IP Library › Granted Patent US 9,250,237

Granted Patent B2

US 9,250,237 · App. 13/990,396 · Granted Feb 2, 2016

Hybrid cyclic libraries and screens thereof

Inventors: Jun O. Liu (Clarkesville, MD); Jingxin Wang (Baltimore, MD); Zufeng Guo (Baltimore, MD); Wei Li (Xiangtan, CN); Shridhar Bhat (Cockeysville, MD); Manisha Das (Centreville, VA)

Assignee: The Johns Hopkins University

G01N33/566 A61K31/436 A61K31/4353 C07D471/04 C07D498/04 C07D498/14 C07D515/04 C07D515/14 C07K17/08

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Quick Facts

Patent No.: US 9,250,237
App. No.: 13/990,396
Granted: Feb 2, 2016
Kind: B2

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Abstract

Provided are novel types of hybrid cyclic libraries that contain a known protein binding domain of a natural product. Also provided are synthetic methods to make such libraries and methods for the deconvolution of hits using partially split-pooled library compounds. Such methods are applicable for use with the entire human proteome to screen such libraries that bind and for the identification of hits.

Claims (240)

1. A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

is a single or double bond;

X 1 is O or NR 6 ;

Y is —C(O)— or

X 2 is (CH 2 ) m , O, or NR 6 ;

Z is

W is O, CH, CH 2 , CR 4 , or CR 5 ;

L 1 and L 2 are each independently a direct bond, substituted or unsubstituted —(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n O(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)—, substituted or unsubstituted —(CH 2 ) n C(O)(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n NH(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n S(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 1 -C 6 )alkyl-, substituted or unsubstituted —(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n O(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n NH(C 1 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n S(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 )—O(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n NH(C 1 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n S(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 2 -C 6 )alkynyl-, wherein each alkyl, alkenyl and alkynyl group may be optionally substituted with alkyl, alkoxy, amino, carboxyl, cyano, nitro, or trifluoromethyl;

each m is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6;

each n is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6;

R 1 is hydrogen, hydroxyl, or OPG, wherein PG is a protecting group, or

R 1 is

wherein

is a resin;

R 2 is hydrogen, hydroxyl, or alkoxy;

R 3 is hydrogen or alkyl;

R 4 and R 5 are each independently hydrogen, hydroxy, alkyl, alkoxy, or OPG, wherein PG is a protecting group;

R 6 is hydrogen or alkyl;

wherein the Effector Domain has Formula II:

wherein:

R 7 , R 9 , R 11 , R 13 , and R 15 are each independently hydrogen or alkyl;

R 8 , R 10 , R 12 , and R 14 are each independently hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted perfluoroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkylaryl, (CH 2 ) n CN, (CH 2 ) n CF 3 , (CH 2 ) n C 2 F 5 , (CH 2 ) n OR 16 , (CH 2 ) n C(O)R 16 , (CH 2 ) n C(O)OR 16 , (CH 2 ) n OC(O)R 16 , (CH 2 ) n NR 17 R 18 , (CH 2 ) n C(O)NR 17 R 18 , (CH 2 ) n N 19 RC(O)R 16 , (CH 2 ) n N 19 RC(O)OR 16 , (CH 2 ) n NR 19 C(O)NR 17 R 18 , (CH 2 ) n SR 16 , (CH 2 ) n S(O) j NR 17 R 18 , (CH 2 ) n N 19 RS(O) j R 16 , or —(CH 2 ) n NR 19 S(O) j NR 17 R 18 ;

n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

j is an integer selected from 0, 1, and 2;

R 16 , R 17 , R 18 , and R 19 are each independently hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, or heteroalkylaryl, or

R 16 and R 19 are as described above, and R 17 and R 18 , together with the N atom to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered heterocycloalkyl or a substituted or unsubstituted 5-membered heteroaryl,

wherein each of the above groups listed for R 8 , R 10 , R 12 , and R 14 may be optionally independently substituted with 1 to 3 groups selected from halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, heteroalkylaryl, (CH 2 ) n CN, (CH 2 ) n CF 3 , (CH 2 ) n C 2 F 5 , (CH 2 ) n OR 16 , (CH 2 ) n C(O)R 16 , (CH 2 ) n C(O)OR 16 , (CH 2 ) n OC(O)R 16 , (CH 2 ) n NR 17 R 18 , (CH 2 ) n C(O)NR 17 R 18 , (CH 2 ) n N 19 RC(O)R 16 , (CH 2 ) n N 19 RC(O)OR 16 , (CH 2 ) n NR 19 C(O)NR 17 R 18 , (CH 2 ) n SR 16 , (CH 2 ) n S(O) j NR 17 R 18 , (CH 2 ) n N 19 RS(O) j R 16 , and —(CH 2 ) n NR 19 S(O) j NR 17 R 18 .

2. The compound of Formula I of claim 1 , wherein:

X is O or NR 6 ;

L 1 and L 2 are each independently —(C 1 -C 6 )alkyl-, —(CH 2 ) n O(C 1 -C 6 )alkyl-, —(CH 2 ) n C(O)(C 1 -C 6 )alkyl-, —(CH 2 ) n C(O)O(C 1 -C 6 )alkyl-, —(CH 2 ) n NH(C 1 -C 6 )alkyl-, —(CH 2 ) n C(O)NH(C 1 -C 6 )alkyl-, —(CH 2 ) n S(C 1 -C 6 )alkyl-, —(CH 2 ) n C(O)(CH 2 ) n S(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl-, —(CH 2 ) n O(C 2 -C 6 )alkenyl-, —(CH 2 ) n C(O)(C 2 -C 6 )alkenyl-, —(CH 2 ) n C(O)O(C 2 -C 6 )alkenyl-, —(CH 2 ) n NH(C 1 -C 6 )alkenyl-, —(CH 2 ) n C(O)NH(C 2 -C 6 )alkenyl-, —(CH 2 ) n S(C 2 -C 6 )alkenyl-, (CH 2 ) n C(O)(CH 2 ) n S(C 2 -C 6 )alkenyl-, wherein each alkyl and alkenyl group may be substituted with alkyl, alkoxy, or carboxyl;

n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

R 1 is hydrogen, hydroxyl, or OPG, wherein PG is a silyl protecting group, or

R 1 is

wherein

is a resin;

R 2 is hydroxyl or alkoxy;

R 3 is hydrogen or alkyl;

R 4 and R 5 are each independently hydrogen, alkyl, alkoxy, or OPG, wherein PG is a silyl protecting group;

R 6 is hydrogen;

R 7 , R 9 , R 11 , R 13 , and R 15 are each independently hydrogen or CH 3 ;

R 8 , R 10 , R 12 , and R 14 are each independently substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cycloheptyl, or substituted or unsubstituted cyclooctyl; or

R 8 , R 10 , R 12 , and R 14 are each independently substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydrothiophenyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted 1,3-dioxolanyl, substituted or unsubstituted pyrazolidinyl, substituted or unsubstituted imidazolidinyl, substituted or unsubstituted 1,4-dioxanyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, or substituted or unsubstituted 1,4-dithianyl; or

R 8 , R 10 , R 12 , and R 14 are each independently substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted naphthylenyl, or substituted or unsubstituted biphenyl; or

R 8 , R 10 , R 12 , and R 14 are each independently substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridizanyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzo(b)thiophenyl, substituted or unsubstituted indolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzisoxazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinoxalinyl, or substituted or unsubstituted naphthyridinyl.

3. The compound of Formula I of claim 1 , wherein:

L 1 and L 2 are each independently —(C 1 -C 6 )alkyl-, —(CH 2 ) n O(C 1 -C 6 )alkyl-, —(CH 2 ) n C(O)(C 1 -C 6 )alkyl-, —(CH 2 ) n NH(C 1 -C 6 )alkyl-, —(CH 2 ) n C(O)NH(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl-, —(CH 2 ) n O(C 2 -C 6 )alkenyl-, —(CH 2 ) n C(O)(C 2 -C 6 )alkenyl-, —(CH 2 ) n NH(C 1 -C 6 )alkenyl-, —(CH 2 ) n C(O)NH(C 2 -C 6 )alkenyl-, wherein each alkyl and alkenyl group may be substituted with alkyl, alkoxy, or carboxyl;

n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

R 1 is hydrogen, hydroxyl or OPG, wherein PG is a tert-butyldimethylsilyl protecting group, or

R 1 is

wherein

is Wang resin;

R 4 and R 5 are each independently hydrogen, hydroxy, alkyl, alkoxy, or OPG, wherein PG is a tert-butyldimethylsilyl protecting group;

R 7 , R 9 , R 11 , R 13 , and R 15 are each independently hydrogen;

R 8 , R 10 , R 12 , and R 14 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted indolyl, (CH 2 ) n OR 5 , (CH 2 ) n C(O)NR 6 R 7 , or (CH 2 ) n SR 5 ; and

R 16 , R 17 , and R 18 are each independently hydrogen or (C 1 -C 6 )alkyl.

4. The compound of Formula I of claim 1 , wherein:

L 1 and L 2 are each independently —(C 1 -C 6 )alkyl-, —O(C 1 -C 6 )alkyl-, —C(O)(C 1 -C 6 )alkyl-, —(CH 2 ) n C(O)NH(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl-, —O(C 2 -C 6 )alkenyl-, —C(O)(C 2 -C 6 )alkenyl-, —(CH 2 ) n C(O)NH(C 2 -C 6 )alkenyl-, wherein each alkyl and alkenyl group may be substituted with alkyl, alkoxy, or carboxyl;

n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

R 8 , R 10 , R 12 , and R 14 are each independently H, CH 3 , CH 2 OH, CH 2 SH, CH(OH)CH 3 , CH 2 C(O)NH 2 , CH 2 CH 2 C(O)NH 2 , CH 2 CH 2 SCH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 C 6 C 5 ,

5. The compound of Formula I of claim 1 , wherein:

L 1 and L 2 are each independently —OCH 2 CH 2 —, —CH 2 C(O)—, —CH 2 CH 2 C(O)—, —C(O)NHCH 2 CH 2 , —CH 2 CH═CHCH 2 —, —OCH 2 CH═CHCH 2 CH 2 —, —OCH 2 CH═CHCH 2 CH(CO2H)—, —CH 2 C(O)NHCH 2 CH 2 —, or CH 2 CH(OCH 3 )═C(CH 3 )CH 2 CH 2 ; and

R 8 , R 10 , R 12 , and R 14 are each independently the sidechain of the amino acid alanine, asparagine, cysteine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

6. The compound of Formula I of claim 1 , wherein the compound has Formulae II, III, IV, V, or VI:

7. The compound of Formula I of claim 1 , wherein the compound has Formulae VII, VIII, IX, or X:

8. A method of treating cancer in a patient in need thereof comprising administering a therapeutically effective amount of the compound of Formula I to the patient.

9. A method of suppressing the immune system in a patient in need thereof comprising administering a therapeutically effective amount of the compound of Formula I to the patient.

10. A method of preparing a compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

is a single or double bond;

X 1 is O or NR 6 ;

Y is —C(O)— or

X 2 is (CH 2 ) m , O, or NR 6 ;

Z is

W is O, CH, CH 2 , CR 4 , or CR 5 ;

L 1 and L 2 are each independently a direct bond, substituted or unsubstituted —(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n O(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)—, substituted or unsubstituted —(CH 2 ) n C(O)(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n NH(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n S(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 1 -C 6 )alkyl-, substituted or unsubstituted —(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n O(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n NH(C 1 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n S(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n O(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n NH(C 1 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n S(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 2 -C 6 )alkynyl-, wherein each alkyl, alkenyl and alkynyl group may be optionally substituted with alkyl, alkoxy, amino, carboxyl, cyano, nitro, or trifluoromethyl;

each m is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6;

each n is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6;

R 1 is hydrogen, hydroxyl, or OPG, wherein PG is a protecting group, or

R 1 is

wherein

is a resin;

R 2 is hydrogen, hydroxyl, or alkoxy;

R 3 is hydrogen or alkyl;

R 4 and R 5 are each independently hydrogen, hydroxy, alkyl, alkoxy, or OPG, wherein PG is a protecting group;

R 6 is hydrogen or alkyl;

wherein the Effector Domain has Formula II:

wherein:

R 7 , R 9 , R 11 , R 13 , and R 15 are each independently hydrogen or alkyl;

n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

j is an integer selected from 0, 1, and 2;

wherein each of the above groups listed for R 8 , R 10 , R 12 , and a R 14 may be optionally independently substituted with 1 to 3 groups selected from halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, heteroalkylaryl, (CH 2 ) n CN, (CH 2 ) n CF 3 , (CH 2 ) n C 2 F 5 , (CH 2 ) n OR 16 , (CH 2 ) n C(O)R 16 , (CH 2 ) n C(O)OR 16 , (CH 2 ) n OC(O)R 16 , (CH 2 ) n NR 17 R 18 , (CH 2 ) n C(O)NR 17 R 18 , (CH 2 ) n N 19 RC(O)R 16 , (CH 2 ) n N 19 RC(O)OR 16 , (CH 2 ) n NR 19 C(O)NR 17 R 18 , (CH 2 ) n SR 16 , (CH 2 ) n S(O) j NR 17 R 18 , (CH 2 ) n N 19 RS(O) j R 16 , and —(CH 2 ) n NR 19 S(O) j NR 17 R 18 ;

the method comprising the steps of: a) coupling and cyclizing a compound of Formula XI with the Effector Domain to provide the compound of Formula I:

11. The method of claim 10 , wherein the reagents benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), N,N-diisopropylethyl-amine (DIPEA), and N-methylpyrrolidine (NIMP) are used in coupling.

12. The method of claim 11 , wherein the reagent benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium is used in cyclizing.

13. A compound of Formula I, prepared by the method of claim 10 .

14. A method of identifying compounds from a library of compounds that binds to a protein encoded in a genome in complex with FKBP, the method comprising the steps of:

a) screening a hybrid combinatorial peptide or non-peptide library of compounds that includes the FKBP-binding domain (FKBP) of the natural product rapamycin or FK506 against the proteins encoded in a genome using a protein chip;

b) detecting the binding of a compound to a protein on the chip using the anti-V5 antibody together with a fluorescently tagged secondary antibody;

c) recording the fluorescence pattern of the protein chip on a chip reader;

d) identifying the proteins based on the physical location of the fluorescent spots on the chip; and

e) determining the function of the protein based on its perturbed biochemical and cellular functions.

15. The method of claim 14 , wherein the genome is the human genome; and the library of compounds has Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

is a single or double bond;

X 1 is O or NR 6 ;

Y is —C(O)— or

X 2 is (CH 2 ) m , O, or NR 6 ;

Z is

W is O, CH, CH 2 , CR 4 , or CR 5 ;

L 1 and L 2 are each independently a direct bond, substituted or unsubstituted —(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n O(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)—, substituted or unsubstituted —(CH 2 ) n C(O)(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n NH(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n S(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 1 -C 6 )alkyl-, substituted or unsubstituted —(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n O(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 2 -C 6 )alkenyl-, substituted or unsubstituted — (CH 2 ) n NH(C 1 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n S(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n O(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n NH(C 1 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n S(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 2 -C 6 )alkynyl-, wherein each alkyl, alkenyl and alkynyl group may be optionally substituted with alkyl, alkoxy, amino, carboxyl, cyano, nitro, or trifluoromethyl;

each m is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6;

each n is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6;

R 1 is hydrogen, hydroxyl, or OPG, wherein PG is a protecting group, or

R 1 is

wherein

is a resin;

R 2 is hydrogen, hydroxyl, or alkoxy;

R 3 is hydrogen or alkyl;

R 4 and R 5 are each independently hydrogen, hydroxy, alkyl, alkoxy, or OPG, wherein PG is a protecting group;

R 6 is hydrogen or alkyl;

wherein the Effector Domain has Formula

wherein:

R 7 , R 9 , R 11 , R 13 , and R 15 are each independently hydrogen or alkyl;

n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

j is an integer selected from 0, 1, and 2;

wherein each of the above groups listed for R 8 , R 10 , R 12 , and R 14 may be optionally independently substituted with 1 to 3 groups selected from halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, heteroalkylaryl, (CH 2 ) n CN, (CH 2 ) n CF 3 , (CH 2 ) n C 2 F 5 , (CH 2 ) n OR 16 , (CH 2 ) n C(O)R 16 , (CH 2 ) n C(O)OR 16 , (CH 2 ) n OC(O)R 16 , (CH 2 ) n NR 17 R 18 , (CH 2 ) n C(O)NR 17 R 18 , (CH 2 ) n N 19 RC(O)R 16 , (CH 2 ) n N 19 RC(O)OR 16 , (CH 2 ) n NR 19 C(O)NR 17 R 18 , (CH 2 ) n SR 16 , CH 2 ) n S(O) j NR 17 R 18 , (CH 2 ) n N 19 RS(O) j R 16 , and —(CH 2 ) n NR 19 S(O) j NR 17 R 18 .

16. The method of claim 14 , wherein the compound of Formula I:

X is O or NR 6 ;

L 1 and L 2 are each independently —(C 1 -C 6 )alkyl-, —(CH 2 ) n O(C 1 -C 6 )alkyl-, —(CH 2 ) n C(O)(C 1 -C 6 )alkyl-, —(CH 2 ) n C(O)O(C C 6 )alkyl-, —(CH 2 ) n NH(C 1 -C 6 )alkyl, —(CH 2 ) n C(O)NH(C 1 -C 6 )alkyl-, —(CH 2 ) n S(C 1 -C 6 )alkyl-, —(CH 2 ) n C(O)(CH 2 ) n S(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl-, —(CH 2 ) n O(C 2 -C 6 )alkenyl-, —(CH 2 ) n C(O)(C 2 -C 6 )alkenyl-, —(CH 2 ) n C(O)O(C 2 -C 6 )alkenyl-, —(CH 2 ) n NH(C 1 -C 6 )alkenyl-, —(CH 2 ) n C(O)NH(C 2 -C 6 )alkenyl-, —(CH 2 ) n S(C 2 -C 6 )alkenyl-, —(CH 2 ) n C(O)(CH 2 ) n S(C 2 -C 6 )alkenyl-, wherein each alkyl and alkenyl group may be substituted with alkyl, alkoxy, or carboxyl;

n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

R 1 is hydrogen, hydroxyl, or OPG, wherein PG is a silyl protecting group, or

R 1 is

wherein

is a resin;

R 2 is hydroxyl or alkoxy;

R 3 is hydrogen or alkyl;

R 4 and R 5 are each independently hydrogen, alkyl, alkoxy, or OPG, wherein PG is a silyl protecting group;

R 6 is hydrogen;

R 7 , R 9 , R 11 , R 13 , and R 15 are each independently hydrogen or CH 3 ;

17. The method of claim 14 , wherein the compound of Formula I:

L 1 and L 2 are each independently —(C 1 -C 6 )alkyl-, —(CH 2 ) n O(C 1 -C 6 )alkyl-, —(CH 2 ) n C(O)(C 1 -C 6 )alkyl-, —(CH 2 ) n NH(C 1 -C 6 )alkyl-, —(CH 2 ) n C(O)NH(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl-, (CH 2 ) n O(C 2 -C 6 )alkenyl-, —(CH 2 ) n C(O)(C 2 -C 6 )alkenyl-, —(CH 2 ) n NH(C 1 -C 6 )alkenyl-, —(CH 2 ) n C(O)NH(C 2 -C 6 )alkenyl-, wherein each alkyl and alkenyl group may be substituted with alkyl, alkoxy, or carboxyl;

n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

R 1 is hydrogen, hydroxyl or OPG, wherein PG is a tert-butyldimethylsilyl protecting group, or

R 1 is

wherein

is Wang resin;

R 4 and R 5 are each independently hydrogen, hydroxy, alkyl, alkoxy, or OPG, wherein PG is a tert-butyldimethylsilyl protecting group;

R 7 , R 9 , R 11 , R 13 , and R 15 are each independently hydrogen;

R 16 , R 17 , and R 18 are each independently hydrogen or (C 1 -C 6 )alkyl.

18. The method of claim 14 , wherein the compound of Formula I:

n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

19. The method of claim 14 , wherein the compound of Formula I:

20. A method of generating a lead compound as a high-affinity ligand of the FKBP isoforms, the method comprising the steps of:

b) detecting the binding of a compound to a protein on the chip using the anti-V5 antibody together with a fluorescently tagged secondary antibody;

c) recording the fluorescence pattern of the protein chip on a chip reader;

d) identifying the proteins based on the physical location of the fluorescent spots on the chip; and

e) determining the structure of the lead compound.

21. The method of claim 20 , wherein the genome is the human genome; and the library of compounds has Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

is a single or double bond;

X 1 is O or NR 6 ;

Y is —C(O)— or

X 2 is (CH 2 ) m , O, or NR 6 ;

Z is

W is O, CH, CH 2 , CR 4 , or CR 5 ;

L 1 and L 2 are each independently a direct bond, substituted or unsubstituted —(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n O(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)—, substituted or unsubstituted —(CH 2 ) n C(O)(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n NH(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n S(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 1 -C 6 )alkyl-, substituted or unsubstituted —(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n O(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n NH(C 1 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n S(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n O(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n NH(C 1 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n S(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 2 -C 6 )alkynyl-, wherein each alkyl, alkenyl and alkynyl group may be optionally substituted with alkyl, alkoxy, amino, carboxyl, cyano, nitro, or trifluoromethyl;

each m is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6;

each n is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6;

R 1 is hydrogen, hydroxyl, or OPG, wherein PG is a protecting group, or

R 1 is

wherein

is a resin;

R 2 is hydrogen, hydroxyl, or alkoxy;

R 3 is hydrogen or alkyl;

R 4 and R 5 are each independently hydrogen, hydroxy, alkyl, alkoxy, or OPG, wherein PG is a protecting group;

R 6 is hydrogen or alkyl;

wherein the Effector Domain has Formula II:

wherein:

R 7 , R 9 , R 11 , R 13 , and R 15 are each independently hydrogen or alkyl;

R 8 , R 10 , R 12 , and R 14 are each independently hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted perfluoroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkylaryl, (CH 2 ) n CN, (CH 2 ) n CF 3 , (CH 2 ) n C 2 F 5 , (CH 2 ) n OR 16 , (CH 2 ) n C(O)R 16 , (CH 2 ) n C(O)OR 16 , (CH 2 )—OC(O)R 16 , (CH 2 ) n NR 17 R 18 , (CH 2 ) n C(O)NR 17 R 18 , (CH 2 ) n N 19 RC(O)R 16 , (CH 2 ) n N 19 RC(O)OR 16 , (CH 2 ) n NR 19 C(O)NR 17 R 18 , (CH 2 )—(CH 2 ) n S(O) n NR 17 R 18 , (CH 2 ) n N 19 RS(O) j R 16 , or —(CH 2 ) n NR 19 S(O) j NR 17 R 18 ;

n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

j is an integer selected from 0, 1, and 2;

wherein each of the above groups listed for R 8 , R 10 , R 12 , and R 14 may be optionally independently substituted with 1 to 3 groups selected from halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, heteroalkylaryl, (CH 2 ) n CN, (CH 2 ) n CF 3 , (CH 2 ) n C 2 F 5 , (CH 2 ) n OR 16 , (CH 2 ) n C(O)R 16 , (CH 2 ) n C(O)OR 16 , (CH 2 )—OC(O)R 16 , (CH 2 ) n NR 17 R 18 , (CH 2 ) n C(O)NR 17 R 18 , (CH 2 ) n N 19 RC(O)R 16 , (CH 2 ) n N 19 RC(O)OR 16 , (CH 2 ) n NR 19 C(O)NR 17 R 18 , (CH 2 ) n SR 16 , (CH 2 ) n S(O) j NR 17 R 18 , (CH 2 ) n N 19 RS(O) j R 16 , and —(CH 2 ) n NR 19 S(O) j NR 17 R 18 .

22. The method of claim 20 , wherein the compound of Formula I:

X is O or NR 6 ;

n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

R 1 is hydrogen, hydroxyl, or OPG, wherein PG is a silyl protecting group, or

R 1 is

wherein

is a resin;

R 2 is hydroxyl or alkoxy;

R 3 is hydrogen or alkyl;

R 4 and R 5 are each independently hydrogen, alkyl, alkoxy, or OPG, wherein PG is a silyl protecting group;

R 6 is hydrogen;

R 7 , R 9 , R 11 , R 13 , and R 15 are each independently hydrogen or CH 3 ;

23. The method of claim 20 , wherein the compound of Formula I:

n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

R 1 is hydrogen, hydroxyl or OPG, wherein PG is a tert-butyldimethylsilyl protecting group, or

R 1 is

wherein

is Wang resin;

R 4 and R 5 are each independently hydrogen, hydroxy, alkyl, alkoxy, or OPG, wherein PG is a tert-butyldimethylsilyl protecting group;

R 7 , R 9 , R 11 , R 13 , and R 15 are each independently hydrogen;

R 16 , R 17 , and R 18 are each independently hydrogen or (C 1 -C 6 )alkyl.

24. The method of claim 20 , wherein the compound of Formula I:

n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

25. The method of claim 20 , wherein the compound of Formula I:

L 1 and L 2 are each independently —OCH 2 CH 2 —, —CH 2 C(O)—, —CH 2 CH 2 C(O)—, —C(O)NHCH 2 CH 2 , —CH 2 CH═CHCH 2 —, —OCH 2 CH═CHCH 2 CH 2 —, OCH 2 CH═CHCH 2 CH(CO2H)—, —CH 2 C(O)NHCH 2 CH 2 —, or CH 2 CH(OCH 3 )═C(CH 3 )CH 2 CH 2 ; and

26. A pharmaceutical composition comprising the compound of Formula I of claim 1 , and a pharmaceutically acceptable vehicle.

27. A library comprising a plurality of the compounds of Formula I of claim 1 .

28. A method of preparing a library of compounds of Formula I, wherein the compounds are prepared by the method of claim 10 .

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 26, 2013

From: LIU, JUN O.; WANG, JINGXIN; GUO, ZUFENG; LI, WEI; BHAT, SHRIDHAR; DAS, MANISHA

To: THE JOHNS HOPKINS UNIVERSITY

Reel/Frame 030693/0598 →

Continuity (2)

Provisional Application 61418038 · Nov 30, 2010

Related Publication 20140073581A1 · Mar 13, 2014