Hydrazonamide compounds that modulate Hsp90 activity

1. A compound according to the formula:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —C(O)R 7 , —C(O)NR 10 R 11 , —C(O)OR 7 , —C(S)R 7 , —C(O)SR 7 , —C(S)SR 7 , —C(S)OR 7 , —C(S)NR 10 R 11 , —C(NR 7 )OR 7 , —C(NR 7 )R 7 , —C(NR 7 )NR 10 R 11 or —C(NR 7 )SR 7 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl represented by R 1 are optionally and independently substituted;

R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, cyano, nitro, —NR 10 R 11 , —OR 7 , —C(S)R 7 , —C(O)SR 7 , —C(S)SR 7 , —C(S)OR 7 , —C(S)NR 10 R 11 , —C(NR 7 )OR 7 , —C(NR 7 )NR 10 R 11 , —C(NR 7 )SR 7 , —OC(O)R 7 , —OC(O)OR 7 , —OC(S)OR 7 , —OC(NR 7 )OR 7 , —SC(O)R 7 , —SC(O)OR 7 , —SC(NR 7 )OR 7 , —OC(S)R 7 , —SC(S)R 7 , —SC(S)OR 7 , —OC(O)NR 10 R 11 , —OC(S)NR 10 R 11 , —OC(NR 7 )NR 10 R 11 , —SC(O)NR 10 R 11 , —SC(NR 7 )NR 10 R 11 , —SC(S)NR 10 R 11 , —OC(NR 7 )R 7 , —SC(NR 7 )R 7 , —NR 7 C(O)R 7 , —NR 7 C(S)R 7 , —NR 7 C(S)OR 7 , —NR 7 C(NR 7 )R 7 , —NR 7 C(O)OR 7 , —NR 7 C(NR 7 )OR 7 , —NR 7 C(O)NR 10 R 11 , —NR 7 C(S)NR 10 R 11 , —NR 7 C(NR 7 )NR 10 R 11 , —S(O) P R 7 , —OS(O) P R 7 , —OS(O) P OR 7 , —OS(O) p NR 10 R 11 , —S(O) P OR 7 , —NR 7 S(O) P R 7 , —NR 7 S(O) P NR 10 R 11 , —NR 7 S(O) P OR 7 , —S(O) P NR 10 R 11 , —SS(O) P R 7 , —SS(O) P OR 7 , —SS(O) P NR 10 R 11 , —OP(O)(OR 7 ) 2 , or —SP(O)(OR 7 ) 2 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl represented by R 2 are optionally and independently substituted;

R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(S)OR 7 , —C(O)NR 10 R 11 , —S(O) P R 7 , —C(S)R 7 and —C(S)NR 10 R 11 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl and heteroaralkyl represented by R 3 is independently and optionally substituted;

R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaralkyl, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(S)OR 7 , —C(O)NR 10 R 11 , —S(O) P R 7 —C(S)R 7 and —C(S)NR 10 R 11 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaralkyl represented by R 4 is independently and optionally substituted;

each R 7 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkyl represented by R 7 is optionally and independently substituted;

each R 10 and R 11 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkyl represented by R 10 or R 11 is optionally and independently substituted; or

R 10 and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

Z is NH or O;

Y is NR 10 ; and

each p is independently 0, 1 or 2;

with the provisos that 1) when Z is O, then R 3 is other than hydrogen; 2) when Z is NH, then R 3 is other than an unsubstituted phenyl or a di-nitro substituted phenyl; or 3) when Z is NH and R 3 is hydrogen, then R 4 is not 1-methyl-indol-5-yl.

2. The compound of claim 1 , represented by the formula:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein:

R 1 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 5-7 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl, 6-14 membered aryl-(C 1 -C 4 )alkyl, 5-10 membered heteroaryl-(C 1 -C 4 )alkyl, —SR 7 , —S(O) 2 R 7 , —C(O)R 7 , —C(O)OR 7 , or —C(O)NR 10 R 11 , wherein each alkyl, cycloalkyl, aryl and heteroaryl represented by R 1 is optionally substituted with one or more halo, cyano, nitro, azido, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl, piperidinyl, imidazolyl, pyrrolidinyl, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(O)NR 10 R 11 , —NR 7 C(O)R 7 , —NR 7 C(O)NR 10 R 11 , —S(O) P R 7 , —OS(O) P R 7 or —S(O) p NR 10 R 11 ;

R 2 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —OR 7 , —SR 7 , —S(O) 2 R 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —C(O)NR 10 R 11 , or —NR 7 C(O)R 7 , wherein each alkyl, alkoxy, thioalkoxy and alkylsulfonyl represented by R 2 is optionally and independently substituted with one or more of halo, cyano, nitro, azido, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl, piperidinyl, imidazolyl, pyrrolidinyl, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(O)NR 10 R 11 , —NR 7 C(O)R 7 , —NR 7 C(O)NR 10 R 11 , —S(O) P R 7 , —OS(O) P R 7 or —S(O) p NR 10 R 11 ;

R 3 is hydrogen, (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, 5-7 membered heterocyclyl, (C 6 -C 10 )aryl, 5-10 membered heteroaryl, (C 6 -C 10 )aryl —(C 1 -C 3 )alkyl, 5-10 membered heteroaryl-(C 1 -C 3 )alkyl, —C(O)R 7 , —C(O)OR 7 , —C(S)R 7 , —C(O)SR 7 , —C(S)SR 7 , —C(S)OR 7 , —C(S)NR 10 R 11 , —C(NR 7 )OR 7 , —C(NR 7 )R 7 , —C(NR 7 )NR 10 R 11 , —C(NR 7 )SR 7 , —SC(O)R 7 , —SC(O)OR 7 , —SC(NR 7 )OR 7 , SC(O)NR 10 R 11 , —SC(NR 7 )NR 10 R 11 , —SC(S)NR 10 R 11 , —S(O) P OR 7 , —S(O) P R 7 , —SP(O)(OR 7 ) 2 or —S(O) p NR 10 R 11 , wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-alkyl and heteroaryl-alkyl is optionally and independently substituted with one or more (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )aminoalkyl, (C 2 -C 3 )alkenyl, (C 2 -C 3 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 5 -C 6 )cycloalkenyl, (5-7 membered) heterocyclyl, (5-7 membered)heterocyclyl-(C 1 -C 3 )alkyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl-(C 1 -C 3 )alkyl, (5-7 membered)-heteroaryl, halo, cyano, nitro, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(S)R 7 , —C(O)SR 7 , —C(S)OR 7 , —C(S)NR 10 R 11 , —C(NR 7 )OR 7 , —C(NR 7 )R 7 , —C(NR 7 )NR 10 R 11 , —OC(O)R 7 , —SC(O)R 7 , —OC(S)R 7 , —OC(O)NR 10 R 11 , —OC(S)NR 10 R 11 , —SC(O)NR 10 R 11 , —OC(NR 7 )R 7 , —C(O)NR 10 R 11 , —NR 7 C(O)R 7 , —NR 7 C(S)R 7 , —NR 7 C(S)OR 7 , —NR 7 C(NR 7 )R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)NR 10 R 11 , —NR 7 C(S)NR 10 R 11 , —S(O) P R 7 , —OS(O) P R 7 , —OS(O) p NR 10 R 11 , —S(O) P OR 7 , —NR 7 S(O) P R 7 , —NR 7 S(O) p NR 10 R 11 —NR 7 S(O) P OR 7 , —S(O) P NR 10 R 11 , —OP(O)(OR 7 ) 2 , or —SP(O)(OR 7 ) 2 ; and

R 4 is (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, 5-7 membered heterocyclyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl-(C 1 -C 3 )alkyl, 5-10 membered heteroaryl-(C 1 -C 3 )alkyl, each of which is optionally substituted with one or more (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )aminoalkyl, (C 2 -C 3 )alkenyl, (C 2 -C 3 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 5 -C 6 )cycloalkenyl, (5-7 membered)heterocyclyl, (5-7 membered)heterocyclyl-(C 1 -C 3 )alkyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl-(C 1 -C 3 )alkyl, (5-7 membered)-heteroaryl, halo, cyano, nitro, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(S)R 7 , —C(O)SR 7 , —C(S)OR 7 , —C(S)NR 10 R 11 , —C(NR 7 )OR 7 , —C(NR 7 )R 7 , —C(NR 7 )NR 10 R 11 , —OC(O)R 7 , —SC(O)R 7 , —OC(S)R 7 , —OC(O)NR 10 R 11 , —OC(S)NR 10 R 11 , —SC(O)NR 10 R 11 , —OC(NR 7 )R 7 , —C(O)NR 10 R 11 , —NR 7 C(O)R 7 , —NR 7 C(S)R 7 , —NR 7 C(S)OR 7 , —NR 7 C(NR 7 )R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)NR 10 R 11 , —NR 7 C(S)NR 10 R 11 , —S(O) P R 7 , —OS(O) P R 7 , —OS(O) p NR 10 R 11 , —S(O) p OR 7 , —NR 7 S(O) P R 7 , —NR 7 S(O) P NR 10 R 11 , —NR 7 S(O) P OR 7 , —S(O) p NR 10 R 11 , —OP(O)(OR 7 ) 2 , or —SP(O)(OR 7 ) 2 .

4. The compound of claim 3 , represented by the following formula:

or a pharmaceutically acceptable salt thereof, wherein:

each R 7 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl, benzyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl, piperidinyl, imidazolyl or pyrrolidinyl, wherein each substituent represented by R 7 , excluding hydrogen, is optionally and independently substituted by halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 thioalkoxy, cyano, —S(O)R 12 , —S(O) 2 R 12 , —N(R 12 ) 2 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —C(O)R 12 , —S(O) 2 N(R 12 ) 2 , —NR 12 C(O)R 12 , —NR 12 S(O) 2 R 12 or phenyl;

each R 10 and R 11 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl, benzyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl, piperidinyl, imidazolyl, pyrrolidinyl, wherein each substituent represented by R 10 or R 11 , excluding hydrogen, is optionally and independently substituted by halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 thioalkoxy, cyano, —S(O)R 12 , —S(O) 2 R 12 , —N(R 12 ) 2 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —C(O)R 12 , —S(O) 2 N(R 12 ) 2 , —NR 12 C(O)R 12 , —NR 12 S(O) 2 R 12 or phenyl; or

R 10 and R 11 taken together with the nitrogen to which they are attached, form a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl each independently and optionally substituted with halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 thioalkoxy, cyano, —S(O)R 12 , —S(O) 2 R 12 , —N(R 12 ) 2 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —C(O)R 12 , —S(O) 2 N(R 12 ) 2 , —NR 12 C(O)R 12 , —NR 12 S(O) 2 R 12 or phenyl; and

R 12 is hydrogen or (C 1 -C 3 )alkyl.

5. The compound of claim 4 , wherein:

R 1 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl, benzyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, naphthyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyridinyl, 1-oxo-pyridinyl, furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, imidazo[1,2-a]pyridyl, benzothienyl, —S(O) 2 R 7 , —C(O)R 7 , —C(O)OR 7 or —C(O)NR 10 R 11 , wherein each value defined by R 1 , excluding hydrogen, is optionally substituted with one or more halo, cyano, nitro, azido, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl, piperidinyl, imidazolyl, pyrrolidinyl, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(O)NR 10 R 11 , —NR 7 C(O)R 7 , —NR 7 C(O)NR 10 R 11 , —S(O) P R 7 , —OS(O) P R 7 or —S(O) p NR 10 R 11 .

6. The compound of claim 5 , wherein R 1 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl, benzyl, —S(O) 2 R 12 , —C(O)R 12 , —C(O)OR 12 or —C(O)N(R 12 ) 2 , wherein each value defined by R 1 , excluding hydrogen, is optionally substituted optionally substituted with one or more halo, cyano, nitro, azido, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl, piperidinyl, imidazolyl, pyrrolidinyl, —N(R 12 ) 2 , —OR 12 , —C(O)R 12 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —NR 12 C(O)R 12 , —NR 12 C(O)N(R 12 ) 2 , —S(O) P R 12 , or —S(O) P N(R 12 ) 2 ; and

R 12 is hydrogen or C 1 -C 3 alkyl.

7. The compound according to claim 6 wherein R 1 is hydrogen, methyl or ethyl.

8. The compound according to claim 7 , wherein R 2 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 alkylsulfonyl, C 3 -C 6 cycloalkyl, —N(R 12 ) 2 , —C(O)R 12 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , Or —NR 12 C(O)R 12 ; and R 12 is hydrogen or (C 1 -C 3 )alkyl.

9. The compound of claim 8 , wherein R 2 is isopropyl.

10. The compound of claim 5 , wherein R 4 is represented by the structure:

wherein each X is independently CR 21 ;

each R 21 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halo, cyano, nitro, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(S)R 7 , —C(O)SR 7 , —C(S)OR 7 , —C(S)NR 10 R 11 , —C(NR 7 )OR 7 , —C(NR 7 )R 7 , —C(NR 7 )NR 10 R 11 , —C(NR 7 )SR 7 , —OC(O)R 7 , —OC(O)OR 7 , —OC(NR 7 )OR 7 , —OC(S)R 7 , —OC(O)NR 10 R 11 , —OC(NR 7 )NR 10 R 11 , —OC(NR 7 )R 7 , —C(O)NR 10 R 11 , —NR 7 C(O)R 7 , —NR 7 C(S)OR 7 , —NR 7 C(NR 7 )R 7 , —NR 7 C(O)OR 7 , —NR 7 C(NR 7 )OR 7 , —NR 7 C(O)NR 10 R 11 , —NR 7 C(NR 7 )NR 10 R 11 , —OS(O) P R 7 , —OS(O) P OR 7 , —OS(O) P NR 10 R 11 , —S(O) P OR 7 , —NR 7 S(O) P R 7 , —NR 7 S(O) p NR 10 R 11 , —NR 7 S(O) P OR 7 , —S(O) P NR 10 R 11 , or OP(O)(OR 7 ) 2 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl and heteroaralkyl represented by R 21 is optionally and independently substituted;

or two adjacent R 21 substituents, together with the atoms to which they are attached, form a cycloalkyl, heterocyclyl, aryl, or heteroaryl moiety, each of which may be optionally substituted;

each R 7 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl, benzyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl, piperidinyl, imidazolyl, pyrrolidinyl, wherein each substituent represented by R 7 , excluding hydrogen, is optionally and independently substituted by CpC 3 alkyl, halo, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, —N(R 12 ) 2 , cyano, —C(O)OR 12 , —C(O)N(R 12 ) 2 , —C(O)R 12 , —NR 12 C(O)R 12 or phenyl;

each R 10 and R 11 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl, benzyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl, piperidinyl, imidazolyl, pyrrolidinyl, wherein each substituent represented by R 10 or R 11 , excluding hydrogen, is optionally and independently substituted by C 1 -C 3 alkyl, halo, C r C 3 haloalkyl, Ci-C 3 alkoxy, —N(R 12 ) 2 , cyano, —C(O)OR 12 , —C(O)N(R 12 ) 2 , C(O)R 12 , —NR 12 C(O)R 12 or phenyl; or

R 10 and R 11 , taken together with the nitrogen to which they are attached, form a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl each independently and optionally substituted with C 1 -C 3 alkyl, halo, C 1 -C 3 haloalkyl, C,-C 3 alkoxy, —N(R 12 ) 2 , cyano, —C(O)OR 12 , —C(O)N(R 12 ) 2 , C(O)R 12 , —NR 12 C(O)R 12 or phenyl;

n is an integer from 0 to 3;

p is an integer from 0 to 2;

q is an integer from 0 to 3; and

B is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halo, cyano, nitro, guanadino, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(S)R 7 , —C(O)SR 7 , —C(S)OR 7 , —C(S)NR 10 R 11 , —C(NR 7 )OR 7 , —C(NR 7 )R 7 , —C(NR 7 )NR 10 R 11 , —C(NR 7 )SR 7 , —OC(O)R 7 , —OC(O)OR 7 , —OC(S)OR 7 , —OC(NR 7 )OR 7 , —SC(O)R 7 , —SC(O)OR 7 , —SC(NR 7 )OR 7 , —OC(S)R 7 , —SC(S)R 7 , —SC(S)OR 7 , —OC(O)NR 10 R 11 , —OC(S)NR 10 R 11 , —OC(NR)NR 10 R 11 , —SC(O)NR 10 R 11 , —SC(NR 7 )NR 10 R 11 , —SC(S)NR 10 R 11 , —OC(NR 7 )R 7 , —SC(NR 7 )R 7 , —C(O)NR 10 R 11 , —NR 7 C(O)R 7 , —NR 7 C(S)R 7 , —NR 7 C(S)OR 7 , —NR 7 C(NR 7 )R 7 , —NR 7 C(O)OR 7 , —NR 7 C(NR 7 )OR 7 , —NR 7 C(O)NR 10 R 11 , —NR 7 C(S)NR 10 R 11 , —NR 7 C(NR 7 )NR 10 R 11 , —S(O) P R 7 , —OS(O) P R 7 , —OS(O) P OR 7 , —OS(O) p NR 10 R 11 , —S(O) P OR 7 , —NR 7 S(O) P R 7 , —NR 7 S(O) p NR 10 R 11 , —NR 7 S(O) P OR 7 , —S(O) p NR 10 R 11 , —SS(O) P R 7 , SS(O) P OR 7 , —SS(O) p NR 10 R 11 , —OR(O)(OR 7 ) 2 , or —SP(O)(OR 7 ) 2 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl and heteroaralkyl represented by B is optionally and independently substituted.

11. The compound of claim 10 , wherein:

wherein R 7 is H, methyl, ethyl or phenyl, and wherein the methyl, ethyl or phenyl is optionally substituted with methoxy, ethoxy, hydroxyl, dimethylamine, methylamine, ethylamine, diethylamine, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperizinyl, 1-methylpiperizinyl, 1-ethylpiperizinyl or piperidinyl; and

each R 10 and R 11 is independently H, methyl, ethyl, propyl, i-propyl, butyl, t-butyl, or i-butyl, wherein each methyl, ethyl, propyl, i-propyl, butyl, t-butyl and i-butyl represented by R 10 or R 11 is independently and optionally substituted with methoxy, ethoxy, hydroxyl, dimethylamine, methylamine, ethylamine, diethylamine, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperizinyl, 1-methylpiperizinyl, 1-ethylpiperizinyl or piperidinyl.

12. The compound of claim 11 , wherein R 4 is represented by the following formula:

wherein:

m is an integer from 0 to 2;

n is an integer from 0 to 1; and

q is an integer from 0 to 1.

13. The compound of claim 12 , represented by the formula:

or a pharmaceutically acceptable salt thereof;

wherein:

q is 0 or 1;

each R 21 is independently alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(O)NR 10 R 11 , —NR 7 C(O)R 7 , —NR 7 C(O)NR 10 R 11 , —S(O) p R 7 , —OS(O) P R 7 , —S(O) P NR 10 R 11 , wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl represented by R 21 is optionally and independently substituted by one or more halo, cyano, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl, piperidinyl, imidazolyl, pyrrolidinyl, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(O)NR 10 R 11 , —NR 7 C(O)R 7 , —NR 7 C(O)NR 10 R 11 , —S(O) p R 7 , —OS(O) P R 7 , —S(O)pNR 10 R 11 ;

or two adjacent R 21 substituents, together with the atoms to which they are attached, form a C 5 -C 6 cycloalkyl, phenyl, 5-6 membered heterocyclyl, or 5-6 membered heteroaryl moiety, each of which may be optionally substituted by one or more by one or more halo, cyano, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl, piperidinyl, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(O)NR 10 R 11 , —NR 7 C(O)R 7 , —NR 7 C(O)NR 10 R 11 , —S(O) P R 7 , —OS(O) P R 7 , or —S(O) P NR 10 R 11 ;

B is hydrogen, heterocyclyl, cycloalkyl, heteroaryl, aryl, alkyl, alkenyl, alkynyl, halo, cyano, nitro, —OR 7 , —SR 7 , —NR 10 R 11 , —NR 10 C(O)R 7 , —S(O) P NR 10 R 11 , —C(O)NR 10 R 11 , —NR 10 C(O)NR 10 R 11 , wherein each heterocyclyl, cycloalkyl, heteroaryl, aryl, alkyl, alkenyl and alkynyl represented by B is optionally and independently substituted by one or more by one or more C 1 -C 3 alkyl, halo, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, —N(R 12 ) 2 , cyano, —C(O)OR 12 , —C(O)N(R 12 ) 2 , C(O)R 12 , —NR 12 C(O)R 12 or phenyl; and

R 12 is hydrogen or C 1 -C 3 alkyl.

14. The compound of claim 13 , wherein:

each R 21 is independently C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl, halo, cyano, nitro, —N(R 12 ) 2 , —OR 12 , —C(O)R 12 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —NR 12 C(O)R 12 or —S(O) P R 12 , wherein each substituent represented by R 21 is optionally and independently substituted by one or more halo, cyano, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, phenyl, —N(R 12 ) 2 or —OR 12 ; and

B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, naphthyl, morpholinyl, thiomorpholinyl, 4-oxo-thiomorpholin-1-yl, 4,4-dioxo-thiomorpholin-1-yl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyridinyl, 1-oxo-pyridinyl, furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, imidazo[1,2-a]pyridyl, or benzothienyl, each of which is optionally and independently substituted with one or more halo, cyano, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, phenyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl, piperidinyl, —N(R 12 ) 2 , —OR 12 , —C(O)R 12 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —NR 12 C(O)R 12 , —NR 12 C(O)N(R 12 ) 2 , —S(O) P R 12 , —OS(O) P R 12 , or —S(O) P N(R 12 ) 2 .

15. The compound of claim 14 , wherein B is morpholinyl, thiomorpholinyl, pyrrolidinyl or piperizinyl, each of which may be optionally and independently substituted with one or more C 1 -C 3 alkyl, —OR 12 , —N(R 12 ) 2 or halo and m is 0 or 1.

16. The compound of claim 13 , wherein:

wherein R 7 is H, methyl, ethyl or phenyl, and wherein the methyl, ethyl or phenyl is optionally substituted with methoxy, ethoxy, hydroxyl, dimethylamine, methylamine, ethylamine, diethylamine, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperizinyl, 1-methylpiperizinyl, 1-ethylpiperizinyl or piperidinyl;

each R 10 and R 11 is independently H, methyl, ethyl, propyl, l-propyl, butyl, l-butyl, or l-butyl, wherein each methyl, ethyl, propyl, l-propyl, butyl, l-butyl and l-butyl represented by R 10 or R 11 is independently and optionally substituted with methoxy, ethoxy, hydroxyl, dimethylamine, methylamine, ethylamine, diethylamine, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperizinyl, 1-methylpiperizinyl, 1-ethylpiperizinyl or piperidinyl;

two adjacent R 21 moieties, along with the atoms to which they are attached, form a 5-6 membered heterocyclyl, optionally substituted with one or more halo, Ci-C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, —N(R 12 ) 2 , —OR 12 , —C(O)R 12 , —C(O)OR 12 , —C(O)N(R 12 ) 2 ;

B is hydrogen;

X is CR 21 ;

m is 2 or 3; and

q is O.

17. The compound of claim 16 , wherein two adjacent R 21 moieties, along with the atoms to which they are attached, form a benzo[1,3]dioxole.

18. The compound of claim 5 , wherein:

R 3 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, imidazolidinyl, furanyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyrimidinyl, triazinyl, pyridazinyl, pyridinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, phenyl, benzyl, tolyl, naphthyl, —C(O)R 7 , —C(O)OR 7 , —C(S)R 7 , —C(O)SR 7 , —C(O)NR 10 R 11 , —C(S)SR 7 , —C(S)OR 7 , —C(S)NR 10 R 11 , —C(NR 7 )OR 7 , —C(NR 7 )R 7 , —C(NR 7 )NR 10 R 11 , —C(NR 7 )SR 7 , —SC(O)R 7 , —SC(O)OR 7 , —SC(NR 7 )OR 7 , SC(O)NR 10 R 11 , —SC(NR 7 )NR 10 R 11 , —SC(S)NR 10 R 11 , —S(O) P OR 7 , —S(O) P R 7 , —SP(O)(OR 7 ) 2 or —S(O) p NR 10 R 11 , wherein each moiety represented by R 3 , excluding hydrogen, is optionally and independently substituted with one or more (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )aminoalkyl, (C 2 -C 3 )alkenyl, (C 2 -C 3 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 5 -C 6 )cycloalkenyl, moφholinyl, thiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, imidazolidinyl, furanyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyrimidinyl, triazinyl, pyridazinyl, pyridinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, phenyl, benzyl, tolyl, naphthyl, halo, cyano, nitro, —N(R 12 ) 2 , —OR 12 , —C(O)R 12 , —C(O)OR 12 , —C(S)R 12 , —C(O)SR 12 , —C(S)OR 12 , —C(S)N(R 12 ) 2 , —C(NR 12 )OR 12 , —C(NR 12 )R 12 , —C(NR 12 )N(R 12 ) 2 , —OC(O)R 12 , —SC(O)R 12 , —OC(S)R 12 , —OC(O)N(R 12 ) 2 , —OC(S)N(R 12 ) 2 , —SC(O)N(R 12 ) 2 , —OC(NR 12 )R 12 , —C(O)N(R 12 ) 2 , —NR 12 C(O)R 12 , —NR 12 C(S)R 12 , —NR 12 C(S)OR 12 , —NR 12 C(NR 12 )R 12 , —NR 12 C(O)OR 12 , —NR 12 C(O)N(R 12 ) 2 , —NR 12 C(S)N(R 12 ) 2 , —S(O)pR 12 , —OS(O) P R 12 , —OS(O) P N(R 12 ) 2 , —S(O) P OR 12 , —NR 12 S(O) p R 12 , —NR 12 S(O) P N(R 12 ) 2 , —NR 12 S(O) P OR 12 , —S(O) P N(R 12 ) 2 , —OP(O)(OR 12 ) 2 , or —SP(O)(OR 12 ) 2 ; and

R 12 is hydrogen or C 1 -C 3 alkyl.

19. The compound of claim 18 wherein R 3 is hydrogen, Ci-C 4 alkyl, phenyl, —C(O)R 7 , —C(O)OR 7 , —S(O) P OR 7 , —S(O) P R 7 —C(O)NR 10 R 11 , —SP(O)(OR 7 ) 2 or —S(O) P NR 10 R 11 , wherein the alkyl and phenyl represented by R 3 is optionally substituted by one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, —N(R 12 ) 2 or —S(O) P R 12 .

20. The compound according to claim 19 wherein R 3 is hydrogen, —S(O) 2 CH 3 , —S(O) 2 Ph or —C(O)Ph.

21. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 1 .