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1. (WO2013106643) COMPOUNDS & METHODS FOR THE ENHANCED DEGRADATION OF TARGETED PROTEINS & OTHER POLYPEPTIDES BY AN E3 UBIQUITIN LIGASE
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

Claims:

1. A compound according to the chemical structure:

ULM

Where L is a linker group and

ULM

is a ubiquitin ligase binding moiety, wherein said linker group is optionally further

PTM

linked to a group.

2. A compound according to the chemical structure:


ULM

is a ubiquitin ligase binding moiety;


is a chemical moiety (protein target moiety) which binds to a target protein or polypeptide which is to be degraded by ubiquitin ligase and is chemically linked directly to

ULM PTM ULM

the group or through a linker moiety L, or is alternatively a

group which is also a ubiquitin ligase binding moiety, which may be the same or different

ULM ULM

than the group and is linked directly to the group directly or through the linker moiety; and

L is a linker moiety which is may be present or absent and when present, chemically

(covalently) links
or

a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof.

3. The compound according to claim 2 wherein
group.

ULM

4. A compound according to any of claims 1-3 wherein is a group according to the chemical structure:


Where R1 is an optionally substituted Cj-Q alkyl group, an optionally substituted

-(CH2)nOH, an optionally substituted -(CH2)nSH, an optionally substituted (CH2)n-0-(C1-C6)alkyl group, an optionally substituted (CH2)n- WCHOCHW-(Co-C6)alkyl group containing an epoxide moiety where W is independently absent or H, an optionally substituted

-(CH2)nCOOH, an optionally substituted -(CH2)nC(0)-(C1-C6 alkyl), an optionally substituted -(CH2)nNR!R2,an optionally substituted -(CH2)nNHC(0)-Rl5 an optionally substituted

-(CH2)„C(0)-lSI iR2, an optionally substituted -(CH2)nOC(0)-NR1R2, -(CH20)nH, an optionally substituted -(CH2)nOC(0)-(C1-C6 alkyl), an optionally substituted -(CH2)nC(0)-0-(Ci-C6 alkyl), an optionally substituted -(CH20)nCOOH, an optionally substituted -(OCH2)nO-(C1-C6 alkyl), an optionally substituted -(CH20)nC(0)-(C1-C6 alkyl), an optionally substituted -(OCH2)nNHC(0)-R1, an optionally substituted -(CH20)nC(0)-NR1R2, -(CH2CH20)nH, an optionally substituted -(CH2CH20)nCOOH, an optionally substituted -(OCH2CH2)nO-(C1-C6 alkyl), an optionally substituted -(CH2CH20)„C(0)-(C1-C6 alkyl), an optionally substituted -(OCH2CH2)nNHC(0)-Rl5 an optionally substituted

-(CH2CH20)nC(0)-NR1R2,an optionally substituted -S02Rs, an optionally substituted S(0)Rs, N02, CN or halogen (F, CI, Br, I, preferably F or CI);

R\ and R2 are each independently H or a Q-C6 alkyl group which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine);

Rs is a Cj-C6 alkyl group, an optionally substituted aryl, heteroaryl or heterocycle group or a -(CFt NR^ group,

X and X' are each independently C=0, C=S, -S(O), S(0)2 , (preferably X and X' are both C=0);

R2 is an optionally substituted -(CH2)n-(C=0)u(NRi)v(S02)w(Ci-C6)alkyl group, an optionally substituted RINR2N -(CH2)n-(C=0)u(NR1)v(S02)wNR1NR2N group, an optionally substituted -(CH2)n-(C=0)u(NR1)v(S02)w-Aryl, an optionally substituted

-(CH2)n-(C=0)u(NR1)v(S02)w-Heteroaryl, an optionally substituted

-(CH2)n-(C=0)vNRi(S02)w-Heterocycle, an optionally substituted

-NR1-(CH2)n-C(0)u(NR1)v(S02)w-Ci-C6 alkyl, an optionally substituted

-NR1-(CH2)n-C(0)u(NR1)v(S02)w- NRiNR2N, an optionally substituted

-NR1-(CH2)„-C(0)u(NR1)v(S02)w-NR1C(0)R1N, an optionally substituted

-NR1-(CH2)n-(C=0)u(NR1)v(S02)w-Aryl, an optionally substituted

-NR1-(CH2)n-(C=0)u(NRi)v(S02)w-Heteroaryl or an optionally substituted

-NR1-(CH2)n-(C=0)vNR1(S02)w-Heterocycle, an optionally substituted

-X -CrQ alkyl group; an optionally substituted

-X - Aryl group; an optionally substituted

R2'

-X - Heteroaryl group; an optionally substituted

R2'

-X - Heterocycle group; an optionally substituted;

R is an optionally substituted Cj-C6 alkyl, an optionally substituted

-(CH2)n-C(0)u(NR1)v(S02)w-Ci-C6 alkyl, an optionally substituted

-(CH2)n-C(0)u(NR1)v(S02)w-NR1NR2N, an optionally substituted

-(CH2)n-C(0)u(NRi)v(S02)w-NR1C(0)R1N, an optionally substituted

-(CH2)n-C(0)u(NRi)v(S02)w-C(0)NR1R2, an optionally substituted

-(CH2)n-C(0)u(NR1)v(S02)w-Aryl, an optionally substituted

-(CH2)n-C(0)u(NR1)v(S02)w-Heteroaryl, an optionally substituted

-(CH2)n-C(0)u(NR1)v(S02)w-Heterocycle, an optionally substituted

-NR1-(CH2)n-C(0)u(NR1)v(SO2)w-C1-C6 alkyl, an optionally substituted

-NR1-(CH2)n-C(0)u(NR1)v(S02)w- NR1NR2N, an optionally substituted

-NR1-(CH2)„-C(0)u(NRi)v(S02)w- NR!C(0)R1N, an optionally substituted

-NR1-(CH2)n-C(0)u(NRi)v(S02)w-Aryl, an optionally substituted

-NR1-(CH2)n-C(0)u(NR1)v(S02)w-Heteroaryl, an optionally substituted

-NR1-(CH2)„-C(0)u(NRi)v(S02)w-Heterocycle, an optionally substituted

-0-(CH2)n-(C=0)u(NR1)v(S02)w-Ci-C6 alkyl, an optionally substituted

-0-(CH2)n-(C=0)u(NRi)v(S02)w-NR1NR2N, an optionally substituted

-0-(CH2)n-(C=0)u(NR1)v(S02)w-NR1C(0)R1N, an optionally substituted

-0-(CH2)n-(C=0)u(NR1)v(S02)w-Aryl, an optionally substituted

-0-(CH2)n-(C=0)u(NRi)v(S02)w-Heteroaryl or an optionally substituted

-0-(CH2)n- (C=0)u(NRi)v(S02)w-Heterocycle;

-(CH2)n-(V)n'-(CH2)n-(V)n'-Cj-C6 alkyl group, an optionally substituted

-(CH2)n-(V)n'-(CH2)n-(V)n'-Aryl group, an optionally substituted

-(CH2)n-(V)n'-(CH2)n-(V)n'-Heteroaryl group, an optionally substituted

-(CH2)n-(V)n'-(CH2)n-(V)n'-Heterocycle group, an optionally substituted

-(CH2)n-N(Rr)(C=0)m'-(V)n'-Ci-C6 alkyl group, an optionally substituted

-(CH2)n-N(Rr)(C=0)m'-(V)n'-Aryl group, an optionally substituted

-(CH2)n-N(R1')(C=0)m'-(V)n-Heteroaryl group, an optionally substituted

-(CH2)n-N(R1 ')(C=0)m'-(V)n'-Heterocycle group, an optionally substituted

-X -C!-C6 alkyl group; an optionally substituted

-X - Aryl group; an optionally substituted

-X - Heteroaryl group; an optionally substituted

-X - Heterocycle group; an optionally substituted;

Where Km and R2N are each independently H, C!-C6 alkyl which is optionally substituted with one or two hydroxyl groups and up to three halogen groups or an optionally substituted

-(CH2)n-Aryl, -(CH2)n-Heteroaryl or -(CH2)n-Heterocycle group;

V is O, S or NR!;

Ri is the same as above;

R! and Rr are each independently H or a C!-C3 alkyl group;

X" and X are each independently an optionally substituted -CH2)n-, -CH2)n- CH(XV)=CH(XV)- (cis or trans), -CH2)n-CH≡CH- , -(CH2CH20)n- or a C3-C6 cycloalkyl group, where Xv is H, a halo or a C1-C3 alkyl group which is optionally substituted;

Each m is independently 0, 1 , 2, 3, 4, 5, 6;

Each m' is independently 0 or 1 ;

Each n is independently 0, 1 , 2, 3, 4, 5, 6;

Each n' is independently 0 or 1 ;

Each u is independently 0 or 1 ;

Each v is independently 0 or 1 ;

Each w is independently 0 or 1 ; and

ULM

wherein any one or more of R^ R^ R^ X and X' of is modified to be covalently

PTM

bonded to said group either directly or through said linker group, or

a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

5. A compound according to any of claims 1-4 wherein
, when

PTM

present as a group, is each independently a group according to the chemical structure:

R1'


Wherein each of R1 ', R2 and RJ are the same as in claim 4 above and X is a C=0, C=S, -S(O) group or a S(0)2 group, and

wherein any one or more ofR1 , R and RJ are modified to bind a linker group which is

PTM

further covalently bonded to the group, or

a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

6. A compound according to claim 5 wherein X is C=0.

7. A compound according to any of claims 4-6 wherein R1 is a hydroxyl group or a group which may be metabolized to a hydroxyl or carboxylic group, such that the compound represents a prodrug form of an active compound.

8. A compound according to any of claims 4-7 wherein R1 is -(CH2)nOH, -(CH2)nSH, (CH2)n-0-(C1-C6)alkyl, -(CH2)nCOOH, -(CH20)nH, an optionally substituted -(CH2)nOC(0)-(C!-C6 alkyl), or an optionally substituted -(CH2)nC(0)-0-(C1-C6 alkyl), wherein n is 0 or 1

9. A compound according to any of claims 4-8 wherein R1 is or contains a carboxylic acid group, a hydroxyl group or an amine group, each of the hydroxyl group, carboxylic acid group or amine group being capable of being further chemically modified to provide a

PTM

covalent link to a linker group to which the group is bonded.

10. The compound according to any of claims 4-9 wherein R is an optionally substituted -NR'-T-Aryl, an optionally substituted -NR^T-Heteroaryl group or an optionally substituted -NR'-T-Heterocycle, where R1 is H or CH3, preferably H; and

T is an optionally substituted -(CH2)n- group, wherein each one of the methylene groups may be optionally substituted with one or two substituents, which may be optionally substituted; and n is 0, 1, 2 or 3.

11. The compound according to claim 10 wherein said Aryl group is an optionally substituted phenyl or naphthyl group, wherein said phenyl or naphthyl group is optionally

PTM

substituted with a linker group to which is attached a 1 ' group, a halogen, an amine, a monoalkyl- or dialkyl amine, OH, SH, COOH, CH3, CF3, OMe, OCF3, N02, CN group or an optionally substituted phenyl group, the phenyl group itself being optionally substituted with

PTM

a linker group attached to a 1 1 group and optionally at least one of F, CI, OH, SH,

COOH, CH3, CF3, OMe, OCF3, N02, or CN group, a naphthyl group, which may be optionally substituted, an optionally substituted heteroaryl or an optionally substituted heterocycle, each of which groups may be optionally substituted with a linker group to which

PTM

is attached a group.

12. The compound according to claim 10 wherein said Aryl group is a phenyl group which is optionally substituted with a heteroaryl group.

13. The compound according to claim 10 wherein said Heteroaryl is an optionally substituted isoxazole, an optionally substituted oxazole, an optionally substituted thiazole, an optionally substituted pyrrole, an optionally substituted imidazole, an optionally substituted diazole, an optionally substituted triazole, or an optionally substituted pyridine group,

wherein said heteroaryl group is optionally substituted with a linker group to which is PTM

attached a ' ' group.

14. The compound according to claim 13 wherein said isoxazole is a methylsubstituted isoxazole, said oxazole is a methyl substituted oxazole, said thiazole is a methyl substituted thiazole, said pyrrole is a methylsubstituted pyrrole, said imidazole is a methylimidazole, a benzylimidazole, methoxybenzylimidazole, oximidazole or methyloximidazole, said diasole is a methyldiazole, said triazole is a methylsubstituted triazole, and said pyridine group is a halo-substituted pyridine, a methylsubstitutedpyridine group or an oxapyridine group where the pyridine group is linked to the phenyl group by an oxygen.

15. The compound according to claim 10 wherein said Aryl group is a phenyl group which is optionally substituted with a heterocycle group.

16. The compound according to claim 15 wherein said heterocycle group is an optionally substituted tetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, oxane, thiane, pyrrolidine or morpholine.

17. The compound according to claim 16 wherein said heterocycle group is optionally

PTM

substituted with a linker group to which is attached a ' 1 group.

18. The compound according to claim 10 wherein said Heterocycle is an optionallyl substituted tetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, oxane, thiane, pyrrollidine or morpholine.

19. The compound according to claim 11 wherein said Aryl group is a phenyl group which is optionally substituted with a halogen, an amine, monoalkylamine, dialkylamine, OH, SH, COOH, C¾, CF3, OMe, OCF3, N02, or CN group, an optionally substituted phenyl group, wherein said phenyl group is itself optionally substituted with at least one of F, CI, OH, SH, COOH, CH3, CF3, OMe, OCF3, N02, or CN group, a naphthyl group, which may be optionally substituted, or an optionally substituted heteroaryl or heterocycle group.

20. The compound according to claim 19 wherein said optionally substituted heteroaryl is an optionally substituted isoxazole, an optionally substituted oxazole, an optionally substituted thiazole, an optionally substituted pyrrole, an optionally substituted imidazole, an optionally substituted benzimidazole, an optionally substituted oximidazole an optionally substituted diazole group, including a methyldiazole group, an optionally substituted triazole group, including a methylsubstituted triazole group, an optionally substituted pyridine group, including a halo- (preferably, F) or methylsubstitutedpyridine group or an oxapyridine group, an optionally substituted furan, an optionally substituted benzofuran, an optionally substituted dihydrobenzofuran, an optionally substituted indole, an optionally substituted indolizine, an optionally substitutedazaindolizine, an optionally substituted quinoline, or an optionally substituted group according to the chemical structure:


Where S° is CHR , NR. , or O;

RHET is H, CN, N02, halo (preferably CI or F), optionally substituted Q-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF3), optionally substituted 0(Ci-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group -C≡C-Ra where Ra is H or a C!-C6 alkyl group (preferably C C3 alkyl);

IT* is H, CN, N02, halo (preferably F or CI), optionally substituted C]-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally

substituted 0-(C!-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted -C(0)(C!-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);

RURE is H, a C]-C6 alkyl (preferably H or C1-C3 alkyl) or a-C(0)(C C6 alkyl) each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine groups, or an optionally substituted phenyl group, an optionally

substituted heteroaryl, or an optionally substituted heterocycle, preferably for example piperidine, morpholine, pyrrolidine, tetrahydrofuran);

RPR0 is H, optionally substituted C!-C6 alkyl or an optionally substituted aryl group or an optionally substituted heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine; RPR01 and RPR02 are each independently H, an optionally subsituted Ci-C3 alkyl group or together form a keto group and

Each n is independently 0, 1, 2, 3, 4, 5, or 6, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

21. The compound according to claim 19 wherein said optionally substituted heterocycle is selected from the group consisting of pyrollidine, furan, tetrahydrofuran, tetrahydrothiene, piperidine, piperazine and morpholine.

22. The compound according to any of claims 1-21 wherein R3' is an optionally substituted -T-Aryl, an optionally substituted, -T-Heteroaryl, an optionally substituted

-T-Heterocycle, an optionally substituted -NR1 -T-Aryl, an optionally substituted

-NR1 -T-Heteroaryl or an optionally substituted -NR1 -T-Heterocycle; and

T is a -(CH2)n group, -(CH20)n- group, a -(OCH2)n- group, a -(CH2CH20)n- group, or a -(OCH2CH2)n- group, each of which groups is optionally substituted with one or two substituents; and n is 0, 1, 2 or 3.

23. The compound according to claim 22 wherein said Aryl group is an optionally

substituted phenyl or naphthyl group, wherein said phenyl or naphthyl group is optionally

PTM

substituted with a linker group to which is attached a 1 ' group, or a halogen group, an amine, a monoalkyl- or dialkyl amine, OH, SH, COOH, CH3, CF3, OMe, OCF3, N02, CN, or a S(0)2 s group where Rs is a Cj-C6 alkyl group, a -(CH2)mNR1R2 group or an optionally substituted aryl, heteroaryl or heterocycle group, each of which may be substituted in ortho-, meta- or para- positions of the phenyl ring, or said Aryl group is optionally substituted, with an optionally substituted aryl group, an optionally substituted heteroaryl or an optionally substituted heterocycle, each of which groups may be optionally substituted with a linker

PTM

group to which is attached a group.

24. The compound according to claim 23 wherein said heteroaryl is an optionally substituted isoxazole, an optionally substituted oxazole, an optionally substituted thiazole, an optionally substituted isothiazole, an optionally substituted pyrrole, an optionally substituted imidazole, an optionally substituted oximidazole, an optionally substituted diazole, an optionally substituted triazole group, an optionally substituted pyridine group or an optionally substituted oxapyridine group, wherein said heteroaryl group is optionally substituted with a

PTM

linker group to which is attached a group.

25. The compound according to claim 24 wherein said optionally substituted isoxazole is a methylsubstituted isoxazole, said optionally substituted oxazole is a methylsubstituted oxazole, said optionally substituted thiazole is a methyl substituted thiazole, said optionally substituted isothiazole is a methyl substituted isothiazole, said optionally substituted pyrrole is a methylsubstituted pyrrole, said optionally substituted imidazole is a

a methylimidazole, a benzylimidazole or a methoxybenzylimidazole, said optionally substituted oximidazole is a methyloximidazole, said optionally substituted diazole is a methyldiazole, said optionally substituted triazole group is a methylsubstituted triazole group, said optionally substituted pyridine group is a halosubstituted or methylsubstitutedpyridine and said oxapyridine group is linked to the phenyl group by an oxygen.

26. The compound according to claim 23 wherein said heterocycle group is an optionally substituted tetrahydroquinoline, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, pyrrollidine, morpholine, oxane or thiane.

27. The compound according to claim 26 wherein said heterocycle group is optionally

PTM

substituted with a linker group to which is attached a ' ' group.

28. The compound according to claim 22 wherein said Heteroaryl group is an optionally substituted quinoline, an optionally substituted indole, an optionally sμbstituted isoxazole, an optionally substituted benzofuran, an optionally substituted thiophene or an optionally substituted pyridine.

29. The compound according to claim 28 wherein said isoxazole is a methylsubstituted isoxazole.

30. The compound according to claim 28 wherein said thiophene is a methylsubstituted thiophene.

31. The compound according to claim 28 wherein said pyridine is methylsubstituted.

32. The compound according to claim 22 wherein said Heterocycle is selected from the group consisting of tetrahydrofuran, tetrahydrothiophene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane or thiane, each of which groups is optionally

PTM

substituted with a linker group to which is attached a group.

33. The compound according to claim 22 wherein said heteroaryl group is an optionally substituted isoxazole, an optionally substituted oxazole, an optionally substituted thiazole, an optionally substituted pyrrole, an optionally substituted imidazole, an optionally substituted oximidazole, an optionally substituted diazole is a methyldiazole, an optionally substituted triazole group, an optionally substituted pyridine group or an optionallyl substituted oxapyridine group.

34. The compound according to claim 33 wherein said optionally substituted isoxazole is a methylsubstituted isoxazole, said optionally substituted oxazole is a methylsubstituted

oxazole, said optionally substituted thiazole a methyl substituted thiazole, said optionally substituted pyrrole is a methylsubstituted pyrrole, said optionally substituted imidazole is a a methylimidazole, a benzylimidazole or a methoxybenzylimidazole, said optionally substituted oximidazole is a methyloximidazole, said optionally substituted diazole is a methyldiazole, said optionally substituted triazole group is a methylsubstituted triazole group, said optionally substituted pyridine group is a halosubstituted or methylsubstitutedpyridine and said oxapyridine group is linked to the phenyl group by an oxygen.

35. The compound according to claim 22 wherein said Heteroaryl group is an optionally substituted quinoline, an optionally substituted indole, an optionally substituted

benzimidazole, an optionally substituted benzodiazole, an optionally substituted

benzoxofuran, an optionally substituted imidazole, an optionally substituted isoxazole, an optionally substituted oxazole, an optionally substituted diazole, an optionally substituted benzofuran, an optionally substituted thiophene, an optionally substituted thiazole, an optionally substituted triazole, a triisopropylsilyl group, an optionally substituted -(CH2)m-0-C]-C6 alkyl group, an optionally substituted -(CH2)m-C(0)-0-C1-C6 alkyl group) or an optionally substituted 2-, 3, or 4-pyridine and m is 0, 1, 2, 3, 4, 5, or 6.

36. The compound according to claim 35 wherein said Heteroaryl group is a

methylsubstituted oxazole or a triazole which is optionally substituted with a methyl group, a triisopropylsilyl group, an optionally substituted -(CH2)m-0-Ci-C6 alkyl group or an optionally substituted -(CH2)m-C(0)-0-Ci-C6 alkyl group).

37. The compound according to claim 22 wherein said Heterocycle is selected from the group consisting of tetrahydroquinoline, tetrahydrofuran, tetrahydrothiene, piperidine, piperazine, pyrrollidine and morpholine, each of which groups may be optionally substituted.

38. A compound according to any of claims 1-4 wherein
, when

PTM

present as a group, is each independently a group according to the chemical structure:


Where R1 is OH or a group which can be metabolized in a patient or subject to OH;

R2' is an optionally substituted -NR^X1 2 -alkyl group, an optionally substituted -NRj-X1*2 - Aryl group; an optionally substituted -NRr Xs2 -HET group, an optionally substituted -NR]- X^'-Aryl-HET group or an optionally substituted -NR X^'-HET-Aryl group,

Ri is H or a C!-C3 alkyl group;

X 2' is an optionally substituted -CH2)n- , -CH2)n-CH(Xv)=CH(Xv)- (cis or trans),

-CH2)n-CH≡CH-, -(CH2CH2O)n- or a C3-C6 cycloalkyl group;

R3 is an optionally substituted -(CH2)n-(V)n'-(CH2)n-(V)n>-RS3 group, an optionally substituted -(CH2)n-N(Rr)(C=O)m-(V)n'-RS3' group, an optionally substituted -XR3'-alkyl group, an optionally substituted -XR3 -Aryl group; an optionally substituted -XR3 -HET group, an optionally substituted -XR3 -Aryl-HET group or an optionally substituted -XR3 -HET-Ajyl group,

RS3 is an optionally substituted Q-CJO alkyl group, an optionally substituted Aryl group or a HET group;

R is H or a Q-C3 alkyl group;

V is O, S or NRr;

XR3' is an optionally substituted -CH2)n- , -CH2)n-CH(Xv)=CH(Xv)- (cis or trans),

-CH2)n-CH≡CH-, -(CH2CH2O)n- or a C3-C6 cycloalkyl group;

Xv is H, a halo or a C1-C3 alkyl group which is optionally substituted with one or two hydroxyl groups or up to three halogen groups;

Alkyl is an optionally substituted Q-Cio alkyl group;

Aryl is an optionally substituted phenyl or naphthyl group; and

HET is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyroUidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline or a group according to the chemical structure:


Where Sc is CHRSS, NR , or O;

RHET is H, CN, N02, halo, optionally substituted Cj-C6 alkyl, optionally substituted 0(Ci-C6 alkyl) or an optionally substituted acetylenic group -C≡C-Ra where Ra is H or a C!-C6 alkyl group;

Rss is H, CN, N02, halo, optionally substituted d-C6 alkyl, optionally substituted 0-(d-C6 alkyl) or an optionally substituted -C(0)(Ci-C6 alkyl;

RURE is H, a d-C6 alkyl or a -C(0)(C!-C6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogens, or an optionally substituted heterocycle; and

Yc is N or C-RYC, where RYC is H, OH, CN, N02, halo, optionally substituted d-C6 alkyl, optionally substituted 0(Ci-C6 alkyl) or an optionally substituted acetylenic group -C≡C-Ra where Ra is the same as above;

RPR0 is H, optionally substituted Ci-C6 alkyl or an optionally substituted aryl or an optionally substituted heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydroiuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine;

RPR01 and RPR02 are each independently H, an optionally subsituted Cj-C3 alkyl group or together form a keto group,

m' is 0 or 1 ;

Each n is independently 0, 1, 2, 3, 4, 5, or 6 and

Each n' is independently 0 or 1 ,

ULM

and wherein said group is covalently bonded to a linker group to which is attached

PTM

group, or a

pharmaceutically acceptable salt, stereoisomer, solvent or polymorph thereof.

39. A compound according to any of claims 1-4 wherein
when

PTM

present as a group, is each independently a group according to the chemical structure:


Where R1' is OH or a group which is metabolized in a patient or subject to OH;

-NH-CH2-Aryl-HET;

RJ is a -CHR^'-NH-C O)-^ , 31P'11 group or a -CHR^ CR3' -R.j3rP2 g. roup

Where RLKJ is a d-C4 alkyl group;

R is C C3 alkyl nOCH3 group

where n is 1 or 2, o
CH3CH20-group is linked to phenyl in a meta or para position, or a morpholino group linked to the carbonyl at the 2- or 3-position;

R3P2 is a
group,

Where Aryl is phenyl;

HET is an optionally substituted thiazole or isothiazole;

RHHT is H or a halo group; and

ULM

wherein said group is covalently bonded to a linker group to which is attached a

PTM

group, or

a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

ULM

40. A compound according to claim 39 wherein said group is a group according to the chemical structure:


326


ULM

wherein said group is covalently bonded to a linker group to which is attached a


group, or

a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

ULM

39. The compound according to any of claims 1-3 wherein said is

Where X is CI, F, Q-C3 alkyl or an optionalllyi substituted heterocycle;

j

R and R are each independently H, C1-C3 alkyl, or phenyl; and

ULM

Where said group is substituted with a linker group or a linker group to which is

PTM

optionally attached a group, or

a pharmaceutically acceptable salt, enantiomer, diasteromer, solvate or polymorph thereof

ULM

40. The compound according to any of claims 1-3 wherein said group is


Where n is 0 or 1 ;

PTM

R is a linker or a linker attached to a group; and

X is H, F, CI, Q-C3 alkyl or heterocycle;

ULM

Wherein said group is substituted with a linker group or a linker group to which is

PTM

optionally attached a group, or

A pharmaceutically acceptable salt, enantiomer, diasteromer, solvate or polymorph thereof.

ULM

41. The compound according to any of claims 1 -4 wherein said group is


Where n is 0 or 1 ;

PTM PTM

R is a linker or a linker attached to a group a linker or a linker attached to a

ULM

group linked to the 1 1 group through an amide, ester, ether or carbamate group;

R1 is C!-C3 alkyl optionally substituted with one or two hydroxyl groups or -C(0)NR3R4 where R3 and R4 are each independently H, C1-C3 alkyl, or phenyl; and

X is H, F, CI, Ci-C3 alkyl or optionally substituted heterocycle, or a pharmaceutically acceptable salt, enantiomer, diasteromer, solvate or polymorph thereof.

ULM

The compound according to claim 1 or 2 wherein said group is:


Where n is 0 or 1;

PTM ULM

R is a linker or a linker attached to a group linked to the group through an amide, ester, ether, carbamate or heterocyclic group; and

R is H, F, CI, C1-C3 alkyl optionally substituted with one or two hydroxyl groups, -O- C(0)NR3R4 or -C(0)NR3R4 wherein each of R3 and R4 is independently H, Q-C3 alkyl or phenyl, or

A pharmaceutically acceptable salt, enantiomer, diasteromer, solvate or polymorph thereof.

ULM

The compound according to any of claims 1-3 wherein said group is:


Where n is 0 or 1 :

PTM ULM

R is a linker or a linker attached to a group linked to the group through an amide, ester, ether, carbamate or heterocyclic group; and

Each X is independently is H, F, CI, C!-C3 alkyl optionally substituted with one or two hydroxyl groups, heterocyle, -0-C(0)NR3R4 or -C(0)NR3R4 wherein each of R3 and R4 is independently H, C1-C3 alkyl (preferably methyl), or phenyl, or

a pharmaceutically acceptable salt, enantiomer, diasteromer, solvate or polymorph thereof.

ULM

The compound according to any of claims 1-3 wherein said group is:


Where n is 0 or 1 ;

PTM ULM

R is a linker or a linker attached to a group linked to the group through an amide, ester, ether, carbamate or heterocyclic group;

R1 is C!-C3 alkyl group optionally substituted with one or two hydroxyl groups,

-0-C(0)NR3R4 or -C(0)NR3R4 wherein each of R3 and R4 is independently H, CrC3 alkyl or phenyl; and

X is independently is H, F, CI, Cj-C3 alkyl optionally substituted with one or two hydroxyl . groups or a heterocycle group, or

a pharmaceutically acceptable salt, enantiomer, diasteromer, solvate or polymorph thereof.

ULM

The compound according to any of claims 1 -3 wherein said group is:


Where n is 0 or 1 ;

PTM ULM

R is a linker or a linker attached to a group linked to the group through an amide, ester, ether, carbamate or heterocyclic group;

R1 is H, Ci-C3 alkyl, which is optionally substituted with one or two hydroxyl groups, -0-C(0)NR3R4 or -C(0)NR3R4 wherein each of R3 and R4 is independently H, Q-C3 alkyl or phenyl; and

Each X is independently is H, F, CI, C1-C3 alkyl optionally substituted with one or two hydroxyl groups or a heterocycle, or

a pharmaceutically acceptable salt, enantiomer, diasteromer, solvate or polymorph thereof.

46. The compound according to any of claims 1-45 wherein said linker group L is a group:

ULM

Where Z is a group which links to X; and

PTM

X is a group linking Z to group ' ' .

47. The compound according to claim 46 wherein Z is absent (a bond), -(CH2)j-0, -(CH2)i-S,


group wherein Xj Yj forms an amide group, or a urethane group, ester or thioester group, or a


Each R is H, or a CrC3 alkyl, an alkanol group or a water soluble heterocyclic group;

Each Y is independently a bond, O, S or N-R;

and each i is independently 0 to 100.

48. The compound according to claim 47 wherein i is 1 to 10.

49. The compound according to claim 47 wherein i is 1 to 5.

50. The compound according to claim 47 wherein said water soluble heterocyclic group is morpholine, piperidine or piperazine.

51. The compound according to any of claims 46-50 wherein X is a


Where each D is independently a bond (absent),

O

— (CH2) -Y-C-Y (CH2) -.

'rri ; or


j is 1 to 100;

k is 1 to 100;

m' is 1 to 100;

n is i to 100;

X1 is 0, S orN-R;

R and Y are the same as in claim 32; and

CON is a bond or a connector group which connects Z to X, when present in the linker group.

52. The compound according to claim 51 wherein j is 1 to 10; k is 1 to 10, m; is 1 to 10 and n is i to 10.

CON

53. The compound according to claim 51 or 52 wherein is a bond (absent), a piperazinyl group or a


group,

Where X2 is O, S, NR4, S(0), S(0)2, -S(0)20, -OS(0)2, or OS(0)20;

X3 is O, S, CHR4, NR4; and

R4 is H or a Cj-C3 alkyl group, which is optionally substituted with onen or two hydroxyl groups.

CO

54. The compound according to any of claims 51-53 wherein I 1


an amide group or a piperazinyl group.

ULM

A compound according to claim 1 wherein said group is a group according to

Affinity Table 2 or Figure 15 hereof which is modified to be covalently bonded to the


group through a linker group.

I IJLM

56. A compound according to claim 1 wherein said 1 group is a group according to the chemical structure:



335

337

338

339

340

341

342

344

PTM

which is modified to be covalently bonded to the group through a linker group, or Or a pharmaceutically acceptable salt thereof.

ULM

57. A compound according to claim 1 wherein said group is a group according to the chemical structure:

346

348

349

351

352

PTM

which is modified to be covalently bonded to the group through a linker group, or Or a pharmaceutically acceptable salt thereof.

58. A compound according to any one of the chemical structures set forth in figure 19 hereof:

wherein any one or more of R1PC, R2pc, R3PC, 4PC, R5PC, R6PC, 7PC, RSPC, ¾PC, RIOPC, Rupc , R12PC , Ri3PC and R14PC is a


group,

PTM

Where L is a linker group and is a protein targeting moiety, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thererof.

59. The compound according to claim 58 wherein no more than two of Ripe, R2P0 R3pc> PC,

R9PC5 RIOPC> Rape , I2PC , Rope and R14pc is a


group and the other of groups R1PC, R2pc, R3PC, RJPC, R5pc, Repc, 7PC, R8PC, R9PC RIOPC, Riipc , R12PC , ope and R1 PC are independently H or a CH3 group.

60. The compound according to claim 59 wherein only one of groups Ripe, R2pc, R3PC, 4PC,

R9PC5 RIOPC> Ri IPC , Ri2pc , Rope and R14pc is a


group and the other of groups R1PC, R2pc, R3PC, 4PC, RSPC, Repc,

R7pc, R8PG, R9PC, RIOPC, RIIPC , R12PC , I3PC and R14pc are independently H or a CH3 group.

61. The compound according to claim 60 wherein said other groups R^c, R2P R3PC» R4P0 R5pc, R6PC, R7PC5 R8PC R9PC5 RIOPC, RI IPC , Ri2pc , RI3PC and R1 PC are each H.

62. A compound according to claim 58 according to the chemical strucure:

Wherein R7P
C and RIOPC are each independently a L- PTM

group or H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

63. The compound according to claim 62 wherein either of R7pc or RIOPC is a

64. A compound according to claim 58 according to the chemical structure:

Wherein
R PC is a L- PTM

group, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

65. A compound of claim 58 according to the chemical structure:


Wherein R7PC, Rnpc Rnpc, npc an R14pc are each ndependently a

group or H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

66. The compound according to claim 65 wherein one of R7PC, Rnpc, i2PC, RBPC andR1 Pc

group, and the other groups are H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

compound according to claim 58 according to the chemical structure:


and RI4PC are each independently a


A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

68. The compound according to claim 67 wherein any one of R4PC, R7PC, Ri lpc, Ri2PC, Ri3Pc
group and the other groups are H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

69. A compound according to claim 58 according to the chemical structure:


RI3PC andR14Pc are each independently a


r H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

70. The compound according to claim 70 wherein one of R3PC, R7pc, Riipc, Ri2Pc, Ri3Pc and


group and the other groups are H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

A compound of claim 58 according to the chemical structure:


group or H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

72. A compound according to claim 71 wherein one of R7PC and RIQPC is a


group and the other group is H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

A compound of claim 58 according to the chemical structure:


Wherein R7pc and Rjopc are each independently a
L- PTM

group or H and R PC is H or CH3, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

74. The compound according to claim 73 wherein one of R7pcandRiopc is a

group and the other group is H and Rgpc is H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

75. A compound according to claim 58 according to the chemical structure:


group or H and Rgpc is H or CH3, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

76. The compound according to claim 75 wherein one of R7pcand R10pc is a


group and the other of R7pc and R10PC is H and Rgpc is H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

77. A compound according to claim 58 according to the chemical structure:


Wherein R7pc andR10pc are each independently a L- PTM

group or H and Rgpc is H or CH3, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

78. A compound according to claim 77 wherein one of R7PC and Riopc is a

group and the other group is H and Rgpc is H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

79. A compound of claim 58 according to the chemical structure:


Wherein R7pc and RIOPC are each independently a L- PTM

group or H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

80. A compound according to claim 79 wherein one of R7pc and RIOPC is a


group and the other group is H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

A compound of claim 58 according to the chemical structure:


group or H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

82. The compound according to claim 81 wherein one of R7PC andR9pc is a

group and the other group is H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

83. A compound of claim 58 according to the chemical structure:

Wherei
n R7PC and RHPC are each independently a L- PTM

group or H and each of R12pc and R]3PC is H or CH3, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

84. The compound according to claim 83 wherein one of R7pc and R14PC is a

group and the other of R7Pc and R14PC group is H and each of R12PC and R13PC is H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

85. A compound of claim 58 according to the chemical structure:


Wherein R pc and R9pc are each independently a
group or H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

86. The compound according to claim 85 wherein one of R7pcandR9pc is a


group and the other group is H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

87. A compound of claim 58 according to the chemical structure:

Wherein R7pc andR9pc
are each independently a group or H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

88. The compound according to claim 87 wherein one of R7pc andR9pc is a

group and the other group is H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

89. A compound according to claim 58 according to the chemical structure:


Wherein R PC andRiopc are each independently a
L- PTM

group or H and R9pc is H or C¾, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

90. The compound according to claim 89 wherein one of R7pcandR10pc is a


group and the other group is H, and R9PC is H, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

91. The compound according to any of claims 58 to 80 wherein said linker group is a polyethylene group containing about 2 to about 20 ethylene glycol units.

92. The compound according to claim 91 wherein said polyethylene glycol group contains between about 2 and 8 ethylene glycol units.

PTM

93. The compound according to any of claims 1-92 wherein said group is a C! to C12 alkylhalo group.

94. The compound according to claim 93 wherein said alkylhalo group is a C2 to C10 alkylhalo group wherein said halo group is CI or Br.

95. The compound according to claim 94 wherein said linker group is a polyethylene glycol group ranging in size from about 2 to about 8 ethylene glycol units.

PTM

96. A compound according to any of claims 1-92 wherein said group is a moiety which binds to a target protein, wherein said target protein is selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, proteins pertinent to the integrated function of a cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catrabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell

differentiation, response to stimulus, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity and translation regulator activity.

PTM

A compound according to any of claims 1-92 wherein said group is a moiety which binds to a target protein, wherein said target protein is selected from the group consisting of B7.1 and B7, TI FRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apotosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCRl, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5 -lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multi drug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinases, CD23, CD 124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L, newokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP Kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus

3C protease, herpes simplex virus- 1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase inhibitors, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptors, neuropeptide Y and receptor, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7),

farnesyltransferases, geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase. Additional protein targets include, for example, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, and chloride channels. Still further target proteins include Acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and

enolpyruvylshikimate-phosphate synthase.

PTM

98. The compound according to any of claims 1-92 wherein said group is

an Hsp90 inhibitor; a kinase inhibitor, a phosphatase inhibitor, an MDM2 inhibitor, a compound which targets human BET Bromodomain-containing proteins, an HDAC inhibitor, a human lysine methyltransferase inhibitor, a compound targeting RAF receptor, a compound targeting FKBP, an angiogenesis inhibitor, an immunosuppressive compound, a compound targeting an aryl hydrocarbon receptor, a compound targeting an androgen receptor, a compound targeting an estrogen receptor, a compound targeting a thyroid hormone receptor, a compound targeting HIV protease, a compound targeting HIV integrase, a compound targeting HCV protease or a compound targeting acyl protein thioesterase 1 and/or 2.

PTM

99. The compound according to any of claims 1-92 wherein said group is

N-[4-(3H-IMIDAZO[4,5-C]PYRIDIN-2-YL)-9H-FLUOREN-9-YL]-SUCCINAMIDE


Derivatized where a linker moiety L or a ULM group is attached via the terminal amide group;

p54

8-[(2,4-dimethylphenyl)sulfanyl]-3-pent-4-yn-1-yl-3H-purin-6-amine


Derivatized where a linker moiety may be attached via the terminal acetylene group;

(5 - [2,4-DIH YDROX Y-5 -( 1 -METH YLETH YL)PHEN YL] -N-ETH YL-4- [4-(MORPHOLIN- -YLMETHYL)PHENYL]ISOXAZOLE-3-CARBOXAMIDE) having the structure:


Derivatized where a linker moiety L -S- L- ULM group is attached via the amide group;

The Hsp90 inhibitor PU3 having the structure:


ULM

Derivatized where a linker moiety L or a group is attached via the butyl group;

The Derivatized Hsp90 inhibitors Geldanamycin ((4E,6Z,8S,95,10E,125,13i?,14S,16i?)-13-hydroxy-8, 14,19-trimethoxy-4, 10, 12, 16-tetramethyl-3 ,20,22-trioxo-2-azabicyclo [16.3.1],

17-alkylamino- 17-desmethoxy geldanamycin ( 17- AAG), or

17-(2-dimethylaminoethyl)amino-17-desmethoxy geldanamycin (17-DMAG)), where a linker may be attached via the amide group;

the tyrosine kinase inhibitor Erlotinib (derivatized)


Where R as a linker moiety L or a L ULM group is attached via the ether group;

The kinase inhibitor Sunitanib (derivatized):

where R is a linker moiety L or a ULM group which is attached to the pyrrole moiety;

The kinase inhibitor Sorafenib (derivatized)


where R is a linker moiety L or a — ¾— L ULM group which is attached to the phenyl moiety;

The kinase inhibitor Desatinib (derivatized)


where R is a linker moiety L or a — ¾— L· ULM group which is attached to the pyrimidine;

The kinase inmhibitor Lapatinib (derivatized

Lapatinib

Where a linker moiety L or a L ULM group is attached via the terminal methyl of the sulfonyl methyl group;


3-(cyclopropylamino)-5 [3-(trifluoromethyl)phenyl]amino}pyrimido[4,5-c]quinoline-8-car-^ acid

Where a linker moiety L or a ULM group is attached via the amine (aniline), carboxylic acid or cyclopropyl group;

The kinase inhibitors Yl W and YIX (derivatized) having the structures:

YIX

1 -ethyl-3-(2-{[3-(1 -methylethyl)[1 ,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)urea

where a linker moiety L or a ULM group is attached via the propyl group;


1 -(3-tert-butyl-1 -phenyl-1 H-pyrazol-5-yl)-3-(2-{[3-(1 -methylethyl)[1 ,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)urea

Derivatized where a linker moiety L or a ULM group is attached via the propyl group or the butyl group;

the kinase inhibitor 6TP and OTP (derivatized) having the structures

6TP

4-amino-2-[4-(tert-butylsulfamoyl)phenyl]-N-methylthieno[3,2-c]pyridine-7-carboxam Thienopyridine 19

where a linker moiety L or a -§- L- ULM group is attached via the terminal methyl group bound to amide moiety;


OTP

4-amino-N-methyl-2-[4-(mo holin-4-yl)pheyl]thieno[3,2-c]pyridine-7-carboxamide Thienopyridine 8

where a linker moiety L or a ULM group is attached via the terminal methyl group bound to the amide moiety;

The kinase inhibitor 07U (derivatized) having the structure:


07U

2-methyl-N~1 ~-[3-(pyridin-4-yl)-2,6-naphthyridin-1 -yl]propane-1 ,2-diamine

where a linker moiety L or a - L— ULM group is attached via the secondary amine or terminal/primary amino group;

The kinase inhibitor YCF (derivatized) having the structure:


where a linker moiety L or a — ¾— ULM group is attached via either of the terminal hydroxyl groups;

The kinase inhibitors XK9 and NXP (derivatized) having the structures:


XK9

N-{4-[(1 E)-N-(N-hydroxycarbamimidoyl)ethanehydrazonoyl]p enyl}-7-nitro-1 H-indole-2-carboxam


NXP

N-{4-[(1 E)-N-CARBAMIMIDOYLETHANEHYDRAZONOYL]PHENYL}-1 H-INDOLE-3-CARBOXAMIDE

Derivatized where a linker moiety L or a group is attached via the terminal hydroxyl group (XK9) or the hydrazone group (NXP);

The kinase inhibitor Afatinib fN-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide), derivatized where a linker moiety L or a 1 group is attached via the aliphatic amine group;

The kinase inhibitor Fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3- oxo-2,3-dihydro-4H-pyrido[3,2-b]-l,4-oxazin-4-yl]methyl disodium phosphate hexahydrate), derivatized where a linker moiety L or a L group is attached via a methoxy group;

The kinase inhibitor Gefitinib (N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine), derivatized where a linker moiety L or a group is attached via a methoxy or ether group;


The kinase inhibitor Lenvatinib (4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide), derivatized where a linker moiety L or a

group 1S attached via the cyclopropyl group);

The kinase inhibitor Vandetanib (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(l-methylpiperidin-4-yl)methoxy]quinazolin-4-amine), derivatized where a linker moiety L or a

—— group is attached via the methoxy or hydroxyl group);

The kinase inhibitor Vemurafenib (propane- 1 -sulfonic acid {3-[5-(4-chlorophenyl)-lH- pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide), derivatized where a linker moiety L or a ULM group is attached via the sulfonyl propyl group);

The kinase inhibitor Gleevac (derivatized):


where R as a linker moiety L or a ULM group is is attached via the amide group or via the aniline amine group;

The kinase inhibitor Pazopanib (derivatized) (VEGFR3 inhibitor):


where R as a linker moiety L or a ? L I ^1^! group is is attached to the phenyl moiety or via the aniline amine group;

The kinase inhibitor AT- 9283 (derivatized) Aurora Kinase Inhibitor


where R is a linker moiety L or a L ULM group which is attached to the phenyl moiety;

The kinase inhibitor TAE684 (derivatized) ALK inhibitor


where R is a linker moiety L or a ? ^ ULM group which is attached to the phenyl moiety;

The kinase inhibitor Nilotanib (derivatized) Abl inhibitor:


where R is a linker moiety L or a ? ^ ULM group which is attached to the phenyl moiety or the aniline amine group;

The kinase inhibitor NVP-BSK805 (derivatized) JAK2 inhibitor


group which is attached to the phenyl moiety or the diazole group;

The kinase inhibitor Crizotinib (derivatized) Alk inhibitor


where R is a linker moiety L or a »— L- ULM group which is attached to the phenyl moiety or the diazole group;

The kinase nhibitor JNJ (derivatized) FMS inhibitor

where R is a linker moiety L or a ? L 1 ULM| group which 1S attached to the phenyl moiety;

The kinase inhibitor Foretinib (derivatized) Met inhibitor


where R is a linker moiety L or a -Ι- L·- ULM group which is attached to the phenyl moiety or a hydroxyl or ether group on the quinoline moiety;

The allosteric protein tyrosine phosphatase inhibitor PTPIB (derivatized):


where a linker group L or a Ϊ- Lr- ULM group is attached at R;

The inhibitor of SHP-2 domain of tyrosine phosphatase (derivatized):


where a linker group L or a ?— Lr- ULM group is attached at R;

The kinase inhibitor (derivatized) of BRAF (BRAF )/MEK:


Where a linker L or a L 1 ULM group is attached at R;

The inhibitor (derivatized) of tyrosine kinase ABL


Where R is a linker group L or a L ULM group;

The MDM2 Inhibitor nutlin-3, nutlin-2, nutlin-1 or Trans-4-Iodo-4'-Boranyl-Chalcone (derivatized),

Trans-4-Iodo-4'-Boranyl-Chalcone, where a linker moiety L or a ULM group is attached via a hydroxy group;

A compound targeting human BET Bromodomain-containing protein Brd2, Brd3, Brd4

An HDAC inhibitor


where R is a linker group L -l- L- ULM group;

A human lysine methyltransferase inhibitor BIX-01294 or UNC0244(derivatized):


BIX-01294

where R is a linker group L or a ULM group;


UNC0224

where R is a linker group L or a ULM group;

Azacitidine (4-amino-l-P-D-ribofuranosyl-l,3,5-triazin-2(lH)-one) derivatized where a

linker group L or a group is attached via the hydroxy or amino groups; and

Decitabine (4-amino-l-(2-deoxy-b-D-erythro-pentofuranosyl)-l, 3, 5-triazin-2(lH)-one) derivatized where a linker group L or a ? L 1 ULM

UL^iVi \ group is attached via either of the hydroxy groups or at the amino group).

An angiogenesis inhibitor selected from the group consisting of :

GA-1 (derivatized);

Estradiol (derivatized);

pihydroxytestosterone (derivatized) ;

Ovalicin (derivatized),

Fumagillin (derivatized);

An immunosuppressive compound selected from the group consisting of

AP21998 (derivatized);

Glucocorticoids, including hydrocortisone, prednisone, prednisolone, and

methylprednisolone), derivatized where a linker group L or a ULM group is bound, and beclometasone dipropionate, where a linker group L or a ULM group is bound;

Methotrexate, derivatized where a linker group L or a — L— -\ ULM group is bound to either of the terminal hydroxyls;

Ciclosporin, derivatized where a linker group L or a L ULM group is bound at any of the butyl groups;

Tacrolimus (FK-506) and rapamycin, derivatized where a linker group L or a

— I— L— ULM group is bound at one of the methoxy groups;

Actinomycin, derivatized where a linker group L or a ULM group is bound at one of the isopropyl groups;

A compound targeting the aryl hydrocarbon receptor (AHR) selected from the group consisting of Apigenin, SRI and LGC006, derivatized to bind a linker group L or a

ULM group;

A compound targeting RAF receptor (kinase) according to the chemical structure:


A compound targeting FKBP according to the chemical structure:


"Where R designates a linker group L or a »— LT- ULM group;

A compound targeting androgen receptor (AR) according to the chemical structure:


Where R designates a linker group L or a ULM group;

A SARM ligand of Androgen Receptor according to the chemical structure:


Where R designates a linker group L or a ULM group;

An Androgen Receptor Ligand DHT according to the chemical structure:


Where R designates a linker group L or a ULM group;

A compound targeting Estrogen Receptor (ER) according to the chemical structure:


Where R designates a linker group L or a L ULM group;

A compound targeting Thyroid Hormone Receptor (TR) according to the chemical structure:


Where R designates a linker group L or a L ULM group and MOMO indicates a methoxymethoxy group;

A compound targeting HIV Protease according to the chemical structure:


Where R designates a linker group L or a ?- L ULM group;

An Inhibitor of HIV Integrase according to the chemical structure:


derivatized where "R" designates a potential site for linker attachment,.


Where R designates a linker group L or a ?— Lr- ULM group;

A compound targeting HCV Protease according to the chemical structure:


Where R designates a linker group L or a ? L I ULMI group;

and

A compound targeting Acyl-protein Thioesterase-1 and -2 (APTl and APT2) according to the chemical structure:


Where R designates a linker group L or a -δ- L·- ULM group.

A compound according to any of claims 1-92 wherein said PTM

group is a


group, where w is 0 to 3.

101. The compound according to claim 100 where w is 1.

102. A compound according to the chemical structure:


or a pharmaceutically acceptable salt thereof.

103. A pharmaceutical composition comprising an effective amount of a compound according to any of claims 1-102 in combination with a pharmaceutically acceptable carrier, additive or excipient and optionally in further combination with an additional bioactive agent.

104. The composition according to claim 103 wherein said additional bioactive agent is an anticancer agent.

105. The composition according to claim 103 wherein said additional bioactive agent is an antiviral agent.

106. The composition according to claim 105 wherein said antiviral agent is an anti-HIV agent.

107. The composition according to claim 105 wherein said antiviral agent is an anti-HCV agent.

108. The composition according to claim 104 wherein said anticancer agent is selected from the group consisting of everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1 152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, a P ARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase inhibitors, an AKT inhibitor, a JAK/STAT inhibitor, a checkpoint- 1 or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111 , 131-I-TM-601 , ALT- 110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, ΓΝΟ 1001 , IPdRi KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311 , romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, S'-deoxy-S-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901 , AZD-6244, capecitabine, L-Glutamic acid, N -[4-[2-(2-amino-4,7-dihydro-4-oxo-1 H - pyrrolo[2,3- d ]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11 , CHIR-258,); 3-[5-(methylsulfonylpiperadinemethyl)- indolylj-quinolone,

vatalanib, AG-013736, AVE-0005, the acetate salt of [D- Ser(Bu t ) 6 ,Azgly 10 ] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t )-Leu-Arg-Pro- Azgly-NH 2 acetate [C59H84Ni8Oi4 -(C2H4O2)x where x = 1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate,

medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KR 951 , aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevac, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291 , squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox,gefitinib, bortezimib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS- 247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA- 923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR- 3339, ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001 , ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11 , dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an N -1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine,

metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof.

109. The composition according to claim 106 wherein said anti-HIV agent is a nucleoside reverse transcriptase inhibitors (NRTI), a non-nucloeoside reverse transcriptase inhibitor, protease inhibitors, a fusion inhibitor or a mixture thereof.

110. A method for regulating protein activity of a target protein in a patient in need comprising administering to said patient an amount of a compound according to any of claims 1-92 to said patient.

111. The method according to claim 110 wherein said target protein is selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, proteins pertinent to the integrated function of a cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catrabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimulus, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity,

pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity and translation regulator activity.

112. The method according to claim 1 10 wherein said target protein is selected from the group consisting of B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apotosis pathway, C5a receptor, HMG-CoA reductase, PDE V

phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo- oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5- lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside

phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multi drug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinases, CD23, CD 124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAMl, Cat+ channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L, newokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP Kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhino virus 3C protease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase inhibitors, angiotensin 11 , glycine receptor, noradrenaline reuptake receptor, endothelin receptors, neuropeptide Y and receptor, estrogen receptors, androgen receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferases, geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase.

Additional protein targets include, for example, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channels, acetyl-CoA carboxylase,

adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.

1 13. A method of treating a disease state or condition in a patient wherein dysregulated protein activity is responsible for said disease state or condition, said method comprising administering to said patient an effective amount of a compound according to any of claims 1-92 to said patient in order to regulate said protein activity in said patient.

114. The method according to claim 113 wherein said disease state or condition is asthma, multiple sclerosis, cancer, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, Coeliac disease, Charcot-Marie-Tooth disease, Cystic fibrosis, Duchenne muscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter's syndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease, (PKD1) or 4 (PKD2) Prader-Willi syndrome, Sickle-cell disease, Tay-Sachs disease, Turner syndrome.

115. The method according to claim 113 wherein said disease state or condition is

Alzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig's disease), Anorexia nervosa, Anxiety disorder, Atherosclerosis, Attention deficit hyperactivity disorder, Autism, Bipolar disorder, Chronic fatigue syndrome, Chronic obstructive pulmonary disease, Crohn's disease, Coronary heart disease, Dementia, Depression, Diabetes mellitus type 1 , Diabetes mellitus type 2, Epilepsy, Guillain-Barre syndrome, Irritable bowel syndrome, Lupus, Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity, Obsessive-compulsive disorder, Panic disorder, Parkinson's disease, Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Stroke, Thromboangiitis obliterans, Tourette syndrome, Vasculitis.

116. The method according to claim 113 wherein said disease state or condition is aceruloplasminemia, Achondrogenesis type II, achondroplasia, Acrocephaly, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, Adenomatous Polyposis Coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, Adrenogenital syndrome,

Adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, Alkaptonuria, Alexander disease, Alkaptonuric ochronosis, alpha 1 -antitrypsin deficiency, alpha- 1

proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alstrom syndrome,

Alexander disease, Amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, Anemia, Angiokeratoma Corporis Diffusum, Angiomatosis retinae (von Hippel-Lindau disease), Apert syndrome, Arachnodactyly

(Marfan syndrome), Stickler syndrome, Arthrochalasis multiplex congenital (Ehlers-Danlos syndrome#arthrochalasia type),ataxia telangiectasia, Rett syndrome, primary pulmonary

hypertension, Sandhoff disease, neurofibromatosis type II, Beare- Stevenson cutis gyrata syndrome, Mediterranean fever, familial, Benjamin syndrome, beta-thalassemia

Bilateral Acoustic Neurofibromatosis (neurofibromatosis type II), factor V Leiden

thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X- linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion disease, Birt-Hogg-Dube syndrome, Brittle bone disease (osteogenesis imperfecta), Broad Thumb-Hallux syndrome (Rubinstein-Taybi syndrome), Bronze Diabetes/Bronzed Cirrhosis (hemochromatosis), Bulbospinal muscular atrophy (Kennedy's disease), Burger-Grutz syndrome (lipoprotein lipase deficiency), CGD Chronic granulomatous disorder, Campomelic dysplasia, biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cri du chat, CAVD (congenital absence of the vas deferens), Caylor cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, Chondrodystrophy syndrome (achondroplasia),

otospondylomegaepiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, Thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous polyposis), Congenital erythropoietic porphyria, Congenital heart disease, Methemoglobinemia/Congenital methaemoglobinaemia, achondroplasia, X-linked

sideroblastic anemia, Connective tissue disease, Conotruncal anomaly face syndrome, Cooley's Anemia (beta-thalassemia), Copper storage disease (Wilson's disease), Copper transport disease (Menkes disease), hereditary coproporphyria, Cowden syndrome,

Craniofacial dysarthrosis (Crouzon syndrome), Creutzfeldt- Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Beare-Stevenson cutis gyrata syndrome, primary hyperoxaluria,

spondyloepimetaphyseal dysplasia (Strudwick type), muscular dystrophy, Duchenne and Becker types (DBMD), Usher syndrome, Degenerative nerve diseases including de Grouchy syndrome and Dejerine- Sottas syndrome, developmental disabilities, distal spinal muscular atrophy, type V, androgen insensitivity syndrome, Diffuse Globoid Body Sclerosis (Krabbe disease), Di George's syndrome, Dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, Dwarfism, erythropoietic protoporphyria

Erythroid 5-aminolevulinate synthetase deficiency, Erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia,, familial paroxysmal polyserositis, porphyria cutanea tarda, familial pressure sensitive neuropathy,

primary pulmonary hypertension (PPH), Fibrocystic disease of the pancreas, fragile X syndrome, galactosemia, genetic brain disorders, Giant cell hepatitis (Neonatal

hemochromatosis), Gronblad-Strandberg syndrome ( pseudoxanthoma elasticum), Gunther disease (congenital erythropoietic porphyria), haemochromatosis, Hallgren syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), Hyperandrogenism, Hypochondroplasia, Hypochromic anemia, Immune system disorders, including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson- Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson- Weiss syndrome, Kidney diseases, including hyperoxaluria, Klinefelter's syndrome, Kniest dysplasia, Lacunar dementia,Langer-Saldino achondrogenesis, ataxia telangiectasia, Lynch syndrome, Lysyl-hydroxylase deficiency, Machado- Joseph disease, Metabolic disorders, including Kniest dysplasia, Marfan syndrome, Movement disorders, Mowat- Wilson syndrome, cystic fibrosis, Muenke syndrome, Multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osier- Weber-Rendu disease, Peutz-Jeghers syndrome, Polycystic kidney disease, polyostotic fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Labhart- Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson Gilford Progeria Syndrome), progressive chorea, chronic hereditary (Huntington) (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen disease (neurofibromatosis type I), Recurrent polyserositis, Retinal disorders, Retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia, and adrenal gland (SBLA) syndrome, sclerosis tuberose (tuberous sclerosis), SDAT, SED congenital

(spondyloepiphyseal dysplasia congenita), SED Strudwick (spondyloepimetaphyseal dysplasia, Strudwick type), SEDc (spondyloepiphyseal dysplasia congenita)

SEMD, Strudwick type (spondyloepimetaphyseal dysplasia, Strudwick type), Shprintzen syndrome, Skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South- African genetic porphyria (variegate porphyria), infantile-onset ascending hereditary spastic paralysis, Speech and communication disorders, sphingolipidosis, Tay-Sachs disease,

spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome,

tetrahydrobiopterin deficiency, beta-thalassemia, Thyroid disease

Tomaculous neuropathy (hereditary neuropathy with liability to pressure palsies) Treacher Collins syndrome, Triplo X syndrome ( triple X syndrome), Trisomy 21

(Down syndrome), Trisomy X, VHL syndrome (von Hippel-Lindau disease), Vision impairment and blindness (Alstrom syndrome), Vrolik disease, Waardenburg syndrome, Warburg Sjo Fledelius Syndrome, Weissenbacher-Zweymiiller syndrome, Wolf-Hirschhorn syndrome, Wolff Periodic disease, Weissenbacher-Zweymiiller syndrome and

Xeroderma pigmentosum.

117. The method according to claim 113 wherein said disease state is cancer.

118. The method according to claim 117 wherein said cancer is squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma,

hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral

neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas,

ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas,

medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor or teratocarcinomas

119. The method according to claim 117 wherein said cancer is T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML

120. The method according to claim 113 wherein said disease state is an HIV infection.

121. The method according to claim 113 wherein said disease state is an HCV infection.

122. A compound library comprising compounds according to any of claims 1-92.

123. A method of screening a library of compounds according to claim 122 to identify a compound containing a targeting moiety which recognizes a target protein associated with a predetermined function of a cell comprising incubating a cell with said library of compounds; monitoring the predetermined function of the cell and identifying a compound or a number of compounds from said library that change the predetermined function of the cell.

124. The method according to claim 124 wherein a number of compounds which change the predetermined function of the cell are identified; said cell is incubated with a compound from said groups of compounds; the predetermined function of the cell is monitored; and a compound is identified that changes the predetermined function of the cell, wherein the identified compound contains a targeting moiety which recognizes said target protein associated with the predetermined function.

125. A method of degrading a target protein in a cell comprising exposing said cell to a compound according to any of claims 1-92 in an effective amount.

126. A method of degrading a target protein in a patient in need comprising administering to said patient an effective of a compound according to any of claims 1-92.

127. The method according to clalim 125 wherein said target protein is heat shock protein 90, a kinase, a phosphatase, MDM2, human BET Bromodomain-containing protein, HDAC, human lysine methyltransferase, a RAF receptor, FKBP, VEGF, an aryl hydrocarbon receptor, an androgen receptor, an estrogen receptor, thyroid hormone receptor, HIV protease, HIV integrase, HCV protease or acyl protein thioesterase 1 and/or 2.

128. The method according to claim 126 wherein said target protein is heat shock protein 90, a kinase, a phosphatase, MDM2, human BET Bromodomain-containing protein, HDAC, human lysine methyltransferase, a RAF receptor, FKBP, VEGF, an aryl hydrocarbon receptor, an androgen receptor, an estrogen receptor, thyroid hormone receptor, HIV protease, HIV integrase, HCV protease or acyl protein thioesterase 1 and/or 2.

129. Use of a compound according to any of claims 1-92 in a first medical application.

130. Use of a compound according to any of claims 1-92 for regulating protein activity of a target protein in a patient in need, comprising administering to said patient an amount of a compound according to any of claims 1-92 to said patient.

131. Use according to claim 130 wherein said target protein is selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, proteins pertinent to the integrated function of a cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catrabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell

differentiation, response to stimulus, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity and translation regulator activity.

132. Use according to claim 130 wherein said target protein is selected from the group consisting of B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apotosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCRl, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5 -lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multi drug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinases, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor,

IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L, newokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP Kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease, herpes simplex virus- 1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase inhibitors, angiotensin 11 , glycine receptor, noradrenaline reuptake receptor, endothelin receptors, neuropeptide Y and receptor, estrogen receptors, androgen receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferases, geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase. Additional protein targets include, for example, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channels, acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.

133. Use of a compound according to any of claims 1-92 for treating a disease state or condition in a patient wherein dysregulated protein activity is responsible for said disease state or condition.

134. Use according to claim 133 wherein said disease state or condition is asthma, multiple sclerosis, cancer, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, Coeliac disease, Charcot-Marie-Tooth disease, Cystic fibrosis, Duchenne muscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter's syndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease, (PKDl) or 4 (PKD2) Prader-Willi syndrome, Sickle-cell disease, Tay-Sachs disease, Turner syndrome.

135. Use according to claim 133 wherein said disease state or condition is Alzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig's disease), Anorexia nervosa, Anxiety

disorder, Atherosclerosis, Attention deficit hyperactivity disorder, Autism, Bipolar disorder, Chronic fatigue syndrome, Chronic obstructive pulmonary disease, Crohn's disease, Coronary heart disease, Dementia, Depression, Diabetes mellitus type 1, Diabetes mellitus type 2, Epilepsy, Guillain-Barre syndrome, Irritable bowel syndrome, Lupus, Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity, Obsessive-compulsive disorder, Panic disorder, Parkinson's disease, Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Stroke, Thromboangiitis obliterans, Tourette syndrome, Vasculitis.

136. Use according to claim 133 wherein said disease state or condition is

aceruloplasminemia, Achondrogenesis type II, achondroplasia, Acrocephaly, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, Adenomatous Polyposis Coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, Adrenogenital syndrome,

Adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, Alkaptonuria, Alexander disease, Alkaptonuric ochronosis, alpha 1 -antitrypsin deficiency, alpha- 1 proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alstrom syndrome,

Alexander disease, Amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, Anemia, Angiokeratoma Corporis Diffusum, Angiomatosis retinae (von Hippel-Lindau disease), Apert syndrome, Arachnodactyly

(Marfan syndrome), Stickler syndrome, Arthrochalasis multiplex congenital (Ehlers-Danlos syndrome#arthrochalasia type),ataxia telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Beare- Stevenson cutis gyrata syndrome, Mediterranean fever, familial, Benjamin syndrome, beta-thalassemia

Bilateral Acoustic Neurofibromatosis (neurofibromatosis type II), factor V Leiden

thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion disease, Birt-Hogg-Dube syndrome, Brittle bone disease (osteogenesis imperfecta), Broad Thumb-Hallux syndrome (Rubinstein-Taybi syndrome), Bronze Diabetes/Bronzed Cirrhosis (hemochromatosis), Bulbospinal muscular atrophy (Kennedy's disease), Burger-Grutz syndrome (lipoprotein lipase deficiency), CGD Chronic granulomatous disorder, Campomelic dysplasia, biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cri du chat, CAVD (congenital absence of the vas deferens), Caylor cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, Chondrodystrophy syndrome (achondroplasia),

otospondylomegaepiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos

syndrome, Thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous polyposis), Congenital erythropoietic porphyria, Congenital heart disease, Methemoglobinemia/Congenital methaemoglobinaemia, achondroplasia, X-linked sideroblastic anemia, Connective tissue disease, Conotruncal anomaly face syndrome, Cooley's Anemia (beta-thalassemia), Copper storage disease (Wilson's disease), Copper transport disease (Menkes disease), hereditary coproporphyria, Cowden syndrome,

Craniofacial dysarthrosis (Crouzon syndrome), Creutzfeldt- Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Beare-Stevenson cutis gyrata syndrome, primary hyperoxaluria,

spondyloepimetaphyseal dysplasia (Strudwick type), muscular dystrophy, Duchenne and Becker types (DBMD), Usher syndrome, Degenerative nerve diseases including de Grouchy syndrome and Dejerine-Sottas syndrome, developmental disabilities, distal spinal muscular atrophy, type V, androgen insensitivity syndrome, Diffuse Globoid Body Sclerosis (Krabbe disease), Di George's syndrome, Dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, Dwarfism, erythropoietic protoporphyria

Erythroid 5-aminolevulinate synthetase deficiency, Erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia,, familial paroxysmal polyserositis, porphyria cutanea tarda, familial pressure sensitive neuropathy,

primary pulmonary hypertension (PPH), Fibrocystic disease of the pancreas, fragile X syndrome, galactosemia, genetic brain disorders, Giant cell hepatitis (Neonatal

hemochromatosis), Gronblad-Strandberg syndrome ( pseudoxanthoma elasticum), Gunther disease (congenital erythropoietic porphyria), haemochromatosis, Hallgren syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), Hyperandrogenism, Hypochondroplasia, Hypochromic anemia, Immune system disorders, including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson- Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson- Weiss syndrome, Kidney diseases, including hyperoxaluria, Klinefelter's syndrome, Kniest dysplasia, Lacunar dementia,Langer-Saldino achondrogenesis, ataxia telangiectasia, Lynch syndrome, Lysyl-hydroxylase deficiency, Machado- Joseph disease, Metabolic disorders, including Kniest dysplasia, Marfan syndrome, Movement disorders, Mowat- Wilson syndrome, cystic fibrosis, Muenke syndrome, Multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome

(Pfeiffer syndrome), Osier- Weber-Rendu disease, Peutz-Jeghers syndrome, Polycystic kidney disease, polyostotic fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Labhart- Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch- Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson Gilford Progeria Syndrome), progressive chorea, chronic hereditary (Huntington) (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen disease (neurofibromatosis type I), Recurrent polyserositis, Retinal disorders, Retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia, and adrenal gland (SBLA) syndrome, sclerosis tuberose (tuberous sclerosis), SDAT, SED congenital

(spondyloepiphyseal dysplasia congenita), SED Strudwick (spondyloepimetaphyseal dysplasia, Strudwick type), SEDc (spondyloepiphyseal dysplasia congenita)

SEMD, Strudwick type (spondyloepimetaphyseal dysplasia, Strudwick type), Shprintzen syndrome, Skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South- African genetic porphyria (variegate porphyria), infantile-onset ascending hereditary spastic paralysis, Speech and communication disorders, sphingolipidosis, Tay-Sachs disease,

spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome,

tetrahydrobiopterin deficiency, beta-thalassemia, Thyroid disease

Tomaculous neuropathy (hereditary neuropathy with liability to pressure palsies)

Treacher Collins syndrome, Triplo X syndrome ( triple X syndrome), Trisomy 21

(Down syndrome), Trisomy X, VHL syndrome (von Hippel-Lindau disease), Vision

impairment and blindness (Alstrom syndrome), Vrolik disease, Waardenburg syndrome, Warburg Sjo Fledelius Syndrome, Weissenbacher-Zweyn uller syndrome, Wolf-Hirschhorn syndrome, Wolff Periodic disease, Weissenbacher-Zweymiiller syndrome and

Xeroderma pigmentosum.

137. Use according to claim 133 wherein said disease state is cancer.

138. Use according to claim 137 wherein said cancer is squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma,

hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral

neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas,

ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas,

medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma,

esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor or teratocarcinomas

139. Use according to claim 137 wherein said cancer is T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML

140. Use according to claim 133 wherein said disease state is an HIV infection.

Use according to claim 133 wherein said disease state is an HCV infection.

142. Use of a compound according to any of claims 1-92 in a compound library.

143. Use of a compound according to any of claims 1-92 for degrading a target protein in a cell.

144. Use of a compound according to any of claims 1 -92 for degrading a target protein in a patient in need.

145. Use according to claim 143 or 144 144 wherein said target protein is heat shock protein 90, a kinase, a phosphatase, MDM2, human BET Bromodomain-containing protein, HDAC, human lysine methyltransferase, a RAF receptor, FKBP, VEGF, an aryl hydrocarbon receptor, an androgen receptor, an estrogen receptor, thyroid hormone receptor, HIV protease, HIV integrase, HCV protease or acyl protein thioesterase 1 and/or 2.