH, —C(O)—NH2, —C(S)—NH2, —S(O)2—NH2, —N(H)—C(O)—NH2, —N(H)—C(S)—NH2, —N(H)—S(O)2—NH2, —C(NH)—NH2, —O—Rr, —S—Rr, —O—C(O)—Rr, —O—C(S)—Rr, —C(O)—Rr, —C(S)—Rr, —C(O)—O—Rr, —C(S)—O—Rr, —S(O)—Rr, —S(O)2—Rr, —C(O)—N(H)—Rr, —C(S)—N(H)—Rr, —C(O)—N(Rr)—Rr, —C(S)—N(Rr)—Rr, —S(O)2—N(H)—Rr, —S(O)2—N(Rr)—Rr, —C(NH)—N(H)—Rr, —C(NH)N(Rs)Rt, —N(H)—C(O)—Rr, —N(H)—C(S)—Rr, —N(Rr)—C(O)—Rr, —N(Rr)—C(S)—Rr, —N(H)—S(O)2—Rr, —N(Rr)—S(O)2—Rr, —N(H)—C(O)—N(H)—Rr, —N(H)—C(S)—N(H)—Rr, —N(Rr)—C(O)—NH2, —N(Rr)—C(S)—NH2, —N(Rr)—C(O)—N(H)—Rr, —N(Rr)—C(S)—N(H)—Rr, —N(H)—C(O)—N(Rr)—Rr, —N(H)—C(S)—N(Rr)—Rr, —N(Rr)—C(O)—N(Rr)—Rr, —N(Rr)—C(S)—N(Rr)—Rr, —N(H)—S(O)2—N(H)—Rr, —N(Rr)—S(O)2—NH2, —N(Rr)—S(O)2—N(H)—Rr, —N(H)—S(O)2—N(Rr)—Rr, —N(Rr)—S(O)2—N(Rr)—Rr, —N(Rr)—Rr, cycloalkylamino, and —Rx;
• each Rr, Rs, and Rt at each occurrence are independently selected from the group consisting of lower alkyl, C3-6 alkenyl, C3-6alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of —Ry, fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein C3-6 alkenyl or C3-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of —Ry, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH2, —NO2, —CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, or Rs and Rt combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —OH, —NH2, —O—Ru, —N(H)—Ru, —N(Ru)—Ru, —Rx, and —Ry;
• each Ru is independently selected from the group consisting of lower alkyl, C3-6 alkenyl, C3-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of —Ry, fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein C3-6 alkenyl or C3-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of —Ry, fluoro, —OH, —NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH2, —NO2, —CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
• each Rx is selected from the group consisting of lower alkyl, lower alkenyl and lower alkynyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of —Ry, fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of —Ry, fluoro, —OH, —NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
• and
• each Ry is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH2, —NO2, —CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino.