WO2005037845A1 - Benzothiazole and thiazole[5,5-b] pyridine compositions and their use as ubiquitin ligase inhibitors - Google Patents

Benzothiazole and thiazole[5,5-b] pyridine compositions and their use as ubiquitin ligase inhibitors Download PDF

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WO2005037845A1
WO2005037845A1 PCT/US2004/034397 US2004034397W WO2005037845A1 WO 2005037845 A1 WO2005037845 A1 WO 2005037845A1 US 2004034397 W US2004034397 W US 2004034397W WO 2005037845 A1 WO2005037845 A1 WO 2005037845A1
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thiazol
benzo
methoxybenzo
benzamide
carboxamide
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PCT/US2004/034397
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French (fr)
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WO2005037845A8 (en
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Francesco Parlati
Usha V. Ramesh
Rajinder Singh
Donald G. Payan
Raymond Lowe
Gary Charles Look
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Rigel Pharmaceuticals, Inc.
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Priority to EP04795543A priority Critical patent/EP1680431A1/en
Publication of WO2005037845A1 publication Critical patent/WO2005037845A1/en
Publication of WO2005037845A8 publication Critical patent/WO2005037845A8/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention is in the field of ubiquitin ligation and inhibitors of the ubiquitination pathway. Additionally, this invention is in the field of treating diseases or conditions associated with ubiquitination.
  • Ubiquitin is a 76 amino acid protein present throughout the eukaryotic kingdom. It is a highly conserved protein and is essentially the identical protein in diverse organisms ranging from humans to yeasts to fruit flies. In eukaryotes, ubiquitin is the key component of the ATP-dependent pathway for protein degradation. Proteins slated for degradation are covalently linked to ubiquitin via an ATP-dependent process catalyzed by three separate enzymes. [0004] Ubiquitin has also been implicated as key components in other biochemical processes.
  • Ubiquitination of the Gag structural protein of Rous Sarcoma virus has been linked to the targeting of Gag to the cell membrane of the host cell where it can assemble into spherical particles and bud from the cell surface.
  • Production of HIV particles has also been associated with ubiquitination and may constitute an important cellular pathway for producing infectious particles.
  • the ubiquitin pathway may be an important target for treatment of HIV positive patients.
  • inhibitors of ubiquitin ligation that can alter the ATP-dependent ubiquitination of proteins. Inhibition of ubiquitination can regulate the degradation of proteins in ways that assist in treating various disorders. Inhibitors of ubiquitin ligases may also help in treating infectious diseases such as bacterial and viral infections that depend on the cellular biochemical machinery.
  • Ubiquitin is first activated in an ATP-dependent manner by a ubiquitin activating agent, for example, an El.
  • a ubiquitin activating agent for example, an El.
  • the C-terminus of a ubiquitin forms a high energy thiolester bond with the ubiquitin activating agent.
  • the ubiquitin is then transferred to a ubiquitin conjugating agent, for example, an E2 (also called ubiquitin moiety carrier protein), also linked to this second ubiquitin agent via a thiolester bond.
  • E2 also called ubiquitin moiety carrier protein
  • ubiquitin ligating agent for example, an E3.
  • monomers or oligomers of ubiquitin are attached to the target protein.
  • each ubiquitin is covalently ligated to the next ubiquitin through the activity of a ubiquitin ligating agent to form polymers of ubiquitin.
  • the enzymatic components of the ubiquitination pathway have received considerable attention (for a review, see Weissman, Nature Reviews 2:169-178 (2001)).
  • the members of the El ubiquitin activating agents and E2 ubiquitin conjugating agents are structurally related and well characterized enzymes.
  • E2 ubiquitin conjugating agents There are numerous species of E2 ubiquitin conjugating agents, some of which act in preferred pairs with specific E3 ubiquitin ligating agents to confer specificity for different target proteins. While the nomenclature for the E2 ubiquitin conjugating agents is not standardized across species, investigators in the field have addressed this issue and the skilled artisan can readily identify various E2 ubiquitin conjugating agents, as well as species homologues (See Haas and Siepmann, FASEB J. 11:1257-1268 (1997)).
  • Ubiquitin agents such as the ubiquitin activating agents, ubiquitin conjugating agents, and ubiquitin ligating agents, are key determinants of the ubiquitin-mediated proteolytic pathway that results in the degradation of targeted proteins and regulation of cellular processes. Consequently, agents that modulate the activity of such ubiquitin agents may be used to upregulate or downregulate specific molecules involved in cellular signal transduction. Disease processes can be treated by such up- or down regulation of signal transducers to enhance or dampen specific cellular responses.
  • This principle has been used in the design of a number of therapeutics, including phosphodiesterase inhibitors for airway disease and vascular insufficiency, kinase inhibitors for malignant transformation and Proteasome inhibitors for inflammatory conditions such as arthritis.
  • an object of the present invention is to provide compounds, compositions and methods of assaying for the physiological role of ubiquitin agents, and for providing methods for determining which ubiquitin agents are involved together in a variety of different physiological pathways.
  • the invention comprises compounds and pharmaceutical compositions of the compounds for inhibiting ubiquitin agents.
  • compositions can be used in treating various conditions where ubiquitination is involved. They can also be used as research tools to study the role of ubiquitin in various natural and pathological processes.
  • the invention comprises compounds that inhibit ubiquitination of target proteins.
  • the invention comprises a pharmaceutical composition comprising an inhibitor of ubiquitination according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent.
  • the invention comprises methods of inhibiting ubiquitination in a cell, comprising contacting a cell in which inhibition of ubiquitination is desired with a pharmaceutical composition comprising a ubiquitin agent inhibitor according to the invention.
  • the invention provides methods for treating cell proliferative diseases or conditions, comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a ubiquitin agent inhibitor according to the invention.
  • the invention also provides for the use of a compound or composition of the invention for the manufacture of a medicament for use in treating cell proliferative diseases or conditions.
  • the invention provides methods for treating HIV infection and related conditions, comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a ubiquitin agent inhibitor according to the invention.
  • the invention also provides for the use of a compound or composition of the invention for the manufacture of a medicament for use in treating HIV infection and related conditions.
  • the invention relates to compounds of the formula: and pharmaceutically acceptable salts thereof, wherein
  • a 1 , A 2 , A 3 , A 4 are independently nitrogen or carbon;
  • R 2 is H, C ⁇ -C 6 alkyl, or is linked to a carbon of R 1 through a carbonyl group;
  • R 3 and R 5 are independently H, halogen, or C ⁇ -C 6 alkyl;
  • R 4 and R 6 are independently H, halogen, C(0)R 7 , NR 8 Rg, nitro, C ⁇ . 5 -alkyl, C ⁇ -alkoxy, 0CF 3 , CF 3 , aryl, -C ⁇ -6 -alkyl-aryl, heteroaryl, -C ⁇ .
  • n is 1 to 5 and each R 12 is th same or different and is C 1-6 -aIkyl, hydroxy, halogen, nitro, oxo, amino, halo-C ⁇ -6 -alkyl, C ⁇ - 6 -alkoxy, halo-C ⁇ . 6 -alkoxy, or cyano, NHC(O)- C ⁇ . 6 -alkyl, NHC(0)-C 2 . 6 -alkylene, C(0)-0-Ci. 6 -alkyl, or C(0)-aryl;
  • R 8 and R 9 are independently hydrogen, or C r C 6 -alkyl
  • R 10 is C ⁇ . 6 -alkyl, C ⁇ -6 -aIkyl-aryl, aryl, or heteroaryl;
  • R n is Ci-e-alkyl, C ⁇ . 5 -alkyl-aryl, aryl, or NR 8 R 9 ; with the proviso that R 4 and R 5 are not simultaneously hydrogen; and wherein each one of the alkyl, aryl, heteroaryl, or heterocyclyl of R i to R 12 is optionally substituted with one or more groups selected from C.- ⁇ -alkyl, C 2 -C 6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-C ⁇ . 8 -alkyl, C ⁇ -alkoxy, halo-C ⁇ . 8 -alkoxy, cyano, NHC(0)-Ci.
  • R 2 is H, C r C 6 alkyl, or is linked to a carbon of Ri through a carbonyl group;
  • R 4 and R 6 are independently H, halogen, C(0)R 7 , NR 8 R 9 , nitro, C ⁇ -alkyl, C ⁇ . 5 -alkoxy, 0CF 3 ,
  • R 7 is hydrogen, C ⁇ . 6 -alkyl, C ⁇ . 6 -alkoxy, C(Z)-R ⁇ where Z is CH 2 or 0, heteroaryl, aryl, or a group of the formula
  • n is 1 to 5 and each R 12 is the same or different and is Ci- 6 -alkyl, hydroxy, halogen, nitro, oxo, amino, halo-C 1-6 -alkyI r Ci. 6 -alkoxy, halo- Ci-e-alkoxy, or cyano, NHC(0)-Ci. 6 -alkyl, NHC(0)-C 2 . 6 -alkylene, C(0)-0- C ⁇ . 5 -alkyl, or C(0)-aryl;
  • R 8 and R 9 are independently hydrogen, or CrC 5 -alkyl
  • Rio Ci-e-alkyl, C 1-6 -aIkyl-aryl, aryl, or heteroaryl
  • Rn Ci-e-alkyl, C ⁇ . 5 -alkyl-aryl, aryl, or NR 8 R 9 ; with the proviso that R 4 and R 6 are not simultaneously hydrogen
  • each one of the alkyl, aryl, heteroaryl, or heterocyclyl of the above groups is optionally substituted with one or more groups selected from Ci-a-alkyl, C 2 -C 6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-C ⁇ .
  • Preferred compounds of formula (ll)-l include those wherein Ri is phenyl or naphthyl, each of which is optionally substituted with one or two groups selected from C ⁇ . 8 -alkyl, C -C 6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-C 1-8 -aIkyl, C ⁇ - 8 - alkoxy, halo-C ⁇ _ 8 -alkoxy, cyano, NHC(0)-C ⁇ . 8 -alkyl, NHC(0)-cycloalkyl, NHC(0)-C 2 .
  • Preferred compounds of formula (ll)-l also include those wherein Ri is phenyl, optionally substituted with one or two groups selected from C ⁇ -8 -alkyl, C 2 -C 6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-C ⁇ .
  • Preferred compounds of formula (II) further include compounds of formula (ll)-3 (and their pharmaceutically acceptable salts), which are compounds of formula (II) wherein L is a bond,
  • Ri is cycloalkyl, optionally substituted with one or more groups selected from Ci-s-alkyl, C 2 -C 6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-C h alky!, C ⁇ . 8 -alkoxy, halo-C ⁇ . 8 -alkoxy, cyano, NHC(0)-Ci. 8 -alkyl, NHC(0)-cycloalkyl, NHC(O)-
  • Preferred compounds of formula (II) further include compounds of formula (11)4 (and their pharmaceutically acceptable salts), which are compounds of formula (II) wherein L is a bond,
  • Ri is heterocyclyl, optionally substituted with one or more groups selected from C ⁇ . 8 -alkyl, C 2 -C 6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-C ⁇ . 8 -alkyl, C ⁇ - 8 -alkoxy, halo-Ci-s-alkoxy, cyano, NHC(0)-Ci. 8 -alkyl, NHC(O)- cycloalkyl, NHC(0)-C 2 . 6 -alkenyl, NHC(0)-aryl-C(0)-0-Ci. 8 -alkyl, C(0)-0-R ⁇ 3 , -0-C(0)-C r C 8 alkyl, or C(0)- aryl, wherein R ⁇ 3 is H or C ⁇ -C 8 alkyl.
  • (ID-2, (ID-3, and (111)4 include: pyyrolidinyl, indolinyl, indolyl, adamantyl, piperidinyl, cyclohexyl, cyclobutenyl, thiophene, pyridinyl, furanyl, pyrrolyl, thiadiazolyl, benzothiophene, 1,3- dioxoisoindolinyl, pyrazolyl, dihydroquinolinyl, cyclopentyl, and azetidinyl.
  • Preferred compounds of formulae (II), (ll)-l, (ll)-2, (ID-3, and (11)4 include compounds of formula (10-5 (and their pharmaceutically acceptable salts), which are compounds of formulae (II),
  • Preferred compounds of formula (ID-5 include those wherein R 6 is hydrogen and R 4 is ethoxy or methoxy.
  • R 4 is methoxy
  • R s is hydrogen
  • R 2 is hydrogen
  • L is a bond
  • Ri is benzimidazolyl attached to the main compound at the 2-position of the benzimidazolyl group.
  • R 7 is hydrogen, Ci. s -alkyl, Ci-e-alkoxy, C(Z)-Ru where Z is CH 2 or 0, heteroaryl, aryl, or a group of the formula
  • n is 1 to 5 and each R i2 is the same or different and is C ⁇ - 6 -alkyl, hydroxy, halogen, nitro, oxo, amino, halo-C ⁇ . 6 -alkyl, C ⁇ - 6 -alkoxy, halo- Ci-e-alkoxy, or cyano, NHC(0)-Ci. 5 -alkyl, NHC(0)-C 2 . 6 -alkylene, C(0)-0- Ci-e-alkyl, or C(0)-aryl; R 8 and R 9 are independently hydrogen, or C ⁇ -C 6 -alkyl; Rio is C ⁇ . 6 -alkyl, C ⁇ .
  • Rn is Ci-e-alkyl, C ⁇ . 6 -alkyl-aryl, aryl, or heteroaryl; Rn is Ci-e-alkyl, C ⁇ . 6 -alkyl-aryl, aryl, or NR 8 R 9 ; with the proviso that R and R 6 are not simultaneously hydrogen; and wherein each one of the alkyl, aryl, heteroaryl, or heterocyclyl of the above groups is optionally substituted with one or more groups selected from C ⁇ . 8 -alkyl, C 2 -C 6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-C ⁇ . 8 -alkyl, C ⁇ . 8 -alkoxy, halo-C ⁇ .
  • Preferred compounds of formula (III) include compounds of formula (IID-l (and their pharmaceutically acceptable salts), which are compounds of formula III wherein Ri is aryl, optionally substituted with one or more groups selected from C ⁇ . 8 -alkyl, C 2 -C 5 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-C ⁇ . 8 -alkyl, Ci-s-alkoxy, halo- C ⁇ . 8 -alkoxy, cyano, NHC(0)-C ⁇ .
  • Preferred compounds of formula (lll)-l include compounds wherein Ri is phenyl, optionally substituted with 1, 2, or 3 groups independently selected from halogen, halo-C ⁇ -C 6 alkyl, cyano, -N-C(0)-C r C 6 alkyl, nitro, C r C 6 alkoxy, and C r C 6 alkyl.
  • Preferred compounds of formula (III) include compounds of formula (lll)-2 (and their pharmaceutically acceptable salts), which are compounds of formula (III) wherein Ri is heteroaryl, optionally substituted with one or more groups selected from C ⁇ .
  • Preferred compounds of formula (IID-2 include compounds wherein Ri is thienyl, benzothienyl, furanyl, benzofuranyl, dibenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, or isoxazolyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, halo-C ⁇ -C 6 alkyl, cyano, -N-C(0)-C r C 5 alkyl, nitro, C r C 6 alkoxy, and C r C 6 alkyl.
  • Preferred compounds of formula (IID-2 include compounds wherein Ri is furanyl or thiophene, which are optionally substituted with 1, 2, or 3 groups independently selected from halogen, halo-C ⁇ -C 6 alkyl, cyano, -N-C(0)-C r C 5 alkyl, nitro, C r C 6 alkoxy, and C r C 6 alkyl.
  • Preferred compounds of formulae (III), (IID-l, and (IID-2 include compounds of formula (IID-3 (and their pharmaceutically acceptable salts), which are compounds of formulae (III), (IID-l, or (IID-2 wherein R 6 is hydrogen, and R 4 is C ⁇ . 6 -alkoxy.
  • Preferred compounds of formula (IID-3 include those wherein R 6 is hydrogen and R 4 is ethoxy or methoxy.
  • Preferred compounds of the formula (I) also include compounds of formula (IV): and pharmaceutically acceptable salts thereof, wherein R 4 is Ci-e-alkoxy; and
  • R is C ⁇ - 6 -alkoxy
  • R ⁇ and R15 are independently H, halogen, amino, nitro, cyano, d-C ⁇ alkyl, Ci-C ⁇ alkoxy, -C(0)- C r C 6 alkyl, -0-C(0)- d-C 6 alkyl, -NH-C(O)- d-C 6 alkyl, -NH-C(0)-C 3 - C 7 cycloalkyl, -NH-C(0)-C 2 -C 6 alkenyl, -S0 2 -NR ⁇ 6 R ⁇ 7 ; Ri 6 and R 1 7 are independently H, or C ⁇ -C 6 alkyl, or Ri6 and R 17 together with the nitrogen to which they are attached form a 4- 8 membered heterocyclic ring, which is optionally substituted.
  • R 12 is Ci-e-alkyl, Ci-e-alkoxy, halogen, nitro, NHC(0)-d. 6 -alkyl, NHC(0)-C 2 . 6 -alkylene, C(O)-O-C ⁇ . 6 -alkyl, or C(0)-aryl
  • Ri is hydrogen or C ⁇ -6 -alky ⁇
  • R 3 , R 4 , R 5 and R 6 are hydrogen, halogen, Ci-e-alkoxy, de-alkyl, or nitro.
  • R 12 is Ci-e-alkyl, NHC(O)- Ci-e-alkyl, or NHC(0)-C 2 . 5 -alkylene
  • R 4 is C ⁇ . 5 -aIkoxy and Ri
  • R 3 , R 5 and R 6 are hydrogen.
  • Compounds in Table 1 are known in the art and commercially available. Compounds in Table 2 can be readily prepared by a person of ordinary skill in the art using the procedures described herein, or by synthetic procedures generally known in the art. Indeed, there is more than one process to prepare the compounds of the invention.
  • Compounds of the invention include those of formula (I), (II), (ID-1, (ID-2, (ll)-3, (11)4, (ll)-5, (III), (lll)-l, (IID-2, (IID-3, (IV), and (V), provided that they are not one of the compounds in Table 1. Table 1.
  • the invention comprises pharmaceutical compositions comprising a compound of formula (I), (ID, (ll)-l, (ID-2, (ID-3, (11)4, (ll)-5, (III), (lll)-l, (IID-2, (IID-3, (IV), or (V) together with a pharmaceutically acceptable carrier, excipient, or diluent.
  • a pharmaceutically acceptable carrier excipient, or diluent.
  • the compounds and pharmaceutical compositions of the invention are useful for inhibiting ubiquitination in a cell.
  • the pharmaceutical compositions target the El activating agent of the ubiquitination process thereby preventing transfer of ATP-activated ubiquitin to the E2 conjugating agent.
  • the invention also comprises methods of inhibiting ubiquitination in a cell comprising contacting a cell in which inhibition of ubiquitination is desired with a compound or pharmaceutical composition according to the invention.
  • the invention also comprises methods for treating cell proliferative diseases and other conditions in a patient in which ubiquitination is an important component.
  • diseases and conditions that can be treated are cancers and conditions related to cancers.
  • any disease and condition in which ubiquitination is a component can be treated with the compounds and pharmaceutical compositions of the invention.
  • the compounds and compositions of the invention are also useful for preventing and/or treating malaria. Accordingly, the invention further comprises methods of treating and of preventing malaria by administering to a subject (preferably human) an amount of a compound or composition of the invention effective to prevent and/or treat malaria.
  • a subject preferably human
  • the invention also provides for the use of a compound or composition of the invention for the manufacture of a medicament for use in treating and/or preventing malaria.
  • chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art.
  • an "alkyl” moiety generally refers to a monovalent radical (e.g.
  • a bivalent linking moiety can be "alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH 2 -CH 2 -), which is equivalent to the term “alkylene.”
  • alkyl in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH 2 -CH 2 -), which is equivalent to the term “alkylene.”
  • aryl refers to the corresponding divalent moiety, arylene.
  • All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for 0, and 2, 4, or 6 for S, depending on the oxidation state of the S).
  • a moiety may be defined, for example, as (A) a -B-, wherein a is 0 or 1. In such instances, when a is 0 the moiety is B- and when a is 1 the moiety is A-B-. Also, a number of moieties disclosed herein exist in multiple tautomeric forms, all of which are intended to be encompassed by any given tautomeric structure. Other stereochemical forms of the compounds of the invention are also encompassed including but not limited to enantiomers, diastereomers, and other isomers such as rotamers.
  • a substituent can be of a particular chemical class differing by the number of atoms or groups of the same kind in the moiety (e.g., alky, which can be C C 2 , C 3 , etc.), the number of repeated atoms or groups is represented by a range (e.g., CrC 6 -alkyl). In such instances each and every number in that range and all sub-ranges are specifically contemplated.
  • C r C 3 -alkyl means C r , C 2 -, C 3 -, C ⁇ - 2 , C 1 .3-, and C 2 - 3 -alkyl.
  • alkyl refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, which is optionally substituted with one, two or three substituents. Unless otherwise specified, the alkyl group may be saturated, unsaturated, or partially unsaturated. As used herein, therefore, the term “alkyl” is specifically intended to include alkenyl and alkynyl groups, as well as saturated alkyl groups, unless expressly stated otherwise.
  • Preferred alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, vinyl, allyl, isobutenyl, ethynyl, and propynyl.
  • a "substituted" alkyl, cycloalkyl, aryl, or heterocyclic group is one having between one and about four, preferably between one and about three, more preferably one or two, non-hydrogen substituents.
  • Suitable substituents include, without limitation, halo, hydroxy, nitro, haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, alkoxycarbonyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.
  • cycloalkyl as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12, preferably 3 to 8 carbons, wherein the cycloalkyl group additionally is optionally substituted.
  • Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, and adamantyl.
  • hydrocarbyl as employed herein includes all alkyl moieties and all cycloalkyl moieties (both as defined above), each alone or in combination.
  • hydrocarbyl includes methyl, ethyl, propyl, n-butyl, i-butyl, cyclopropyl, cyclohexyl, cyclopropyl-CH 2 -, cyclohexyl-(CH 2 ) 3 -, etc.
  • An "aryl” group is a C 6 -C ⁇ 4 aromatic moiety comprising one to three aromatic rings, which is optionally substituted.
  • the aryl group is a C 6 -C 10 aryl group.
  • Preferred aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.
  • arylalkyl group comprises an aryl group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted.
  • the aralkyl group is CrC 6 -alkyl-(C 6 -C ⁇ o)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
  • An "alkaryl” or “alkylaryl” group is an aryl group having one or more alkyl substituents. Examples of alkaryl groups include, without limitation, tolyl, xylyl, mesityl, ethylphenyl, tert-butylphenyl, and methylnaphthyl.
  • a “heterocyclic” group is a non-aromatic mono-, bi-, or tricyclic structure having from about 3 to about 14 atoms, wherein one or more atoms are selected from the group consisting of N, 0, and S.
  • One ring of a bicyclic heterocycle or two rings of a tricyclic heterocycle may be aromatic, as in indan and 9,10-dihydro-anthracene.
  • the heterocyclic group is optionally substituted on carbon with oxo or with one of the substituents listed above.
  • the heterocyclic group may also independently be substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or on sulfur with oxo or lower alkyl.
  • Preferred heterocyclic groups include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino.
  • the heterocyclic group is a heteroaryl group.
  • heteroaryl refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, between one and about three heteroatoms selected from the group consisting of N, 0, and S.
  • Preferred heteroaryl groups include, without limitation, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, and isoxazolyl.
  • C 5 -C 6 -heterocyclyl is a 5- or 6- membered ring having at least one heteroatom, and includes pyrrolidinyl (C 5 ) and piperidinyl (C 6 );
  • C 6 -hetoaryl includes, for example, pyridyl and pyrimidyl.
  • the heterocyclic group is fused to an aryl or heteroaryl group.
  • fused heterocycles include, without limitation, tetrahydroquinolinyl and dihydrobenzofuranyl.
  • Additional preferred heterocyclyls and heteroaryls include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, lH-indazolyl, indolenyl
  • a moiety that is substituted is one in which one or more hydrogens have been independently replaced with another chemical substituent.
  • substituted phenyls include 2-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluor-3-propylphenyl.
  • substituted n-octyls include 2,4 dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. Included within this definition are methylenes (-CH 2 -) substituted with oxygen to form carbonyl -CO-).
  • Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular -CH- substituted with oxo is -C(0)-) nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, , alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.
  • Preferred substituents, which are themselves not further substituted are:
  • R 30 and R 31 taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents from (a), above.
  • halogen or halo as employed herein refers to chlorine, bromine, fluorine, or iodine.
  • acyl refers to an alkylcarbonyl or arylcarbonyl substituent.
  • acylamino refers to an amide group attached at the nitrogen atom.
  • carbamoyl refers to an amide group attached at the carbonyl carbon atom.
  • the nitrogen atom of an acylamino or carbamoyl substituent may be additionally substituted.
  • sulfonamido refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom.
  • amino is meant to include NH 2 , alkylamino, arylamino, and cyclic amino groups.
  • compositions comprising an inhibitor of ubiquitination according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent.
  • Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
  • compounds of the invention are administered intravenously in a hospital setting.
  • administration may preferably be by the oral route.
  • compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, flavors, dyes and other materials well known in the art.
  • diluents fillers, salts, buffers, stabilizers, solubilizers, flavors, dyes and other materials well known in the art.
  • pharmaceutically acceptable salts refers to salts and complexes that retain the desired biological activity of the compounds of the invention and exhibit minimal or no undesired toxicological effects.
  • salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid.
  • inorganic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid
  • the compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR + Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -0-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
  • R is hydrogen, alkyl, or benzyl
  • Z is a counterion, including chloride, bromide, iodide, -0-alkyl, toluenesulfonate, methylsulfonate
  • the compounds of the invention can also be administered as prodrugs which can be converted to the active form in vivo.
  • the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated.
  • a preferred dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 500 mg/kg, preferably 0.1 to 100 mgAg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient per day.
  • a typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier.
  • the effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
  • the invention provides a method of inhibiting ubiquitination in a cell, comprising contacting a cell in which inhibition of ubiquitination is desired with an inhibitor of ubiquitination of the invention.
  • Measurement of the ubiquitination can be achieved using known methodologies. (See, for example, WO 01/75145, US-2002-0042083-A1 and WO 03/076608, each of which is incorporated by reference in its entirety.)
  • the method according to the third aspect of the invention causes an inhibition of cell proliferation of contacted cells.
  • the phrase "inhibiting cell proliferation” is used to denote an ability of an inhibitor of ubiquitination to retard the growth of cells contacted with the inhibitor as compared to cells not contacted.
  • An assessment of cell proliferation can be made by counting contacted and non-contacted cells using a Coulter Cell Counter (Coulter, Miami, FL), photographic analysis with Array Scan II (Cellomics) or a hemacytometer. Where the cells are in a solid growth (e.g., a solid tumor or organ), such an assessment of cell proliferation can be made by measuring the growth with calipers and comparing the size of the growth of contacted cells with non-contacted cells.
  • growth of cells contacted with the inhibitor is retarded by at least 50% as compared to growth of non-contacted cells. More preferably, cell proliferation is inhibited by 100% ( e., the contacted cells do not increase in number). Most preferably, the phrase "inhibiting cell proliferation" includes a reduction in the number or size of contacted cells, as compared to non-contacted cells.
  • an inhibitor of ubiquitination according to the invention that inhibits cell proliferation in a contacted cell may induce the contacted cell to undergo growth retardation, to undergo growth arrest, to undergo programmed cell death (i.e., to apoptose), or to undergo necrotic cell death.
  • the contacted cell is a neoplastic cell.
  • neoplastic cell is used to denote a cell that shows aberrant cell growth.
  • the aberrant cell growth of a neoplastic cell is increased cell growth.
  • a neoplastic cell may be a hyperplastic cell, a cell that shows a lack of contact inhibition of growth in vitro, a benign tumor cell that is incapable of metastasis in vivo, or a cancer cell that is capable of metastasis in vivo and that may recur after attempted removal.
  • tumorgenesis is used to denote the induction of cell proliferation that leads to the development of a neoplastic growth.
  • the ubiquitination inhibitor induces cell differentiation in the contacted cell.
  • a neoplastic cell when contacted with an inhibitor of ubiquitination may be induced to differentiate, resulting in the production of a non-neoplastic daughter cell that is phylogenetically more advanced than the contacted cell.
  • the contacted cell is in an animal.
  • the invention provides a method for treating a cell proliferative disease or condition in an animal, comprising administering to an animal in need thereof an effective amount of an inhibitor of ubiquitination of the invention.
  • the animal is a mammal, more preferably a domesticated mammal. Most preferably, the animal is a human.
  • cell proliferative disease or condition is meant to refer to any condition characterized by aberrant cell growth, preferably abnormally increased cellular proliferation.
  • examples of such cell proliferative diseases or conditions include, but are not limited to, cancer, restenosis, and psoriasis.
  • the invention provides a method for inhibiting neoplastic cell proliferation in an animal comprising administering to an animal having at least one neoplastic cell present in its body a therapeutically effective amount of a ubiquitination inhibitor of the invention.
  • the invention provides a method for treating cancer comprising administering to a patient in need thereof an effective amount of an inhibitor of ubiquitination of the invention.
  • terapéuticaally effective amount is meant to denote a dosage sufficient to cause inhibition of ubiquitination in the cells of the subject, or a dosage sufficient to inhibit cell proliferation or to induce cell differentiation in the subject.
  • Administration may be by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
  • compounds of the invention are administered intravenously in a hospital setting.
  • administration may preferably be by the oral route.
  • the ubiquitination inhibitor When administered systemically, the ubiquitination inhibitor is preferably administered at a sufficient dosage to attain a blood level of the inhibitor from about 0.01 ⁇ M to about 100 ⁇ M, more preferably from about 0.05 ⁇ M to about 50 ⁇ M, still more preferably from about 0.1 ⁇ M to about 25 ⁇ M, and still yet more preferably from about 0.5 ⁇ M to about 20 ⁇ M.
  • concentrations For localized administration, much lower concentrations than this may be effective, and much higher concentrations may be tolerated.
  • concentrations may be effective, and much higher concentrations may be tolerated.
  • the dosage of ubiquitination inhibitor necessary to produce a therapeutic effect may vary considerably depending on the tissue, organ, or the particular animal or patient to be treated.
  • the contacted cell is a cell infected with HIV in a patient.
  • the invention provides a method for treating HIV infection as well as conditions related to HIV in a patient, comprising administering to a patient in need thereof an effective amount of an inhibitor of ubiquitination of the invention.
  • the preparation, dosage and administration of the inhibitors of ubiquitination of the invention for the treatment of HIV and related conditions can be carried out as described above.
  • the inhibitors of ubiquitination of the invention are useful for the treatment of HIV infection and related conditions because they can inhibit the replication and spread of HIV.
  • the replication and spread of HIV is decreased by the enzyme AP0BEC3G, which acts by causing extensive mutations in the cDNA reverse transcribed from the HIV genomic RNA. This has the effect of terminating the life cycle of HIV.
  • AP0BEC3G HIV encodes the protein Vif that functions by decreasing the translation of APOBEC3G and increasing the post- translational degradation of AP0BEC3G.
  • the post-translational degradation of AP0BEC3G is catalyzed by the 26S proteasome and depends on the polyubiquitination of AP0BEC3G.
  • Polyubiquitination serves as a signal for the 26S proteasome to degrade AP0BEC3G.
  • inhibitors of ubiquination of the invention can inhibit the function of the 26S proteasome by prevent the targeting of AP0BEC3G to the 26S proteasome so that the intracellular concentration of AP0BEC3G is increased. This increased concentration of AP0BEC3G in turn inhibits the replication and spread of HIV by diminishing the effect of Vif.
  • Biological assays for determining the transfer of ubiquitin from the El activating agent to the E2 conjugating agent are described in United States Patent Application No.'s 09/542,497 and 09/826,312 as well as in the PCT Application WO 01/75145, all of which are incorporated by reference in their entirety.
  • the following assay example illustrates one way by which the ubiquitin ligase inhibitory activity of the compounds of the invention can be assayed. This assay example is not meant to limit in any way the use of the compounds of the invention as ubiquitin ligase inhibitors.
  • the blocked Nickel- substrate plate was then washed three times with 200 ⁇ l of PBST (0.1% Tween-20 in PBS). Subsequently, Flag-ubiquitin reaction solution was added to each well so that the final concentration was 62.5mM Tris pH 7.5, 6.25 mg MgCI 2 , 0.75 mM DTT, 1.0 ⁇ M ATP (low ATP), and lOOng Flag-ubiquitin. The final reaction solution volume was fixed to 80 ⁇ l with with Milipore- filtered water.
  • the folowing a ubiquitin agent inhibitor in 10 ⁇ l of DMSO, 10 ⁇ l of El and His-E2 UbchlO in 20mM Tris buffer, pH 7.5, and 5% glycerol so that there was 10 ng/well of El and 20 ng/well of His-E2 UbchlO. The reaction was then allowed to proceed at room temperature for 1 hour.
  • the table below illustrates the ATP competitive inhibition properties of the pharmaceutical compositions of the invention comprising the compounds listed in the table using the ATP competitive assay described above. Inhibition was measured using IC50 values.
  • Table 5 also shows ATP inhibition properties for additional compounds described herein. Inhibition was measured using IC50 values.
  • the compounds of the invention can be prepared using general synthetic procedures.
  • the starting components are readily prepared from benzene and phenols to which any kind of substitutions can be made according to procedures well known to those skilled in the art and commercially available. Many of the compounds are available commercially.
  • the compounds of the invention can be prepared according to Scheme 1.
  • the amine la is reacted with the acyl chloride 2a to produce the 2-substituted benzothiazole 3a.
  • the benzoyl chloride 2a can be replaced with any suitable acyl chloride.
  • N-(5-methoxvthiazolo[5,4-b]pyridin-2-yl)th ⁇ ophene-2-carboxamide [0093] A solution of 2-Amino-5-methoxythiazolo[5,4-b]pyridine (45 mg, 0.25 mmol) and 2- thiophenecarbonyl chloride (53 mL, 0.50 mmol) in pyridine was heated at 100 C overnight. The reaction mixture was cooled, diluted with ethyl acetate and rinsed with brine. The solution was dried over MgS0 4 , eluted through a small silica column (1:1 ethyl acetate:hexanes), and concentrated in vacuo.
  • a sample of A (100 mg, 0.235 mmol) was treated with a solution of trifluoroacetic acid (3 mL), CH 2 CI 2 (300 uL), and H 2 0 (100 uL) at room temperature for 5 hours.
  • the reaction mixture was concentrated in vacuo and used for the next step without purification.
  • the crude reaction mixture was dissolved in 1,4-dioxane (3 mL) and allowed to stir at 60 C for 4 days.

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Abstract

This invention describes compounds and pharmaceutical compositions useful as ubiquitin agent inhibitors. The compounds and pharmaceutical compositions of the invention are useful as inhibitors of the biochemical pathways of organisms in which ubiquitination is involved. The invention also comprises the use of the compounds and pharmaceutical compositions of the invention for the treatment of conditions that require inhibition of ubiquitination. Furthermore, the invention comprises methods of inhibiting ubiquitination in a cell comprising contacting a cell in which inhibition of ubiquitination is desired with a pharmaceutical composition according to the invention.

Description

BENZOTHIAZOLE AND THIAZOLE » 5 , 5-B ! PYRIDINE COMPOSITIONS AND THEIR USE AS UBIQUITIN LIGASE INHIBITORS
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority from U.S. Provisional Application Serial No. 60/512,034, filed October 17, 2003, and U.S. Provisional Application Serial No. 60/609,288, filed September 13, 2004, both of which are incorporated herein by reference in their entirety.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] This invention is in the field of ubiquitin ligation and inhibitors of the ubiquitination pathway. Additionally, this invention is in the field of treating diseases or conditions associated with ubiquitination.
Summary of the Related Art
[0003] Ubiquitin is a 76 amino acid protein present throughout the eukaryotic kingdom. It is a highly conserved protein and is essentially the identical protein in diverse organisms ranging from humans to yeasts to fruit flies. In eukaryotes, ubiquitin is the key component of the ATP-dependent pathway for protein degradation. Proteins slated for degradation are covalently linked to ubiquitin via an ATP-dependent process catalyzed by three separate enzymes. [0004] Ubiquitin has also been implicated as key components in other biochemical processes. Ubiquitination of the Gag structural protein of Rous Sarcoma virus has been linked to the targeting of Gag to the cell membrane of the host cell where it can assemble into spherical particles and bud from the cell surface. Production of HIV particles has also been associated with ubiquitination and may constitute an important cellular pathway for producing infectious particles. Thus, the ubiquitin pathway may be an important target for treatment of HIV positive patients. [0005] There is a need for inhibitors of ubiquitin ligation that can alter the ATP-dependent ubiquitination of proteins. Inhibition of ubiquitination can regulate the degradation of proteins in ways that assist in treating various disorders. Inhibitors of ubiquitin ligases may also help in treating infectious diseases such as bacterial and viral infections that depend on the cellular biochemical machinery.
[0006] The ubiquitination of these target proteins is known to be mediated by the enzymatic activity of three ubiquitin agents. Ubiquitin is first activated in an ATP-dependent manner by a ubiquitin activating agent, for example, an El. The C-terminus of a ubiquitin forms a high energy thiolester bond with the ubiquitin activating agent. The ubiquitin is then transferred to a ubiquitin conjugating agent, for example, an E2 (also called ubiquitin moiety carrier protein), also linked to this second ubiquitin agent via a thiolester bond. The ubiquitin is finally linked to its target protein (e.g. substrate) to form a terminal isopeptide bond under the guidance of a ubiquitin ligating agent, for example, an E3. In this process, monomers or oligomers of ubiquitin are attached to the target protein. On the target protein, each ubiquitin is covalently ligated to the next ubiquitin through the activity of a ubiquitin ligating agent to form polymers of ubiquitin. [0007] The enzymatic components of the ubiquitination pathway have received considerable attention (for a review, see Weissman, Nature Reviews 2:169-178 (2001)). The members of the El ubiquitin activating agents and E2 ubiquitin conjugating agents are structurally related and well characterized enzymes. There are numerous species of E2 ubiquitin conjugating agents, some of which act in preferred pairs with specific E3 ubiquitin ligating agents to confer specificity for different target proteins. While the nomenclature for the E2 ubiquitin conjugating agents is not standardized across species, investigators in the field have addressed this issue and the skilled artisan can readily identify various E2 ubiquitin conjugating agents, as well as species homologues (See Haas and Siepmann, FASEB J. 11:1257-1268 (1997)). [0008] Ubiquitin agents, such as the ubiquitin activating agents, ubiquitin conjugating agents, and ubiquitin ligating agents, are key determinants of the ubiquitin-mediated proteolytic pathway that results in the degradation of targeted proteins and regulation of cellular processes. Consequently, agents that modulate the activity of such ubiquitin agents may be used to upregulate or downregulate specific molecules involved in cellular signal transduction. Disease processes can be treated by such up- or down regulation of signal transducers to enhance or dampen specific cellular responses. This principle has been used in the design of a number of therapeutics, including phosphodiesterase inhibitors for airway disease and vascular insufficiency, kinase inhibitors for malignant transformation and Proteasome inhibitors for inflammatory conditions such as arthritis.
[0009] Due to the importance of ubiquitin-mediated proteolysis in cellular process, for example cell cycle regulation, there is a need for a fast and simple means for identifying the physiological role of ubiquitin agents that are catalytic components of this enzymatic pathway, and for identifying which ubiquitin agents are involved in various regulatory pathways. Thus, an object of the present invention is to provide compounds, compositions and methods of assaying for the physiological role of ubiquitin agents, and for providing methods for determining which ubiquitin agents are involved together in a variety of different physiological pathways. BRIEF SUMMARY OF THE INVENTION [0010] The invention comprises compounds and pharmaceutical compositions of the compounds for inhibiting ubiquitin agents. The pharmaceutical compositions can be used in treating various conditions where ubiquitination is involved. They can also be used as research tools to study the role of ubiquitin in various natural and pathological processes. [0011] In a first aspect, the invention comprises compounds that inhibit ubiquitination of target proteins.
[0012] In a second aspect, the invention comprises a pharmaceutical composition comprising an inhibitor of ubiquitination according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent.
[0013] In a third aspect, the invention comprises methods of inhibiting ubiquitination in a cell, comprising contacting a cell in which inhibition of ubiquitination is desired with a pharmaceutical composition comprising a ubiquitin agent inhibitor according to the invention. [0014] In a fourth aspect, the invention provides methods for treating cell proliferative diseases or conditions, comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a ubiquitin agent inhibitor according to the invention. The invention also provides for the use of a compound or composition of the invention for the manufacture of a medicament for use in treating cell proliferative diseases or conditions. [0015] In a fifth aspect, the invention provides methods for treating HIV infection and related conditions, comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a ubiquitin agent inhibitor according to the invention. The invention also provides for the use of a compound or composition of the invention for the manufacture of a medicament for use in treating HIV infection and related conditions. [0016] The foregoing only summarizes certain aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below. All patent applications and publications of any sort referred to in this specification are hereby incorporated by reference in their entirety. In the event of a discrepancy between the express disclosure of this specification and a patent application or publication incorporated by reference, the express disclosure of this specification shall control.
DETAILED DESCRIPTION OF THE INVENTION [0017] The invention relates to compounds of the formula:
Figure imgf000005_0001
and pharmaceutically acceptable salts thereof, wherein
A1, A2, A3, A4 are independently nitrogen or carbon;
L is a bond, -CrC6 alkylene-, -C2-C6 alkenylene-, -NH-, or -NH-C(=0)-;
Ri is Cι-C6 alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, -aryl-W-aryl, -aryl-W-heterocyclyl, or heterocyclyl-W-aryl, wherein W is a bond, -0-, -S02-, or -C(=0)-; R2 is H, Cι-C6 alkyl, or is linked to a carbon of R1 through a carbonyl group; R3 and R5 are independently H, halogen, or Cι-C6 alkyl;
R4 and R6 are independently H, halogen, C(0)R7, NR8Rg, nitro, Cι.5-alkyl, C^-alkoxy, 0CF3, CF3, aryl, -Cι-6-alkyl-aryl, heteroaryl, -Cι.5-alkyI-heteroaryl, C(0)NR8R9, C(0)C(0)NR8R9, Cι-C5 a!kyl-C(0)-NH-, NR8R9-S02- or Rιo-S02-; or R3 and R4 together with the carbon atoms to which they attached form a 5-6 membered aryl or heteroaryl group, wherein the group is optionally substituted with CrC6 alkyl; or R4 and R5 together with the carbon atoms to which they are attached form a 5-6 membered aryl or heteroaryl group, wherein the group is optionally substituted with CrC6 alkyl; provided that if A1 is nitrogen, R3 is absent, if A2 is nitrogen, R is absent, of A3 is nitrogen, R5 is absent, and if A4 is nitrogen, R6 is absent; R7 is hydrogen, Cι.6-alkyl, Ci.6-alkoxy, C(Z)-Rπ where Z is CH2 or 0, heteroaryl, aryl, or a group of the formula
Figure imgf000005_0002
wherein n is 1 to 5 and each R12 is th same or different and is C1-6-aIkyl, hydroxy, halogen, nitro, oxo, amino, halo-Cι-6-alkyl, Cι-6-alkoxy, halo-Cι.6-alkoxy, or cyano, NHC(O)- Cι.6-alkyl, NHC(0)-C2.6-alkylene, C(0)-0-Ci.6-alkyl, or C(0)-aryl;
R8 and R9 are independently hydrogen, or CrC6-alkyl;
R10 is Cι.6-alkyl, Cι-6-aIkyl-aryl, aryl, or heteroaryl;
Rn is Ci-e-alkyl, Cι.5-alkyl-aryl, aryl, or NR8R9; with the proviso that R4 and R5 are not simultaneously hydrogen; and wherein each one of the alkyl, aryl, heteroaryl, or heterocyclyl of R i to R12 is optionally substituted with one or more groups selected from C.-β-alkyl, C2-C6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-Cι.8-alkyl, C^-alkoxy, halo-Cι.8-alkoxy, cyano, NHC(0)-Ci.8-alkyl, NHC(0)-cycloalkyl, NHC(0)-C2.5-alkenyl, NHC(0)-aryl-C(0)-0-Ci.8-alkyl, C(0)-0-Rι3, -0-C(0)-Cι-C8 alkyl, or C(0)-aryl, wherein Rι3 is H or Cι-C8 alkyl, and two substituents on aryl, together with the atoms to which they are attached, optionally form a dioxane ring. ] Preferred compounds of the formula (I) include compounds of formula (II):
Figure imgf000006_0001
and pharmaceutically acceptable salts thereof, wherein L is a bond, -CrC6 alkylene-, -C2-C6 alkenylene-, -NH-, or -NH-C(=0)-; Ri is Cr-C6 alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, -aryl-W-aryl, -aryl-W-heterocyclyl, or heterocyclyl-W-aryl, wherein W is a bond, -0-, -S02-, or -C(=0)-; R2 is H, CrC6 alkyl, or is linked to a carbon of Ri through a carbonyl group; R4 and R6 are independently H, halogen, C(0)R7, NR8R9, nitro, C^-alkyl, Cι.5-alkoxy, 0CF3,
CF3, aryl, -Cι.6-alkyl-aryl, heteroaryl, -Cι.6-alkyl-heteroaryl, C(0)NR8R9, C(0)C(0)NR8R9,
Cι-C6 alkyl-C(0)-NH-, NR8R9-S02- or Rιo-S02-;
R7 is hydrogen, Cι.6-alkyl, Cι.6-alkoxy, C(Z)-Rπ where Z is CH2 or 0, heteroaryl, aryl, or a group of the formula
Figure imgf000006_0002
wherein n is 1 to 5 and each R12 is the same or different and is Ci-6-alkyl, hydroxy, halogen, nitro, oxo, amino, halo-C1-6-alkyIr Ci.6-alkoxy, halo- Ci-e-alkoxy, or cyano, NHC(0)-Ci.6-alkyl, NHC(0)-C2.6-alkylene, C(0)-0- Cι.5-alkyl, or C(0)-aryl;
R8 and R9 are independently hydrogen, or CrC5-alkyl;
Rio is Ci-e-alkyl, C1-6-aIkyl-aryl, aryl, or heteroaryl; Rn is Ci-e-alkyl, Cι.5-alkyl-aryl, aryl, or NR8R9; with the proviso that R4 and R6 are not simultaneously hydrogen; and wherein each one of the alkyl, aryl, heteroaryl, or heterocyclyl of the above groups is optionally substituted with one or more groups selected from Ci-a-alkyl, C2-C6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-Cι.8-alkyl, Ci-s-alkoxy, halo-Cι.8-alkoxy, cyano, NHC(0)-C^-alkyl, NHC(0)-cycloalkyl, NHC(O)- C2-S-alkenyl, NHC(0)-aryl-C(0)-0-C1.8-alkyl, C(0)-0-Rι3, -0-C(0)-CrC8 alkyl, or C(0)-aryl, wherein Rι3 is H or CrC8 alkyl, and two substituents on aryl, together with the atoms to which they are attached, optionally form a dioxane ring. [0019] Preferred compounds of formula (II) include compounds of formula (ll)-l (and their pharmaceutically acceptable salts), which are compounds of formula (II) in which L is a bond, -NH- , or -NH-C(=0)-, and Ri is aryl, optionally substituted with one or more groups selected from Ci-s-alkyl, C2-C6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo- Cι.8-alkyl, Cι.8-alkoxy, halo-Cι.8-alkoxy, cyano, NHC(0)-Ci.8-alkyl, NHC(0)-cycloalkyl, NHC(O)- C2.6-alkenyl, NHC(0)-aryl-C(0)-0-Ci.8-alkyl, C(0)-0-Rι3, -0-C(0)-CrC8 alkyl, or C(0)-aryl, wherein Ri3 is H or Ci-Cs alkyl, and two substituents on aryl, together with the atoms to which they are attached, optionally form a dioxane ring.
[0020] Preferred compounds of formula (ll)-l include those wherein Ri is phenyl or naphthyl, each of which is optionally substituted with one or two groups selected from Cι.8-alkyl, C -C6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-C1-8-aIkyl, Cι-8- alkoxy, halo-Cι_8-alkoxy, cyano, NHC(0)-Cι.8-alkyl, NHC(0)-cycloalkyl, NHC(0)-C2.5-alkenyl, NHC(O)- aryl-C(0)-0-Ci.8-alkyl, C(0)-0-Rι3, -0-C(0)-CrC8 alkyl, or C(0)-aryl, wherein Ri3 is H or CrC8 alkyl. [0021] Preferred compounds of formula (ll)-l also include those wherein Ri is phenyl, optionally substituted with one or two groups selected from Cι-8-alkyl, C2-C6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-Cι.8-alkyl, C^-alkoxy, halo- Cι.8-aIkoxy, cyano, NH^O-C^-alky!, NHC(0)-cycloalkyl, NHC(0)-C2.6-alkenyl, NHC(0)-aryl-C(0)-0- Cι.8-alkyl, C(0)-0-R13, -0-C(0)-CrC8 alkyl, or C(0)-aryl, wherein R13 is H or CrC8 alkyl. [0022] Preferred compounds of formula (II) further include compounds of formula (ll)-2 (and their pharmaceutically acceptable salts), which are compounds of formula (II) wherein L is a bond, -NH-, or -NH-C(=0)-, and Ri is heteroaryl, optionally substituted with one or more groups selected from Ci-s-alkyl, C -C6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-Cι-8-alkyl, C^-alkoxy, halo-Cι.8-alkoxy, cyano, NHC(0)-Ci.8-alkyl, NHC(0)-cycloalkyl, NHC(O)- C2.6-alkenyl, NHC(0)-aryl-C(0)-0-Ci.8-alkyl, C(0)-0-Rι3, -0-C(0)-CrC8 alkyl, or C(0)-aryl, wherein R13 is
H or Cι-C8 alkyl.
[0023] Preferred compounds of formula (II) further include compounds of formula (ll)-3 (and their pharmaceutically acceptable salts), which are compounds of formula (II) wherein L is a bond,
-NH-, or -NH-C(=0)-, and Ri is cycloalkyl, optionally substituted with one or more groups selected from Ci-s-alkyl, C2-C6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-Chalky!, Cι.8-alkoxy, halo-Cι.8-alkoxy, cyano, NHC(0)-Ci.8-alkyl, NHC(0)-cycloalkyl, NHC(O)-
C2-5-alkenyl, NHC(0)-aryl-C(0)-0-Ci.8-alkyl, C(0)-0-R13, -0-C(0)-CrC8 alkyl, or C(0)-aryl, wherein R13 is
H or Cι-C8 alkyl.
[0024] Preferred compounds of formula (II) further include compounds of formula (11)4 (and their pharmaceutically acceptable salts), which are compounds of formula (II) wherein L is a bond,
-NH-, or -NH-C(=0)-, and Ri is heterocyclyl, optionally substituted with one or more groups selected from Cι.8-alkyl, C2-C6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-Cι.8-alkyl, Cι-8-alkoxy, halo-Ci-s-alkoxy, cyano, NHC(0)-Ci.8-alkyl, NHC(O)- cycloalkyl, NHC(0)-C2.6-alkenyl, NHC(0)-aryl-C(0)-0-Ci.8-alkyl, C(0)-0-Rι3, -0-C(0)-CrC8 alkyl, or C(0)- aryl, wherein Rι3 is H or Cι-C8 alkyl.
[0025] Preferred heteroaryl, cycloakyl, and heterocyclyl groups in compounds of formulae
(ID-2, (ID-3, and (111)4 include: pyyrolidinyl, indolinyl, indolyl, adamantyl, piperidinyl, cyclohexyl, cyclobutenyl, thiophene, pyridinyl, furanyl, pyrrolyl, thiadiazolyl, benzothiophene, 1,3- dioxoisoindolinyl, pyrazolyl, dihydroquinolinyl, cyclopentyl, and azetidinyl.
[0026] Preferred compounds of formulae (II), (ll)-l, (ll)-2, (ID-3, and (11)4 include compounds of formula (10-5 (and their pharmaceutically acceptable salts), which are compounds of formulae (II),
(ll)-l, (ID-2, (ID-3, or (11)4 wherein R6 is hydrogen, and R4 is Cι.6-alkoxy.
[0027] Preferred compounds of formula (ID-5 include those wherein R6 is hydrogen and R4 is ethoxy or methoxy.
[0028] Preferably excluded from the invention is the compound of formula (II) wherein R4 is methoxy, Rs is hydrogen, R2 is hydrogen, L is a bond, and Ri is benzimidazolyl attached to the main compound at the 2-position of the benzimidazolyl group.
[0029] Preferred compounds of the formula (I) include compounds of formula (III):
Figure imgf000009_0001
and pharmaceutically acceptable salts thereof, wherein Ri is Cι-C5 alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, -aryl-W-aryl, -aryl-W-heterocyclyl, or heterocyclyl-W-aryl, wherein W is a bond, -0-, -S02-, or -C(=0)-; R2 is H, Cι-C6 alkyl, or is linked to a carbon of Ri through a carbonyl group; R4 and R6 are independently H, halogen, C(0)R7, NR8Rg, nitro, Cι-6-alkyl, Cι.6-alkoxy, OCF3, CF3, aryl, -Cι.5-alkyl-aryl, heteroaryl, -C1-6-alkyI-heteroaryl, C(0)NR8R9, C(0)C(O)NR8R9, Ci-Ce alkyl-C(0)-NH-, NR8R9-S02- or Rι0-S02-;
R7 is hydrogen, Ci.s-alkyl, Ci-e-alkoxy, C(Z)-Ru where Z is CH2 or 0, heteroaryl, aryl, or a group of the formula
Figure imgf000009_0002
wherein n is 1 to 5 and each Ri2 is the same or different and is Cι-6-alkyl, hydroxy, halogen, nitro, oxo, amino, halo-Cι.6-alkyl, Cι-6-alkoxy, halo- Ci-e-alkoxy, or cyano, NHC(0)-Ci.5-alkyl, NHC(0)-C2.6-alkylene, C(0)-0- Ci-e-alkyl, or C(0)-aryl; R8 and R9 are independently hydrogen, or Cι-C6-alkyl; Rio is Cι.6-alkyl, Cι.6-alkyl-aryl, aryl, or heteroaryl; Rn is Ci-e-alkyl, Cι.6-alkyl-aryl, aryl, or NR8R9; with the proviso that R and R6 are not simultaneously hydrogen; and wherein each one of the alkyl, aryl, heteroaryl, or heterocyclyl of the above groups is optionally substituted with one or more groups selected from Cι.8-alkyl, C2-C6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-Cι.8-alkyl, Cι.8-alkoxy, halo-Cι.8-alkoxy, cyano, NHC(0)-Ci.8-alkyl, NHC(0)-cycloalkyl, NHC(O)- C2.6-alkenyl, NHC(O)-aryl-C(O)-O-C1-8-alkyi, C(0)-0-Rι3, -0-C(0)-CrC8 alkyl, or C(0)-aryl, wherein Ri3 is H or Cι-C8 alkyl, and two substituents on aryl, together with the atoms to which they are attached, optionally form a dioxane ring. [0030] Preferred compounds of formula (III) include compounds of formula (IID-l (and their pharmaceutically acceptable salts), which are compounds of formula III wherein Ri is aryl, optionally substituted with one or more groups selected from Cι.8-alkyl, C2-C5 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-Cι.8-alkyl, Ci-s-alkoxy, halo- Cι.8-alkoxy, cyano, NHC(0)-Cι.8-alkyl, NHC(0)-cycloalkyl, NHC(0)-C2-e-alkenyl, NHC(0)-aryl-C(0)-0- Cι.8-alkyl, C(0)-0-Rι3, -0-C(0)-CrC8 alkyl, or C(0)-aryl, wherein Ri3 is H or CrC8 alkyl, and two substituents on aryl, together with the atoms to which they are attached, optionally form a dioxane ring.
[0031] Preferred compounds of formula (lll)-l include compounds wherein Ri is phenyl, optionally substituted with 1, 2, or 3 groups independently selected from halogen, halo-Cι-C6 alkyl, cyano, -N-C(0)-CrC6 alkyl, nitro, CrC6 alkoxy, and CrC6 alkyl. [0032] Preferred compounds of formula (III) include compounds of formula (lll)-2 (and their pharmaceutically acceptable salts), which are compounds of formula (III) wherein Ri is heteroaryl, optionally substituted with one or more groups selected from Cι.8-alkyl, C2-C6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-Cι.8-alkyl, Cι.8-alkoxy, halo- Cι.8-alkoxy, cyano, NHC(O)-C1-8-alkyl, NHC(0)-cycloalkyl, NHC(0)-C2.6-alkenyl, NHC(0)-aryl-C(0)-0- Ci-s-alkyl, C(0)-0-Rι3, -0-C(0)-CrC8 alkyl, or C(0)-aryl, wherein Ri3 is H or CrC8 alkyl. [0033] Preferred compounds of formula (IID-2 include compounds wherein Ri is thienyl, benzothienyl, furanyl, benzofuranyl, dibenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, or isoxazolyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, halo-Cι-C6 alkyl, cyano, -N-C(0)-CrC5 alkyl, nitro, CrC6 alkoxy, and CrC6 alkyl. [0034] Preferred compounds of formula (IID-2 include compounds wherein Ri is furanyl or thiophene, which are optionally substituted with 1, 2, or 3 groups independently selected from halogen, halo-Cι-C6 alkyl, cyano, -N-C(0)-CrC5 alkyl, nitro, CrC6 alkoxy, and CrC6 alkyl. [0035] Preferred compounds of formulae (III), (IID-l, and (IID-2 include compounds of formula (IID-3 (and their pharmaceutically acceptable salts), which are compounds of formulae (III), (IID-l, or (IID-2 wherein R6 is hydrogen, and R4 is Cι.6-alkoxy.
[0036] Preferred compounds of formula (IID-3 include those wherein R6 is hydrogen and R4 is ethoxy or methoxy. [0037] Preferred compounds of the formula (I) also include compounds of formula (IV):
Figure imgf000011_0001
and pharmaceutically acceptable salts thereof, wherein R4 is Ci-e-alkoxy; and
Rι4 and Rι5 are independently H, halogen, amino, nitro, cyano, Cι-C6 alkyl, CrC6 alkoxy, - C(O)- CrC6 alkyl, -O-C(O)- CrC6 alkyl, -NH-C(O)- CrC6 alkyl, -NH-C(0)-C3-C7 cycloalkyl, - NH-C(0)-C2-C5 alkenyl, -S02-NRι6Ri7, or Ri4 and Ri5 together with the atoms to which they are attached form a six membered ring containing one or two heteroaroms atoms selected from -NH- and -0-; Ri6 and Rι7 are independently H, or CrC6 alkyl, or Ri6 and RJ7 together with the nitrogen to which they are attached form a 4-8 membered heterocyclic ring, which is optionally substituted. [0038] Preferred compounds of the formula (I) also include compounds of formula (V):
Figure imgf000011_0002
and pharmaceutically acceptable salts thereof, wherein R is Cι-6-alkoxy; and
Rι and R15 are independently H, halogen, amino, nitro, cyano, d-Cε alkyl, Ci-Cβ alkoxy, -C(0)- CrC6 alkyl, -0-C(0)- d-C6 alkyl, -NH-C(O)- d-C6 alkyl, -NH-C(0)-C3- C7 cycloalkyl, -NH-C(0)-C2-C6 alkenyl, -S02-NRι6Rι7; Ri6 and R17 are independently H, or Cι-C6 alkyl, or Ri6 and R17 together with the nitrogen to which they are attached form a 4- 8 membered heterocyclic ring, which is optionally substituted. [0039] Among preferred compounds of formula (I) are those wherein R12 is Ci-e-alkyl, Ci-e-alkoxy, halogen, nitro, NHC(0)-d.6-alkyl, NHC(0)-C2.6-alkylene, C(O)-O-Cι.6-alkyl, or C(0)-aryl, Ri is hydrogen or Cι-6-alkyϊ. and R3, R4, R5 and R6 are hydrogen, halogen, Ci-e-alkoxy, de-alkyl, or nitro. [0040] Other preferred compounds of formula (I) are those wherein R12 is Ci-e-alkyl, NHC(O)- Ci-e-alkyl, or NHC(0)-C2.5-alkylene, R4 is Cι.5-aIkoxy and Ri, R3, R5 and R6 are hydrogen. [0041] Still other preferred compounds of formula (I) are those wherein Rι2 is methyl, NHC(0)-CH3, or NHC(0)-(C=CH2)-CH3, R is methoxy, and Ri, R3, R5, and R6 are hydrogen. [0042] We have found that the foregoing compounds are useful inhibitors of ubiquitinization, as described more fully below.
[0043] Some useful compounds according to one aspect of the invention are given in the following Tables 1 and 2. Compounds in Table 1 are known in the art and commercially available. Compounds in Table 2 can be readily prepared by a person of ordinary skill in the art using the procedures described herein, or by synthetic procedures generally known in the art. Indeed, there is more than one process to prepare the compounds of the invention. [0044] Compounds of the invention include those of formula (I), (II), (ID-1, (ID-2, (ll)-3, (11)4, (ll)-5, (III), (lll)-l, (IID-2, (IID-3, (IV), and (V), provided that they are not one of the compounds in Table 1. Table 1.
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
005/037845
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Table 2
Figure imgf000033_0002
Figure imgf000034_0001
Figure imgf000035_0001
Cmpd Structure Name
H4-cyanophenyl)-3-(6-
137 methoxybenzo[d]thiazol-2-yl)urea
N-(5-methoxythiazolo[5,4-
138 b]pyridin-2-yl)thiophene-2- carboxamide
2,4-dichloro-N-(5-
140 methoxythiazolo[5,4-b]pyridin-2- yDbenzamide
3-fluoro-N-(5-
141 methoxythiazolo[5,4-b]pyridin-2- yDbenzamide
3-chloro-N-(5-
142 methoxythiazolo[5,4-b]pyridin-2- yObenzamide
N-(5-methoxythiazolo[5,4-
143 b]pyridin-2-yl)-3-methylthiophene-
2-carboxamide
Figure imgf000036_0001
Cmpd Structure Name
3-chloro-N-(5-
144 methoxythiazolo[5,4-b]pyridin-2- yl)thiophene-2-carboxamide
2,6-difluoro-N-(5-
145 methoxythiazolo[5,4-b]pyridin-2- yDbenzamide
3,4-difluoro-N-(5-
146 methoxythiazolo[5,4-b]pyridin-2- yDbenzamide
N-(5-methoxythiazolo[5,4-
147 b]pyridin-2-yl)4-
(trifluoromethyl)benzamide
4 4--ccyyaannoo--NN--((55--
148 methoxythiazolo[5,4-b]pyridin-2- yDbenzamide
4-acetamido-N-(5-
149 methoxythiazolo[5,4-b]pyridin-2- yDbenzamide
150 N-(5-methoxythiazolo[5,4- b]pyridin-2-yD4-nitrobenzamide
Figure imgf000037_0001
Figure imgf000038_0001
[0045] The compounds in the tables above can be prepared using art recognized methods. All of the compounds in this application were named using Chemdraw Ultra version 6.0.2, which is available through Cambridgesoft.co, 100 Cambridge Park Drive, Cambridge, MA 02140, Namepro version 5.09, which is available from ACD labs, 90 Adelaide Street West, Toronto, Ontario, M5H, 3V9, Canada, or were derived therefrom.
[0046] In a second aspect the invention comprises pharmaceutical compositions comprising a compound of formula (I), (ID, (ll)-l, (ID-2, (ID-3, (11)4, (ll)-5, (III), (lll)-l, (IID-2, (IID-3, (IV), or (V) together with a pharmaceutically acceptable carrier, excipient, or diluent. [0047] The compounds and pharmaceutical compositions of the invention are useful for inhibiting ubiquitination in a cell. Specifically, the pharmaceutical compositions target the El activating agent of the ubiquitination process thereby preventing transfer of ATP-activated ubiquitin to the E2 conjugating agent. The inhibition of the El activating agent prevents ubiquitination of proteins since it also interrupts the downstream function of the E2 conjugating agent and the E3 ligating agent in the ubiquitination pathway. Thus, the pharmaceutical compositions of the invention indirectly inhibit both the E2 conjugating agent and the E3 ligating agent. [0048] Accordingly, the invention also comprises methods of inhibiting ubiquitination in a cell comprising contacting a cell in which inhibition of ubiquitination is desired with a compound or pharmaceutical composition according to the invention. The invention also comprises methods for treating cell proliferative diseases and other conditions in a patient in which ubiquitination is an important component. For example, diseases and conditions that can be treated are cancers and conditions related to cancers. However, any disease and condition in which ubiquitination is a component can be treated with the compounds and pharmaceutical compositions of the invention.
[0049] The compounds and compositions of the invention are also useful for preventing and/or treating malaria. Accordingly, the invention further comprises methods of treating and of preventing malaria by administering to a subject (preferably human) an amount of a compound or composition of the invention effective to prevent and/or treat malaria. The invention also provides for the use of a compound or composition of the invention for the manufacture of a medicament for use in treating and/or preventing malaria.
[0050] For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an "alkyl" moiety generally refers to a monovalent radical (e.g. CH3-CH2-), in certain circumstances a bivalent linking moiety can be "alkyl," in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term "alkylene." (Similarly, in circumstances in which a divalent moiety is required and is stated as being "aryl," those skilled in the art will understand that the term "aryl" refers to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for 0, and 2, 4, or 6 for S, depending on the oxidation state of the S). On occasion a moiety may be defined, for example, as (A)a-B-, wherein a is 0 or 1. In such instances, when a is 0 the moiety is B- and when a is 1 the moiety is A-B-. Also, a number of moieties disclosed herein exist in multiple tautomeric forms, all of which are intended to be encompassed by any given tautomeric structure. Other stereochemical forms of the compounds of the invention are also encompassed including but not limited to enantiomers, diastereomers, and other isomers such as rotamers. [0051] For simplicity, when a substituent can be of a particular chemical class differing by the number of atoms or groups of the same kind in the moiety (e.g., alky, which can be C C2, C3, etc.), the number of repeated atoms or groups is represented by a range (e.g., CrC6-alkyl). In such instances each and every number in that range and all sub-ranges are specifically contemplated. Thus, CrC3-alkyl means Cr, C2-, C3-, Cι-2, C1.3-, and C2-3-alkyl.
[0052] In addition to individual preferred embodiments of each substituent defined herein, the invention also comprises all combinations of preferred substituents.
[0053] The term "alkyl" as employed herein refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, which is optionally substituted with one, two or three substituents. Unless otherwise specified, the alkyl group may be saturated, unsaturated, or partially unsaturated. As used herein, therefore, the term "alkyl" is specifically intended to include alkenyl and alkynyl groups, as well as saturated alkyl groups, unless expressly stated otherwise. Preferred alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, vinyl, allyl, isobutenyl, ethynyl, and propynyl.
[0054] As employed herein, a "substituted" alkyl, cycloalkyl, aryl, or heterocyclic group is one having between one and about four, preferably between one and about three, more preferably one or two, non-hydrogen substituents. Suitable substituents include, without limitation, halo, hydroxy, nitro, haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, alkoxycarbonyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.
[0055] The term "cycloalkyl" as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12, preferably 3 to 8 carbons, wherein the cycloalkyl group additionally is optionally substituted. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, and adamantyl.
[0056] The term "hydrocarbyl" as employed herein includes all alkyl moieties and all cycloalkyl moieties (both as defined above), each alone or in combination. Thus, for example, hydrocarbyl includes methyl, ethyl, propyl, n-butyl, i-butyl, cyclopropyl, cyclohexyl, cyclopropyl-CH2-, cyclohexyl-(CH2)3-, etc.
[0057] An "aryl" group is a C6-Cι4 aromatic moiety comprising one to three aromatic rings, which is optionally substituted. Preferably, the aryl group is a C6-C10 aryl group. Preferred aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl. An "aralkyl" or
"arylalkyl" group comprises an aryl group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted. Preferably, the aralkyl group is CrC6-alkyl-(C6-Cιo)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl. An "alkaryl" or "alkylaryl" group is an aryl group having one or more alkyl substituents. Examples of alkaryl groups include, without limitation, tolyl, xylyl, mesityl, ethylphenyl, tert-butylphenyl, and methylnaphthyl.
[0058] A "heterocyclic" group (or "heterocyclyl") is a non-aromatic mono-, bi-, or tricyclic structure having from about 3 to about 14 atoms, wherein one or more atoms are selected from the group consisting of N, 0, and S. One ring of a bicyclic heterocycle or two rings of a tricyclic heterocycle may be aromatic, as in indan and 9,10-dihydro-anthracene. The heterocyclic group is optionally substituted on carbon with oxo or with one of the substituents listed above. The heterocyclic group may also independently be substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or on sulfur with oxo or lower alkyl. Preferred heterocyclic groups include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino.
[0059] In certain preferred embodiments, the heterocyclic group is a heteroaryl group. As used herein, the term "heteroaryl" refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, between one and about three heteroatoms selected from the group consisting of N, 0, and S. Preferred heteroaryl groups include, without limitation, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, and isoxazolyl. [0060] For simplicity, reference to a "C„-Cm" heterocyclyl or "Cn-Cm" heteroaryl means a heterocyclyl or heteroaryl having from "n" to "m" annular atoms, where "n" and "m" are integers. Thus, for example, a C5-C6-heterocyclyl is a 5- or 6- membered ring having at least one heteroatom, and includes pyrrolidinyl (C5) and piperidinyl (C6); C6-hetoaryl includes, for example, pyridyl and pyrimidyl.
[0061] In certain other preferred embodiments, the heterocyclic group is fused to an aryl or heteroaryl group. Examples of such fused heterocycles include, without limitation, tetrahydroquinolinyl and dihydrobenzofuranyl.
[0062] Additional preferred heterocyclyls and heteroaryls include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isothiazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, quinazolinyl, 4H-quinolizinyl, quinuclidinyl, tetrahydroisoquinolinyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl, cyclobutenyl and 1,3- dioxoisoindolyl.
[0063] A moiety that is substituted is one in which one or more hydrogens have been independently replaced with another chemical substituent. As a non-limiting example, substituted phenyls include 2-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluor-3-propylphenyl. As another non-limiting example, substituted n-octyls include 2,4 dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. Included within this definition are methylenes (-CH2-) substituted with oxygen to form carbonyl -CO-).
[0064] Unless otherwise stated, as employed herein, when a moiety (e.g., cycloalkyl, hydrocarbyl, aryl, heteroaryl, heterocyclic, urea, etc.) is described as "optionally substituted" it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents. Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular -CH- substituted with oxo is -C(0)-) nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, , alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups. Preferred substituents, which are themselves not further substituted (unless expressly stated otherwise) are:
(a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino,
(b) CrC5 alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, Cι-C8 alkyl, CrC8 alkenyl, CrC8 alkoxy, Cι-C8 alkoxycarbonyl, aryloxycarbonyl, C2-C8 acyl, C2-C8 acylamino, Cι-C8 alkylthio, arylalkylthio, arylthio, CrC8 alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, CrC8 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, C0-C6 /V-alkyl carbamoyl, C2-Cι5 /V, -dialkylcarbamoyl , C3-C7 cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C3-C heterocycle, C5-C15 heteroaryl, or any of these rings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above; and (c) -(CH2)s-NR30R31, wherein s is from 0 (in which case the nitrogen is directly bonded to the moiety that is substituted) to 6, and R30 and R31 are each independently hydrogen, cyano, oxo, carboxamido, amidino, CrC8 hydroxyalkyl, CrC3 alkylaryl, aryl-CrC3 alkyl, Cι-C8 alkyl, CrC8 alkenyl, CrC8 alkoxy, CrC8 alkoxycarbonyl, aryloxycarbonyl, aryl-CrC3 alkoxycarbonyl, C2-C8 acyl, CrC8 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, aroyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above; or
R30 and R31 taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents from (a), above. [0065] The term "halogen" or "halo" as employed herein refers to chlorine, bromine, fluorine, or iodine.
[0066] As herein employed, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent.
[0067] The term "acylamino" refers to an amide group attached at the nitrogen atom. The term "carbamoyl" refers to an amide group attached at the carbonyl carbon atom. The nitrogen atom of an acylamino or carbamoyl substituent may be additionally substituted. The term "sulfonamido" refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom. The term "amino" is meant to include NH2, alkylamino, arylamino, and cyclic amino groups.
Pharmaceutical compositions [0068] In a second aspect, the invention provides pharmaceutical compositions comprising an inhibitor of ubiquitination according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain preferred embodiments, compounds of the invention are administered intravenously in a hospital setting. In certain other preferred embodiments, administration may preferably be by the oral route.
[0069] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, pharmaceutical compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, flavors, dyes and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in many well known references to one skilled in the art, for example, Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA, 1990. [0070] As used herein, the term pharmaceutically acceptable salts refers to salts and complexes that retain the desired biological activity of the compounds of the invention and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR + Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -0-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate). Moreover, the compounds of the invention can also be administered as prodrugs which can be converted to the active form in vivo. [0071] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. A preferred dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 500 mg/kg, preferably 0.1 to 100 mgAg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
Inhibition of Ubiquitination [0072] In a third aspect, the invention provides a method of inhibiting ubiquitination in a cell, comprising contacting a cell in which inhibition of ubiquitination is desired with an inhibitor of ubiquitination of the invention.
[0073] Measurement of the ubiquitination can be achieved using known methodologies. (See, for example, WO 01/75145, US-2002-0042083-A1 and WO 03/076608, each of which is incorporated by reference in its entirety.)
[0074] Preferably, the method according to the third aspect of the invention causes an inhibition of cell proliferation of contacted cells. The phrase "inhibiting cell proliferation" is used to denote an ability of an inhibitor of ubiquitination to retard the growth of cells contacted with the inhibitor as compared to cells not contacted. An assessment of cell proliferation can be made by counting contacted and non-contacted cells using a Coulter Cell Counter (Coulter, Miami, FL), photographic analysis with Array Scan II (Cellomics) or a hemacytometer. Where the cells are in a solid growth (e.g., a solid tumor or organ), such an assessment of cell proliferation can be made by measuring the growth with calipers and comparing the size of the growth of contacted cells with non-contacted cells.
[0075] Preferably, growth of cells contacted with the inhibitor is retarded by at least 50% as compared to growth of non-contacted cells. More preferably, cell proliferation is inhibited by 100% ( e., the contacted cells do not increase in number). Most preferably, the phrase "inhibiting cell proliferation" includes a reduction in the number or size of contacted cells, as compared to non-contacted cells. Thus, an inhibitor of ubiquitination according to the invention that inhibits cell proliferation in a contacted cell may induce the contacted cell to undergo growth retardation, to undergo growth arrest, to undergo programmed cell death (i.e., to apoptose), or to undergo necrotic cell death.
[0076] In some preferred embodiments, the contacted cell is a neoplastic cell. The term "neoplastic cell" is used to denote a cell that shows aberrant cell growth. Preferably, the aberrant cell growth of a neoplastic cell is increased cell growth. A neoplastic cell may be a hyperplastic cell, a cell that shows a lack of contact inhibition of growth in vitro, a benign tumor cell that is incapable of metastasis in vivo, or a cancer cell that is capable of metastasis in vivo and that may recur after attempted removal. The term "tumorigenesis" is used to denote the induction of cell proliferation that leads to the development of a neoplastic growth. In some embodiments, the ubiquitination inhibitor induces cell differentiation in the contacted cell. Thus, a neoplastic cell, when contacted with an inhibitor of ubiquitination may be induced to differentiate, resulting in the production of a non-neoplastic daughter cell that is phylogenetically more advanced than the contacted cell.
Treatment for Cell Proliferative Diseases or Conditions [0077] In some preferred embodiments, the contacted cell is in an animal. Thus, in a fourth aspect the invention provides a method for treating a cell proliferative disease or condition in an animal, comprising administering to an animal in need thereof an effective amount of an inhibitor of ubiquitination of the invention. Preferably, the animal is a mammal, more preferably a domesticated mammal. Most preferably, the animal is a human.
[0078] The term "cell proliferative disease or condition" is meant to refer to any condition characterized by aberrant cell growth, preferably abnormally increased cellular proliferation. Examples of such cell proliferative diseases or conditions include, but are not limited to, cancer, restenosis, and psoriasis. In particularly preferred embodiments, the invention provides a method for inhibiting neoplastic cell proliferation in an animal comprising administering to an animal having at least one neoplastic cell present in its body a therapeutically effective amount of a ubiquitination inhibitor of the invention. Most preferrably, the invention provides a method for treating cancer comprising administering to a patient in need thereof an effective amount of an inhibitor of ubiquitination of the invention.
[0079] The term "therapeutically effective amount" is meant to denote a dosage sufficient to cause inhibition of ubiquitination in the cells of the subject, or a dosage sufficient to inhibit cell proliferation or to induce cell differentiation in the subject. Administration may be by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain particularly preferred embodiments, compounds of the invention are administered intravenously in a hospital setting. In certain other preferred embodiments, administration may preferably be by the oral route.
[0080] When administered systemically, the ubiquitination inhibitor is preferably administered at a sufficient dosage to attain a blood level of the inhibitor from about 0.01 μM to about 100 μM, more preferably from about 0.05 μM to about 50 μM, still more preferably from about 0.1 μM to about 25 μM, and still yet more preferably from about 0.5 μM to about 20 μM. For localized administration, much lower concentrations than this may be effective, and much higher concentrations may be tolerated. One of skill in the art will appreciate that the dosage of ubiquitination inhibitor necessary to produce a therapeutic effect may vary considerably depending on the tissue, organ, or the particular animal or patient to be treated.
Treatment of HIV and Related Conditions [0081] In some preferred embodiments, the contacted cell is a cell infected with HIV in a patient. Thus, in a fifth aspect, the invention provides a method for treating HIV infection as well as conditions related to HIV in a patient, comprising administering to a patient in need thereof an effective amount of an inhibitor of ubiquitination of the invention. The preparation, dosage and administration of the inhibitors of ubiquitination of the invention for the treatment of HIV and related conditions can be carried out as described above.
[0082] The inhibitors of ubiquitination of the invention are useful for the treatment of HIV infection and related conditions because they can inhibit the replication and spread of HIV. The replication and spread of HIV is decreased by the enzyme AP0BEC3G, which acts by causing extensive mutations in the cDNA reverse transcribed from the HIV genomic RNA. This has the effect of terminating the life cycle of HIV. To counteract this effect of AP0BEC3G, HIV encodes the protein Vif that functions by decreasing the translation of APOBEC3G and increasing the post- translational degradation of AP0BEC3G. The post-translational degradation of AP0BEC3G is catalyzed by the 26S proteasome and depends on the polyubiquitination of AP0BEC3G. Polyubiquitination serves as a signal for the 26S proteasome to degrade AP0BEC3G. Thus, inhibitors of ubiquination of the invention can inhibit the function of the 26S proteasome by prevent the targeting of AP0BEC3G to the 26S proteasome so that the intracellular concentration of AP0BEC3G is increased. This increased concentration of AP0BEC3G in turn inhibits the replication and spread of HIV by diminishing the effect of Vif. The role of AP0BEC3G in decreasing HIV replication and spread as well as methods for measuring the activity of the 26S proteasome, AP0BEC3G and Vif are described in Stopak et al., "HIV-1 Vif Blocks the Antiviral Activity of AP0BEC3G by Impairing Both Its Translation and Intracellular Stability," Mol. Cell (2003), 12:pp 591-601, which is incorporated by reference in its entirety. [0083] The following examples are intended to further illustrate certain preferred embodiments of the invention, and are not intended to limit the scope of the invention. Biological Activity [0084] Biological assays for determining the transfer of ubiquitin from the El activating agent to the E2 conjugating agent are described in United States Patent Application No.'s 09/542,497 and 09/826,312 as well as in the PCT Application WO 01/75145, all of which are incorporated by reference in their entirety. The following assay example illustrates one way by which the ubiquitin ligase inhibitory activity of the compounds of the invention can be assayed. This assay example is not meant to limit in any way the use of the compounds of the invention as ubiquitin ligase inhibitors.
Assay Example 1 El to E2 Transfer Assay [0085] The attachment of a ubiquitin moiety to the E2 conjugating agent was assayed using Flag-ubiquitin that was purified from E. coli, E2 UbchlO that was purified as a His-UbchlO from E. coli, and El that was purified from Sf9 insect cells (Affiniti Research Products, Exeter, U.K.). The wells of a Nickel-substrate 96-well plate (Pierce Chemical) were blocked with 100 μl of 1% casein/phosphate buffered saline (PBS) for 1 hour at room temperature. The blocked Nickel- substrate plate was then washed three times with 200 μl of PBST (0.1% Tween-20 in PBS). Subsequently, Flag-ubiquitin reaction solution was added to each well so that the final concentration was 62.5mM Tris pH 7.5, 6.25 mg MgCI2, 0.75 mM DTT, 1.0 μM ATP (low ATP), and lOOng Flag-ubiquitin. The final reaction solution volume was fixed to 80 μl with with Milipore- filtered water. To this was added the folowing: a ubiquitin agent inhibitor in 10 μl of DMSO, 10 μl of El and His-E2 UbchlO in 20mM Tris buffer, pH 7.5, and 5% glycerol so that there was 10 ng/well of El and 20 ng/well of His-E2 UbchlO. The reaction was then allowed to proceed at room temperature for 1 hour.
[0086] After 1 hour, the wells were washed three times with 200 μl of PBST and the amount of E2-ubiquitin complex was measured. For measuring the amount of the E2-ubiquitin complex, 100 μl of Mouse anti-flag diluted 1:10, 000 (Sigma Aldrich Fluka Chemicals, St. Louis, MO) and anti-mouse HRP diluted 1:15,000 (Jackson Immunoresearch labs, West Grove, PA) in PBST were added to each well and allowed to incubate at room temperature for another hour. The wells were then washed three times with 200 μl of PBST and 100 μl of luminol substrate (1/5 dilution) was added. The luminescence of each well was then measured using a fluorimeter to calculate the amount of E2-ubiquitin complex. This procedure was repeated using His-E2 UbchδC instead of His-E2 UbchlO. [0087] The table below illustrates the inhibitory properties of the pharmaceutical compositions of the invention comprising the compounds listed in the table using the assays described above. Inhibition was measured using IC50 values.
Table 3
Figure imgf000049_0001
Assay Example 2 ATP Competitive Assay [0088] The procedure for carrying out the ATP competitive binding assay was essentially the same as that for the plate binding assay described above with the exceptaion that the concentration of ATP was 200 μM ATP (high ATP).
[0089] The table below illustrates the ATP competitive inhibition properties of the pharmaceutical compositions of the invention comprising the compounds listed in the table using the ATP competitive assay described above. Inhibition was measured using IC50 values.
Table 4
Figure imgf000049_0002
++ indicates high inhibition; -+ indicates marginal inhibition
[0090] Table 5 also shows ATP inhibition properties for additional compounds described herein. Inhibition was measured using IC50 values.
Table 5
Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000050_0003
Figure imgf000051_0004
Figure imgf000051_0002
Figure imgf000051_0003
++ indicates inhibition at 50 μM or or less ; - - indicates marginal or no inhibition detected with this assay
General Synthetic Procedure [0091] The compounds of the invention can be prepared using general synthetic procedures. The starting components are readily prepared from benzene and phenols to which any kind of substitutions can be made according to procedures well known to those skilled in the art and commercially available. Many of the compounds are available commercially. [0092] The compounds of the invention can be prepared according to Scheme 1. The amine la is reacted with the acyl chloride 2a to produce the 2-substituted benzothiazole 3a. One skilled in the art would recognize that to obtain compounds with a variety of groups attached at the 2-position of the benzothiazole, the benzoyl chloride 2a can be replaced with any suitable acyl chloride. Similarly, replacing the amine la with any suitable amine, for example, 2-amino-indole or 2- aminobenzoimidazole, the corresponding 2-substituted indole or 2-substituted benzoimidazole can be obtained. Scheme 1 is only one way to prepare the compounds of the invention and is not meant to be limiting in any way.
Scheme 1
Figure imgf000051_0001
Chemistry Examples
N-(5-methoxvthiazolo[5,4-b]pyridin-2-yl)thϊophene-2-carboxamide [0093] A solution of 2-Amino-5-methoxythiazolo[5,4-b]pyridine (45 mg, 0.25 mmol) and 2- thiophenecarbonyl chloride (53 mL, 0.50 mmol) in pyridine was heated at 100 C overnight. The reaction mixture was cooled, diluted with ethyl acetate and rinsed with brine. The solution was dried over MgS04, eluted through a small silica column (1:1 ethyl acetate:hexanes), and concentrated in vacuo. The residue was purified by preparative HPLC. l NMR (DMSO-d6, 300 MHz) δ 8.27 (br d, J = 3.3 Hz, IH), 8.04 (d, J = 8.7 Hz, IH), 7.99 (dd, J = 1.2, 12.3 Hz, IH), 7.26 (dd, J = 3.6, 4.8 Hz, IH), 6.92 (d, J = 8.7 Hz, IH), 3.91 (s, 3H). LCMS purity 100%. MS Found 292 (MH+).
2,4-dichloro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide [0094] *H NMR (DMSO-d6, 300 MHz) δ 8.07 (d, J = 8.7 Hz, IH), 7.79 (m, IH), 7.72 (d, J = 8.4 Hz, IH), 7.57 (dd, J = 2.1, 8.4 Hz, IH), 6.93 (d, J = 8.7 Hz, IH), 3.93 (s, 3H). LCMS purity 100%. MS Found 354 (MH+).
3-fluoro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide
[0095] !H NMR (DMSO-d6, 300 MHz) δ 8.07 (d, J = 8.7 Hz, IH), 7.97-7.91 (m, 2H), 7.65-7.47
(m, 2H), 6.93 (d, J = 4.8 Hz, IH), 3.93 (s, 3H).
LCMS purity 100%. MS Found 304 (MH+).
3-chloro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide
[0096] *H NMR (DMSO-d6, 300 MHz) δ 8.16 (m, IH), 8.08-8.03 (m, 2H), 7.71 (br d, J = 7.8 Hz,
IH), 7.57 (t, J = 7.8 Hz, IH), 6.92 (d, J = 8.4 Hz, IH), 3.92 (s, 3H).
LCMS purity 100%. MS Found 320 (MH+).
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-3-methylthiophene-2-carboxamide [0097] *H NMR (DMSO-d6, 300 MHz) δ 7.98 (br d, J = 8.7 Hz, IH), 7.76 (d, J = 4.8 Hz, IH), 7.06 (d, J = 4.8 Hz, IH), 6.91 (d, J = 8.7 Hz, IH), 3.91 (s, 3H), 2.52 (s, 3H). LCMS purity 100%. MS Found 306 (MH+).
3-chloro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)thiophene-2-carboxamide
[0098] !H NMR (DMS0-d5, 300 MHz) δ 7.97 (br d, J = 5.1 Hz, 2H), 7.24 (d, J = 5.1 Hz, IH),
6.93 (d, J = 8.7 Hz, IH), 3.92 (s, 3H).
LCMS purity 100%. MS Found 326 (MH+).
2,6-difluoro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide [0099] JH NMR (DMSO-d6l 300 MHz) δ 8.08 (d, J = 9 Hz, IH), 7.69-7.59 (m, IH), 7.27 (t, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, IH), 3.93 (s, 3H). LCMS purity 100%. MS Found 322 (MH+). 3,4-difluoro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide
[0100] *H NMR (DMSO-de, 300 MHz) δ 8.22-8.15 (m, IH), 8.06 (d, J = 8.7 Hz, IH), 8.02-7.98
(m, IH), 7.68-7.59 (m, IH), 6.93 (d, J = 8.4 Hz, IH), 3.92 (s, 3H).
LCMS purity 100%. MS Found 322 (MH+).
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-4-(trifluoromethyl)benzamide
[0101] *H NMR (DMSO-de, 300 MHz) δ 8.27 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 8.7 Hz, IH), 7.92
(d, J = 8.7 Hz, 2H), 6.94 (d, J = 9 Hz, IH), 3.93 (s, 3H).
LCMS purity 100%. MS Found 354 (MH+).
4-cyano-N-(5-methoxythiazolo[5f4-b]pyridin-2-yl)benzamide
[0102] X NMR (DMSO-de, 300 MHz) δ 8.22 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.7 Hz, IH), 8.04
(d, J = 8.4 Hz, IH), 6.94 (d, J = 8.7 Hz, IH), 3.93 (s, 3H).
LCMS purity 100%. MS Found 311 (MH+).
4-acetamido-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide
[0103] !H NMR (DMSO-de, 300 MHz) δ 10.27 (s, IH), 8.06 (t, J = 8.7 Hz, 3H), 7.72 (d, J = 9 Hz,
2H), 6.91 (d, J = 8.7 Hz, IH), 3.92 (s, 3H), 2.09 (s, 3H).
LCMS purity 100%. MS Found 343 (MH+).
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-4-nitrobenzamϊde
[0104] *H NMR (DMSO-de, 300 MHz) δ 8.38-8.29 (m, 4H), 8.08 (d, J = 8.7 Hz, IH), 6.95 (d, J =
9.6 Hz), 3.94 (s, 3H).
LCMS purity 100%. MS Found 331 (MH+).
4-methoxy-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide
[0105] !H NMR (DMSO-de, 300 MHz) δ 8.11 (d, J = 9 Hz, 2H), 8.04 (d, J = 8.4 Hz, IH), 7.08 (d,
J = 9.3 Hz, 2H), 6.91 (d, J = 8.7 Hz, IH), 3.92 (s, 3H), 3.85 (s, 3H).
LCMS purity 100%. MS Found 316 (MH+). N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)furan-2-carboxamide
[0106] XH NMR (DMSO-d6, 300 MHz) δ 8.05-8.02 (m, 2H), 7.70 (d, J = 3.6 Hz, IH), 6.91 (d, J
8.7 Hz, IH), 6.75-6.74 (m, IH), 3.91 (s, 3H).
LCMS purity 100%. MS Found 276 (MH+).
4-fluoro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide
[0107] !H NMR (DMSO-de, 300 MHz) δ 8.20-8.16 (m, 2H), 8.05 (d, J = 8.7 Hz, IH), 7.39 (t, J =
8.7 Hz, IH), 6.92 (d, J = 8.7 Hz, IH), 3.92 (s, 3H).
LCMS purity 100%. MS Found 304 (MH+).
N-(6-methoxybenzo[d]thiazol-2-yl)-lH-indole-2-carboxamide
Figure imgf000054_0001
A
[0108] Compound A. A solution of 2-amino-6-methoxybenzothiazole (100 mg, 0.6 mmol), 1- [(fert-butyl)oxycarbonyl]-(±)-indoline-2-carboxylic acid (237 mg, 0.9 mmol), bromo-tris-pyrrolidino- phosphonium hexafluorophosphate (468 mg, 0.9 mmol), and A/,A/-diisopropylethylamine (300 μL, 1.8 mmol) was prepared at room temperature and allowed to stir over night. The reaction mixture was diluted with CH2CI2, and rinsed with saturated citric acid, and brine. The organic fraction was dried over MgS04, filtered, and concentrated. The residue was purified by silica gel chromatography (1:4 to 1:1 ethyl acetate:hexanes) to afford product (A) as a white solid (210 mg, 82%) which was pure by LCMS analysis. LCMS purity 100%. MS Found 426 (MH+), 326 (MH+- BOC) t
Figure imgf000055_0001
[0109] A sample of A (100 mg, 0.235 mmol) was treated with a solution of trifluoroacetic acid (3 mL), CH2CI2 (300 uL), and H20 (100 uL) at room temperature for 5 hours. The reaction mixture was concentrated in vacuo and used for the next step without purification. The crude reaction mixture was dissolved in 1,4-dioxane (3 mL) and allowed to stir at 60 C for 4 days. The reaction mixture was concentrated in vacuo and the residue purified by silica gel chromatography (1:4 to 1:2 ethyl acetate:hexanes) to afford N-(6-methoxybenzo[d]thiazol-2-yl)-lH-indole-2-carboxamide as a light yellow solid (51 mg, 67% yield).
*H NMR (CDCI3, 300 MHz) δ 11.91 (br s, IH), 7.68-7.67 (m, 2H), 7.65(d, J = 3 Hz, IH), 7.60 (d, J = 2.7 Hz, IH), 7.46 (d, J = 8 Hz, IH), 7.25 (t, J = 6.9 Hz, IH), 7.09-7.02 (m, 2H), 3.81 (s, 3H). LCMS purity 100%. MS Found 324 (MH+).
[0110] The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

We claim:
1. A pharmaceutical composition comprising, together with a pharmaceutically acceptable carrier, diluent, or excipient, a compound having the structure:
Figure imgf000056_0001
or a pharmaceutically acceptable salt thereof, wherein
A1, A2, A3, A4 are independently nitrogen or carbon;
L is a bond, -CrC6 alkylene-, -C2-C5 alkenylene-, -NH-, or -NH-C(=0)-;
Ri is Ci-C6 alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, -aryl-W-aryl, -aryl-W-heterocyclyl, or heterocyclyl-W-aryl, wherein W is a bond, -0-, -S02-, or -C(=0)-; R2 is H, Cι-C6 alkyl, or is linked to a carbon of Ri through a carbonyl group; R3 and R5 are independently H, halogen, or Cι-C6 alkyl;
R and R6 are independently H, halogen, C(0)R7, NR8R9, nitro, Cι-6-aIkyl, Ci-6-alkoxy, 0CF3, CF , aryl, -d-e-alkyl-aryl, heteroaryl, -C1-6-alkyl-heteroaryl, C(0)NR8R9, C(0)C(0)NR8R9, Cι-C6 alkyl-C(0)-NH-, NR8R9-S02- or Rι0-S02-; or
R3 and R together with the carbon atoms to which they attached form a 5-6 membered aryl or heteroaryl group, wherein the group is optionally substituted with Cι-C6 alkyl; or R4 and R5 together with the carbon atoms to which they attached form a 5-6 membered aryl or heteroaryl group, wherein the group is optionally substituted with Cι-C6 alkyl; provided that if A1 is nitrogen, R3 is absent, if A2 is nitrogen, R4 is absent, of A3 is nitrogen, R5 is absent, and if A4 is nitrogen, R6 is absent; R7 is hydrogen, Cι.6-alkyl, Cι.6-alkoxy, C(Z)-Rn where Z is CH2 or 0, heteroaryl, aryl, or a group of the formula
Figure imgf000057_0001
wherein n is 1 to 5 and each R12 is the same or different and is Cι-6-alkyl, hydroxy, halogen, nitro, oxo, amino, halo-Cι-6-alkyl, Ci-6-alkoxy, halo-Ci-6-alkoxy, or cyano, NHC(0)-Ci.5-alkyl, NHC(0)-C2-6-alkylene, C(0)-0-Ci.6-alkyl, or C(0)-aryl;
R8 and R9 are independently hydrogen, or CrC6-alkyl;
Rio is Ci-6-alkyl, Cι-6-alkyl-aryl, aryl, or heteroaryl;
Rii is Ci-e-alkyl, Cι-6-alkyl-aryl, aryl, or NR8R9; with the proviso that R and R6 are not simultaneously hydrogen; and wherein each one of the alkyl, aryl, heteroaryl, or heterocyclyl of R i to R12 is optionally substituted with one or more groups selected from C1-8-aIkyl, C2-C6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, haIo-C1-8-alkyl, Cι-8-alkoxy, halo-Ci.8-alkoxy, cyano, NHC(0)-Cw-alkyl, NHC(0)-cycloalkyl, NHC(0)-C2-5-alkenyl, NHC(O)- aryl-C(0)-0-Ci.8-alkyl, C(0)-0-Rι3, -0-C(0)-Ci-C8 alkyl, or C(0)-aryl, wherein Ri3 is H or CrC8 alkyl, and two substituents on aryl, together with the atoms to which they are attached, optionally form a dioxane ring.
The composition of claim 1 wherein the compound is of the formula (II):
Figure imgf000057_0002
3. The composition of claim 2 wherein L in the compound of formula (II) is a bond, -NH-, or -NH- C(=OK
4. The composition of claim 3 wherein Ri is optionally substituted aryl.
5. The composition of claim 3 wherein Ri is optionally substituted heteroaryl.
6. The composition of claim 3 wherein Ri is optionally substituted cycloalkyl, or optionally substituted heterocyclyl.
7. The composition of claim 1 wherein the compound is of the formula (III):
Figure imgf000058_0001
8. The composition of claim 7 wherein Ri in the compound of formula (III) is optionally substituted aryl.
9. The composition of claim 8 wherein Ri is phenyl, optionally substituted with 1, 2, or 3 groups independently selected from halogen, halo-CrCe alkyl, cyano, -N-C(0)-Cι-C6 alkyl, nitro, Cι-C6 alkoxy, and CrC6 alkyl.
10. The composition of claim 7 wherein Ri in the compound of formula (111) is optionally substituted heteroaryl.
11. The composition according to claim 1 in which the compound is: /V-(6-bromo-l,3-benzothiazol-2-yl)-4-methoxybenzamide; /V-(6-methoxy-l,3-benzothiazol-2-yl)-4-methylbenzamide; 4-(acetylamino)-/V-(6-methoxy-l,3-benzothiazol-2-yl)benzamide; 4-(methacryloylamino)-A/-(6-methoxy-l,3-benzothiazol-2-yl)benzamide; IV-(6-bromo-l,3-benzothiazol-2-yl)-3-methylbenzamide; 3,5-dichloro-/V-(4-methoxy-6-nitro-l,3-benzothiazol-2-yl)benzamide; 3-bromo-/V-(4-methoxy-6-nitro-l,3-benzothiazol-2-yl)benzamide; /V-(4,6-dimethyl-l,3-benzothiazol-2-yl)-2-methoxybenzamide;
4-chloro-Λ/-(6-ethoxy-l,3-benzothiazol-2-yl)-3-nitrobenzamide;
4-benzoyl-/V-(6-nitro-l,3-benzothiazol-2-yl)benzamide;
/V-(6-bromo-l,3-benzothiazol-2-yl)-4-nitrobenzamide;
N-(5-methoxy-l,3-benzothiazol-2-yl)-2,3-dihydro-l,4-benzodioxine-6-carboxamide;
N-(6-bromo-l,3-benzothiazol-2-yl)-4-methoxybenzamide;
N-(6-methoxy-l,3-benzothiazol-2-yl)-4-methylbenzamide;
4-(acetylamino)-N-(6-methoxy-l,3-benzothiazol-2-yl)benzamide;
4-(methacryloylamino)-N-(6-methoxy-l,3-benzothiazol-2-yl)benzamide;
N-(6-bromo-l ,3-benzothiazol-2-yl)-3-methylbenzamide;
3,5-dichloro-N-(4-methoxy-6-nitro-l,3-benzothiazol-2-yl)benzamide;
3-bromo-N-(4-methoxy-6-nitro-l,3-benzothiazol-2-yl)benzamide;
N-(4,6-dimethyl-l,3-benzothiazol-2-yl)-2-methoxybenzamide;
4-chloro-N-(6-ethoxy-l,3-benzothiazol-2-yl)-3-nitrobenzamide;
4-benzoyl-N-(6-nitro-l,3-benzothiazol-2-yl)benzamide;
N-(6-bromo-l,3-benzothiazol-2-yl)-4-nitrobenzamide;
N-(5-methoxy-l,3-benzothiazol-2-yl)-2,3-dihydro-l,4-benzodioxine-6-carboxamide;
4-methacrylamido-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
4-amino-N-(6-methoxybenzo[d]thiazol-2-yI)benzamide;
4-acetamido-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
2-chloro-N-(6-methoxybenzo[d]thiazol-2-yl)-4-nitrobenzamide;
4-(cyclohexanecarboxamido)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-3-methyl-4-nitrobenzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-4-methylbenzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-3,4-dimethylbenzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-4-methyl-3-nitrobenzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-4-nitrobenzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-2-naphthamide; methyl 4-((6-methoxybenzo[d]thiazoI-2-yl)carbamoyl)benzoate;
4-((6-methoxybenzo[d]thiazol-2-yl)carbamoyl)phenyl acetate;
4-acetyl-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide; N-(6-methoxybenzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxamide;
4-chloro-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
4-cyano-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
4'-methoxy-N-(6-methoxy-l,3-benzothiazol-2-yl)biphenyl-4-carboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-4-(pyrrolidin-l-ylsulfonyl)benzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-4-phenoxybenzamide;
4-methoxy-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-l-tosylpyrrolidine-2-carboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)indoline-2-carboxamide;
(R)-N-(6-methoxybenzo[d]thiazol-2-yl)indoline-2-carboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-2-(l-methyl-lH-indol-2-yl)acetamide;
N-(6-methoxybenzo[d]thiazol-2-yl)acetamide;
N-(6-methoxy-l,3-benzothiazol-2-yl)adamantane-l-carboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-2-phenylacetamide;
N-(6-methoxybenzo[d]thiazol-2-yl)piperidine-4-carboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-4-propylcyclohexanecarboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)cyclobutanecarboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)isobutyramide;
N-(6-methoxybenzo[d]thiazol-2-yl)pivalamide;
N-(6-methoxybenzo[d]thiazol-2-yl)thiophene-2-carboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-5-nitrothiophene-2-carboxamide;
2-(6-methoxybenzo[d]thiazol-2-yl)isoindoline-l,3-dione;
N-(6-methoxybenzo[d]thiazol-2-yl)isonicotinamide;
N-(6-methoxybenzo[d]thiazol-2-yl)nicotinamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-3-nitrobenzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-l-naphthamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-3-methylbenzamide;
4-fluoro-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
3-fluoro-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
2-fluoro-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide; 3-methoxy-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
2-methoxy-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
N-(4-(4-cyanophenyl)thiazol-2-yl)-4-methylbenzamide;
4-methyl-N-(4-p-tolylthiazol-2-yl)benzamide;
N-(4-(2-methoxyphenyl)thiazol-2-yl)-4-methylbenzamide;
N-(4-(4-iodophenyl)thiazol-2-yl)-4-methylbenzamide;
4-methyI-N-(4-(naphthalen-2-yl)thiazol-2-yl)benzamide;
N-(4-(4-fluorophenyl)thiazol-2-yl)-4-methylbenzamide;
3-methyl-N-(7-methyl[l,3]thiazolo[4,5-g][l,3]benzothiazol-2-yl)benzamide;
2,4,6-trimethyl-N-(thiazol-2-yl)benzamide;
N-(6-chlorobenzo[d]thiazol-2-yl)-4-methylbenzamide;
4-methyl-N-(4-methylbenzo[d]thiazol-2-yl)benzamide;
N-(6-acetamidobenzo[d]thiazol-2-yl)-4-methylbenzamide;
N-[6-(aminosulfonyl)-l,3-benzothiazol-2-yl]-4-methylbenzamide; methyl 4-((6-aminobenzo[d]thiazol-2-yl)carbamoyl)benzoate;
4-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)benzamide;
3,4-dimethyl-N-(4-methylbenzo[d]thiazol-2-yl)benzamide;
4-ethyl-N-(6-methoxybenzo[d]thiazoI-2-yl)benzamide;
4-ethyl-N-(6-methylbenzo[d]thiazol-2-yl)benzamide;
3,4-dimethyl-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide;
3,4-dimethyl-N-(6-methylbenzo[d]thiazol-2-yl)benzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-4-propylbenzamide;
4-butyl-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
4-hexyl-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
N-(benzo[d]thiazol-2-yl)-4-methylbenzamide;
N-(benzo[d]thiazol-2-yl)-4-ethylbenzamide;
4-amino-N-(benzo[d]thiazol-2-yl)benzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)furan-2-carboxamide;
N-(benzo[d]thiazol-2-yl)furan-2-carboxamide;
N-(benzo[d]thiazol-2-yl)thiophene-2-carboxamide;
N-(6-ethoxybenzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxamide; N-(6-ethoxybenzo[d]thiazol-2-yl)-4-ethylbenzamide;
N-(6-ethoxybenzo[d]thiazol-2-yl)-4-methylbenzamide;
N-(6-ethoxybenzo[d]thiazol-2-yl)-3,4-dimethylbenzamide;
4-acetamido-N-(6-ethoxybenzo[d]thiazol-2-yl)benzamide;
3,4-dichloro-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
3,4-dichloro-N-(6-ethoxybenzo[d]thiazol-2-yl)benzamide;
N-l-adamantyl-N'-(6-methoxy-l,3-benzothiazol-2-yl)urea; l-(6-methoxybenzo[d]thiazol-2-yl)-3-phenylurea; l-(4-chlorophenyl)-3-(6-methoxybenzo[d]thiazol-2-yl)urea; l-(3-fluorophenyl)-3-(6-methoxybenzo[d]thiazol-2-yl)urea;
N-(6-methoxybenzo[d]thiazol-2-yl)-2,4-dimethylbenzamide;
3-(5-((6-methoxybenzo[d]thiazol-2-yl)carbamoyl)-2,4-dimethyl-lH-pyrrol-3-yl)propanoic acid;
N-(6-methoxybenzo[d]thiazol-2-yl)-3-methylthiophene-2-carboxamide;
3-chloro-N-(6-methoxybenzo[d]thiazol-2-yl)thiophene-2-carboxamide; l-(2,6-dichlorobenzoyl)-3-(5-methylbenzo[d]thiazol-2-yl)urea; l-(5-chlorobenzo[d]thiazol-2-yl)-3-(2,6-dichlorobenzoyl)urea; l-(2,6-dichlorobenzoyl)-3-(5-fluorobenzo[d]thiazol-2-yl)urea; l-(benzo[d]thiazol-2-yl)-3-(l,2,3-thiadiazole-4-carbonyl)urea; l-(3,4-dichlorophenyl)-3-(6-methoxybenzo[d]thiazol-2-yl)urea; l-(5-chloro-2-methoxyphenyl)-3-(4-chlorobenzo[d]thiazol-2-yl)urea; l-(4-chlorobenzo[d]thiazol-2-yl)-3-(3-fluorophenyl)urea; l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-chlorobenzo[d]thiazol-2-yl)urea; l-(4-chlorobenzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea; l-(4-chlorobenzo[d]thiazol-2-yl)-3-(2-fluorophenyl)urea; l-(2-chloro-5-(trifluoromethyl)phenyl)-3-(4-chlorobenzo[d]thiazol-2-yl)urea; l-(2,5-difluorophenyl)-3-(5,6-dimethylbenzo[d]thiazol-2-yl)urea; l-(5,6-dimethylbenzo[d]thiazol-2-yl)-3-(3-(trifluoromethyl)phenyl)urea; l-(7-chlorobenzo[d]thiazol-2-yl)-3-(2,5-difluorophenyl)urea; l-(4-chlorobenzo[d]thiazol-2-yl)-3-(2,5-dimethoxyphenyl)urea; l-(2,5-dimethoxyphenyl)-3-(6-methoxybenzo[d]thiazol-2-yl)urea; l-(4-chlorobenzo[d]thiazol-2-yl)-3-(2,5-difluorophenyl)urea; l-(5,6-dimethylbenzo[d]thiazol-2-yl)-3-(3-fluorophenyl)urea; l-(4-chlorobenzo[d]thiazol-2-yl)-3-(2,3-dichlorophenyl)urea; l-(2,3-dichlorophenyl)-3-(6-methoxybenzo[d]thiazol-2-yl)urea; ethyl 4-(3-(4-chlorobenzo[d]thiazol-2-yl)ureido)benzoate; ethyl 4-(3-(6-methoxybenzo[d]thiazol-2-yl)ureido)benzoate; l-(4-chlorobenzo[d]thiazol-2-yl)-3-(4-fluoro-3-nitrophenyl)urea; l-(4-chloro-2-(trifluoromethyl)phenyl)-3-(4-chlorobenzo[d]thiazol-2-yl)urea; l-(3-chloro-4-methylphenyl)-3-(4-chlorobenzo[d]thiazol-2-yl)urea; l-(4-methoxybenzo[d]thiazol-2-yl)-3-p-tolylurea; l-(4-chlorophenyl)-3-(6-(methylsulfonyl)benzo[d]thiazol-2-yl)urea; l-(6-methoxybenzo[d]thiazol-2-yl)-3-phenylurea; l-(6-nitrobenzo[d]thiazol-2-yl)-3-phenylurea; ethyl 4-(3-(6-chlorobenzo[d]thiazol-2-yl)ureido)benzoate; l-(4-chlorophenyl)-3-(4-methoxybenzo[d]thiazol-2-yl)urea; ethyl 4-(3-(6-ethoxybenzo[d]thiazol-2-yl)ureido)benzoate; l-(4-cyanophenyl)-3-(6-methoxybenzo[d]thiazol-2-yl)urea;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)thiophene-2-carboxamide;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
2,4-dichloro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
3-fluoro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
3-chloro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-3-methylthiophene-2-carboxamide;
3-chloro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)thiophene-2-carboxamide;
2,6-difluoro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
3,4-difluoro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-4-(trifluoromethyl)benzamide;
4-cyano-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
4-acetamido-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-4-nitrobenzamide;
4-methoxy-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-4-methylbenzamide; N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)furan-2-carboxamide;
4-fluoro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
4-chloro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(benzo[d]thiazol-2-yl)-5-nitrofuran-2-carboxamide; ethyl 6-(benzo[d]thiazol-2-ylcarbamoyl)picolinate;
N-(benzo[d]thiazol-2-yl)-3-chlorobenzo[b]thiophene-2-carboxamide;
N-(benzo[d]thiazol-2-yl)-2-bromobenzamide;
2'-[(l,3-benzothiazol-2-ylamino)carbonyl]biphenyl-2-carboxylic acid;
N-(benzo[d]thiazol-2-yl)-4-butylbenzamide;
(E)-N-(benzo[d]thiazol-2-yl)-3-(2-methoxyphenyl)acrylamide;
N-(benzo[d]thiazol-2-yl)-4-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)-2-fluorobenzamide;
N-l,3-benzothiazol-2-yladamantane-l-carboxamide;
N-(benzo[d]thiazol-2-yl)-2,4-dichlorobenzamide;
N-(benzo[d]thiazol-2-yl)-5-chloro-2-methoxybenzamide;
N-(benzo[d]thiazol-2-yl)benzamide;
N-(benzo[d]thiazol-2-yl)-2-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)-4-propylbenzamide;
N-(benzo[d]thiazol-2-yl)-l-tosylpyrrolidine-2-carboxamide;
N-(benzo[d]thiazol-2-yl)-4-bromobenzamide;
N-(benzo[d]thiazol-2-yl)-4-chloro-3-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)-3-fluorobenzamide;
(E)-N-(benzo[d]thiazol-2-yl)-3-(4-methoxyphenyl)acrylamide;
N-(benzo[d]thiazol-2-yl)-4-tert-butylbenzamide;
N-(benzo[d]thiazol-2-yl)nicotinamide;
N-(benzo[d]thiazol-2-yl)-4-methoxybenzamide;
N-(benzo[d]thiazol-2-yl)-4-fluorobenzamide;
2-(benzo[d]thiazol-2-ylcarbamoyl)-3-nitrobenzoic acid;
2-(benzo[d]thiazol-2-yl)-l,3-dioxoisoindoline-5-carboxylic acid;
N-(benzo[d]thiazol-2-yl)-4-methyl-3-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)-2-chloronicotinamide; N-(benzo[d]thiazol-2-yl)-2-(4-nitrophenyl)acetamide;
3-(benzo[d]thiazol-2-ylcarbamoyl)-2,2,3-trimethylcyclopentanecarboxylic acid;
N-(benzo[d]thiazol-2-yl)-3-chlorobenzamide;
N-(benzo[d]thiazol-2-yl)-4-bromo-l-methyl-lH-pyrazole-3-carboxamide;
N-(benzo[d]thiazol-2-yl)-4-chloro-2-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)-3-methoxybenzamide;
N-(benzo[d]thiazol-2-yl)-4-methoxy-3-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)-2,6-dichlorobenzamide; methyl 3-(benzo[d]thiazol-2-ylcarbamoyl)-5-nitrobenzoate;
N-(benzo[d]thiazol-2-yl)-2-methyl-3-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)-2-chlorobenzamide;
N-(benzo[d]thiazol-2-yl)-3-iodobenzamide; l-allyl-N-(benzo[d]thiazol-2-yl)-4-hydroxy-2-oxo-l,2-dihydroquinoline-3-carboxamide;
N-(benzo[d]thiazol-2-yl)-4-hydroxy-l-methyl-2roxo-l,2-dihydroquinoline-3-carboxamide;
N-(benzo[d]thiazol-2-yl)-3,4-dichlorobenzamide;
N-(benzo[d]thiazol-2-yl)-4-chloro-l-methyl-lH-pyrazole-3-carboxamide;
3-(benzo[d]thiazol-2-ylcarbamoyl)-l,2,2-trimethylcyclopentanecarboxylic acid;
N-(benzo[d]thiazol-2-yl)-l-ethyl-4-hydroxy-2-oxo-l,2-dihydroquinoline-3-carboxamide;
N-(benzo[d]thiazol-2-yl)-4-(5-ethylpyridin-2-yl)benzamide;
N-(benzo[d]thiazol-2-yl)-2-chloro-4-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)-3-methyl-4-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)cyclohexanecarboxamide;
N-(benzo[d]thiazol-2-yl)-2-chloro-5-nitrobenzamide; methyl 6-(benzo[d]thiazol-2-ylcarbamoyl)picolinate;
N-(benzo[d]thiazol-2-yl)-5-bromofuran-2-carboxamide;
N-(benzo[d]thiazol-2-yl)-l-butyl-4-hydroxy-2-oxo-l,2-dihydroquinoline-3-carboxamide;
N-(benzo[d]thiazol-2-yl)-4-(4-pentylcyclohexyl)benzamide;
N-(benzo[d]thiazol-2-yl)-4-(5-pentylpyridin-2-yl)benzamide;
4-(benzo[d]thiazol-2-ylcarbamoyl)phenyl octanoate;
N-(benzo[d]thiazol-2-yl)-4-hexylbenzamide;
N-(benzo[d]thiazol-2-yl)-4-(pentyloxy)benzamide; N-(benzo[d]thiazoI-2-yl)-2-chloronicotinamide; N-(benzo[d]thiazol-2-yl)-4-(4-propylcyclohexyl)benzamide; l-allyl-N-(benzo[d]thiazol-2-yl)-4-hydroxy-2-oxo-l,2-dihydroquinoline-3-carboxamide; N-(benzo[d]thiazol-2-yl)-4-(5-propylpyridin-2-yl)benzamide; N-(benzo[d]thiazol-2-yl)-5-bromonicotinamide; N-(benzo[d]thiazol-2-yl)-4-(hexyloxy)benzamide; N-l,3-benzothiazoI-2-yl-4'-methoxybiphenyl-4-carboxamide; N-(benzo[d]thiazol-2-yl)-4-isopropylbenzamide; N-(benzo[d]thiazol-2-yl)-2-(dimethylamino)benzamide; (R)-N-(benzo[d]thiazol-2-yl)azetidine-2-carboxamide; N-(benzo[d]thiazol-2-yl)piperidine-4-carboxamide; N-(6-methoxybenzo[d]thiazol-2-yl)-lH-indole-2-carboxamide, or a pharmaceutically acceptable salt thereof.
12. A method of inhibiting ubiquitin ligation in a cell comprising contacting a cell in which inhibition of ubiquitination is desired with a pharmaceutical composition according to claim 1.
13. The method according to claim 12 wherein the compound in the pharmaceutical composition is of the formula (II):
Figure imgf000066_0001
14. The method of claim 13 wherein L in the compound of formula (II) is a bond, -NH-, or -NH- C(=0
15. The method of claim 14 wherein Ri is optionally substituted aryl.
17. The method of claim 14 wherein Ri is optionally substituted heteroaryl.
18. The method of claim 14 wherein Ri is optionally substituted cycloalkyl, or optionally substituted heterocyclyl.
19. The method of claim 12 wherein the compound in the pharmaceutical composition is of the formula (111):
Figure imgf000067_0001
20. The method of claim 19 wherein Ri in the compound of formula (111) is optionally substituted aryl.
21. The method of claim 20 wherein Ri is phenyl, optionally substituted with 1, 2, or 3 groups independently selected from halogen, halo-CrC6 alkyl, cyano, -N-C(0)-Cι-C6 alkyl, nitro, Cι-C6 alkoxy, and Ci-Ce alkyl.
22. The method of claim 19 wherein Ri in the compound of formula (111) is optionally substituted heteroaryl.
23. The method according to claim 12 in which the compound is:
/V-(6-bromo-l,3-benzothiazol-2-yl)-4-methoxybenzamide;
/V-(6-methoxy-l,3-benzothiazol-2-yl)-4-methylbenzamide;
4-(acetylamino)-N-(6-methoxy-l,3-benzothiazol-2-yl)benzamide;
4-(methacryloylamino)-/V-(6-methoxy-l,3-benzothiazol-2-yl)benzamide;
/V-(6-bromo-l,3-benzothiazoI-2-yl)-3-methylbenzamide; 3,5-dichloro-rV-(4-methoxy-6-nitro-l,3-benzothiazol-2-yl)benzamide;
3-bromo-/V-(4-methoxy-6-nitro-l,3-benzothiazol-2-yl)benzamide; rV-(4,6-dimethyl-l,3-benzothiazol-2-yl)-2-methoxybenzamide;
4-chloro-N-(6-ethoxy-l,3-benzothiazol-2-yl)-3-nitrobenzamide;
4-benzoyl-/V-(6-nitro-l,3-benzothiazol-2-yl)benzamide;
/V-(6-bromo-l,3-benzothiazoI-2-yl)-4-nitrobenzamide;
N-(5-methoxy-l,3-benzothiazol-2-yl)-2,3-dihydro-l,4-benzodioxine-6-carboxamide;
N-(6-bromo-l,3-benzothiazol-2-yl)-4-methoxybenzamide;
N-(6-methoxy-l,3-benzothiazol-2-yl)-4-methylbenzamide;
4-(acetylamino)-N-(6-methoxy-l,3-benzothiazol-2-yl)benzamide;
4-(methacryloylamino)-N-(6-methoxy-l,3-benzothiazoI-2-yl)benzamide;
N-(6-bromo-l,3-benzothiazol-2-yl)-3-methylbenzamide;
3,5-dichloro-N-(4-methoxy-6-nitro-l,3-benzothiazoI-2-yl)benzamide;
3-bromo-N-(4-methoxy-6-nitro-l,3-benzothiazol-2-yl)benzamide;
N-(4,6-dimethyl-l,3-benzothiazol-2-yl)-2-methoxybenzamide;
4-chloro-N-(6-ethoxy-l,3-benzothiazol-2-yl)-3-nitrobenzamide;
4-benzoyl-N-(6-nitro-l,3-benzothiazol-2-yl)benzamide;
N-(6-bromo-l,3-benzothiazol-2-yl)-4-nitrobenzamide;
N-(5-methoxy-l,3-benzothiazol-2-yl)-2,3-dihydro-l,4-benzodioxine-6-carboxamide;
4-methacrylamido-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
4-amino-N-(6-methoxybenzo[d]thiazoI-2-yl)benzamide;
4-acetamido-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
2-chloro-N-(6-methoxybenzo[d]thiazol-2-yl)-4-nitrobenzamide;
4-(cyclohexanecarboxamido)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-3-methyl-4-nitrobenzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-4-methylbenzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-3,4-dimethylbenzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-4-methyl-3-nitrobenzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-4-nitrobenzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-2-naphthamide; methyl 4-((6-methoxybenzo[d]thiazol-2-yl)carbamoyl)benzoate; 4-((6-methoxybenzo[d]thiazol-2-yl)carbamoyl)phenyl acetate;
4-acetyl-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxamide;
4-chloro-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
4-cyano-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
4'-methoxy-N-(6-methoxy-l,3-benzothiazol-2-yl)biphenyl-4-carboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-4-(pyrrolidin-l-ylsulfonyl)benzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-4-phenoxybenzamide;
4-methoxy-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-l-tosylpyrrolidine-2-carboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)indoline-2-carboxamide;
(R)-N-(6-methoxybenzo[d]thiazol-2-yl)indoline-2-carboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-2-(l-methyl-lH-indol-2-yl)acetamide;
N-(6-methoxybenzo[d]thiazol-2-yl)acetamide;
N-(6-methoxy-l,3-benzothiazol-2-yl)adamantane-l-carboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-2-phenylacetamide;
N-(6-methoxybenzo[d]thiazol-2-yl)piperidine-4-carboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-4-propylcyclohexanecarboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)cyclobutanecarboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)isobutyramide;
N-(6-methoxybenzo[d]thiazol-2-yl)pivalamide;
N-(6-methoxybenzo[d]thiazol-2-yl)thiophene-2-carboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-5-nitrothiophene-2-carboxamide;
2-(6-methoxybenzo[d]thiazol-2-yl)isoindoline-l,3-dione;
N-(6-methoxybenzo[d]thiazol-2-yl)isonicotinamide;
N-(6-methoxybenzo[d]thiazol-2-yl)nicotinamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-3-nitrobenzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-l-naphthamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-3-methylbenzamide;
4-fluoro-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide; 3-fluoro-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
2-fluoro-N-(6-methoxybenzo[d]thiazoI-2-yl)benzamide;
3-methoxy-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
2-methoxy-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
N-(4-(4-cyanophenyl)thiazol-2-yl)-4-methylbenzamide;
4-methyl-N-(4-p-tolyIthiazol-2-yl)benzamide;
N-(4-(2-methoxyphenyl)thiazol-2-yl)-4-methylbenzamide;
N-(4-(4-iodophenyl)thiazol-2-yI)-4-methylbenzamide;
4-methyl-N-(4-(naphthalen-2-yl)thiazol-2-yl)benzamide;
N-(4-(4-fluorophenyl)thiazol-2-yl)-4-methylbenzamide;
3-methyl-N-(7-methyl[l,3]thiazolo[4,5-g][l,3]benzothiazol-2-yl)benzamide;
2,4,6-trimethyl-N-(thiazol-2-yl)benzamide;
N-(6-chlorobenzo[d]thiazol-2-yI)-4-methylbenzamide;
4-methyl-N-(4-methylbenzo[d]thiazol-2-yl)benzamide;
N-(6-acetamidobenzo[d]thiazol-2-yl)-4-methylbenzamide;
N-[6-(aminosulfonyl)-l,3-benzothiazol-2-yl]-4-methylbenzamide; methyl 4-((6-aminobenzo[d]thiazol-2-yl)carbamoyl)benzoate;
4-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)benzamide;
3,4-dimethyl-N-(4-methylbenzo[d]thiazol-2-yl)benzamide;
4-ethyl-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
4-ethyl-N-(6-methylbenzo[d]thiazol-2-yl)benzamide;
3,4-dimethyl-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide;
3,4-dimethyl-N-(6-methylbenzo[d]thiazol-2-yl)benzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-4-propylbenzamide;
4-butyl-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
4-hexyl-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
N-(benzo[d]thiazol-2-yl)-4-methylbenzamide;
N-(benzo[d]thiazol-2-yl)-4-ethylbenzamide;
4-amino-N-(benzo[d]thiazol-2-yl)benzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)furan-2-carboxamide;
N-(benzo[d]thiazol-2-yl)furan-2-carboxamide; N-(benzo[d]thiazol-2-yl)thiophene-2-carboxamide;
N-(6-ethoxybenzo[d]thiazol-2-yl)-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxamide;
N-(6-ethoxybenzo[d]thiazol-2-yl)-4-ethylbenzamide;
N-(6-ethoxybenzo[d]thiazol-2-yl)-4-methylbenzamide;
N-(6-ethoxybenzo[d]thiazol-2-yl)-3,4-dimethylbenzamide;
4-acetamido-N-(6-ethoxybenzo[d]thiazol-2-yl)benzamide;
3,4-dichloro-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
3,4-dichloro-N-(6-ethoxybenzo[d]thiazol-2-yl)benzamide;
N-l-adamantyl-N'-(6-methoxy-l,3-benzothiazol-2-yl)urea; l-(6-methoxybenzo[d]thiazol-2-yl)-3-phenylurea; l-(4-chlorophenyl)-3-(6-methoxybenzo[d]thiazol-2-yl)urea; l-(3-fluorophenyl)-3-(6-methoxybenzo[d]thiazol-2-yl)urea;
N-(6-methoxybenzo[d]thiazol-2-yl)-2,4-dimethylbenzamide;
3-(5-((6-methoxybenzo[d]thiazol-2-yl)carbamoyl)-2,4-dimethyl-lH-pyrrol-3-yl)propanoic acid;
N-(6-methoxybenzo[d]thiazol-2-yl)-3-methylthiophene-2-carboxamide;
3-chloro-N-(6-methoxybenzo[d]thiazol-2-yl)thiophene-2-carboxamide; l-(2,6-dichlorobenzoyl)-3-(5-methylbenzo[d]thiazol-2-yl)urea; l-(5-chlorobenzo[d]thiazol-2-yl)-3-(2,6-dichlorobenzoyl)urea; l-(2,6-dichlorobenzoyl)-3-(5-fluorobenzo[d]thiazol-2-yl)urea; l-(benzo[d]thiazol-2-yl)-3-(l,2,3-thiadiazole-4-carbonyl)urea; l-(3,4-dichlorophenyl)-3-(6-methoxybenzo[d]thiazol-2-yl)urea; l-(5-chloro-2-methoxyphenyl)-3-(4-chlorobenzo[d]thiazol-2-yl)urea; l-(4-chlorobenzo[d]thiazol-2-yl)-3-(3-fluorophenyl)urea; l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-chlorobenzo[d]thiazol-2-yl)urea; l-(4-chIorobenzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea; l-(4-chlorobenzo[d]thiazol-2-yl)-3-(2-fluorophenyl)urea; l-(2-chloro-5-(trifluoromethyl)phenyl)-3-(4-chlorobenzo[d]thiazol-2-yl)urea; l-(2,5-difluorophenyl)-3-(5,6-dimethylbenzo[d]thiazol-2-yl)urea; l-(5,6-dimethylbenzo[d]thiazol-2-yl)-3-(3-(trifluoromethyI)phenyl)urea; l-(7-chlorobenzo[d]thiazol-2-yl)-3-(2,5-difluorophenyl)urea; l-(4-chlorobenzo[d]thiazol-2-yl)-3-(2,5-dimethoxyphenyl)urea; l-(2,5-dimethoxyphenyl)-3-(6-methoxybenzo[d]thiazol-2-yl)urea; l-(4-chlorobenzo[d]thiazol-2-yl)-3-(2,5-difluorophenyl)urea; l-(5,6-dimethylbenzo[d]thiazol-2-yl)-3-(3-fluorophenyl)urea; l-(4-chIorobenzo[d]thiazol-2-yl)-3-(2,3-dichlorophenyl)urea; l-(2,3-dichlorophenyl)-3-(6-methoxybenzo[d]thiazol-2-yl)urea; ethyl 4-(3-(4-chlorobenzo[d]thiazoI-2-yl)ureido)benzoate; ethyl 4-(3-(6-methoxybenzo[d]thiazol-2-yl)ureido)benzoate; l-(4-chIorobenzo[d]thiazol-2-yl)-3-(4-fluoro-3-nitrophenyl)urea; l-(4-chloro-2-(trifluoromethyl)phenyl)-3-(4-chlorobenzo[d]thiazol-2-yl)urea; l-(3-chloro-4-methylphenyl)-3-(4-chlorobenzo[d]thiazol-2-yl)urea; l-(4-methoxybenzo[d]thiazol-2-yl)-3-p-tolylurea; l-(4-chlorophenyl)-3-(6-(methylsulfonyl)benzo[d]thiazol-2-yl)urea; l-(6-methoxybenzo[d]thiazol-2-yl)-3-phenylurea; l-(6-nitrobenzo[d]thiazol-2-yI)-3-phenylurea; ethyl 4-(3-(6-chlorobenzo[d]thiazoI-2-yl)ureido)benzoate; l-(4-chlorophenyl)-3-(4-methoxybenzo[d]thiazol-2-yl)urea; ethyl 4-(3-(6-ethoxybenzo[d]thiazol-2-yl)ureido)benzoate; l-(4-cyanophenyl)-3-(6-methoxybenzo[d]thiazol-2-yl)urea;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)thiophene-2-carboxamide;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
2,4-dichloro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
3-fluoro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
3-chloro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yI)-3-methylthiophene-2-carboxamide;
3-chloro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)thiophene-2-carboxamide;
2,6-difluoro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
3,4-difluoro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-4-(trifluoromethyl)benzamide;
4-cyano-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
4-acetamido-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-4-nitrobenzamide; 4-methoxy-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-4-methylbenzamide;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)furan-2-carboxamide;
4-fluoro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
4-chloro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(benzo[d]thiazol-2-yl)-5-nitrofuran-2-carboxamide; ethyl 6-(benzo[d]thiazol-2-ylcarbamoyl)picolinate;
N-(benzo[d]thiazol-2-yl)-3-chlorobenzo[b]thiophene-2-carboxamide;
N-(benzo[d]thiazol-2-yl)-2-bromobenzamide;
2'-[(l,3-benzothiazol-2-ylamino)carbonyl]biphenyl-2-carboxylic acid;
N-(benzo[d]thiazol-2-yl)-4-butylbenzamide;
(E)-N-(benzo[d]thiazol-2-yl)-3-(2-methoxyphenyl)acrylamide;
N-(benzo[d]thiazol-2-yl)-4-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)-2-fluorobenzamide;
N-l,3-benzothiazol-2-yladamantane-l-carboxamide;
N-(benzo[d]thiazol-2-yl)-2,4-dichlorobenzamide;
N-(benzo[d]thiazol-2-yl)-5-chloro-2-methoxybenzamide;
N-(benzo[d]thiazol-2-yl)benzamide;
N-(benzo[d]thiazol-2-yl)-2-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)-4-propylbenzamide;
N-(benzo[d]thiazol-2-yl)-l-tosylpyrrolidine-2-carboxamide;
N-(benzo[d]thiazol-2-yl)-4-bromobenzamide;
N-(benzo[d]thiazol-2-yl)-4-chloro-3-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)-3-fluorobenzamide;
(E)-N-(benzo[d]thiazol-2-yl)-3-(4-methoxyphenyl)acrylamide;
N-(benzo[d]thiazol-2-yl)-4-tert-butylbenzamide;
N-(benzo[d]thiazol-2-yl)nicotinamide;
N-(benzo[d]thiazol-2-yl)-4-methoxybenzamide;
N-(benzo[d]thiazol-2-yl)-4-fluorobenzamide;
2-(benzo[d]thiazol-2-ylcarbamoyl)-3-nitrobenzoic acid;
2-(benzo[d]thiazol-2-yl)-l,3-dioxoisoindoline-5-carboxylic acid; N-(benzo[d]thiazol-2-yl)-4-methyl-3-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)-2-chloronicotinamide;
N-(benzo[d]thiazoI-2-yl)-2-(4-nitrophenyl)acetamide;
3-(benzo[d]thiazol-2-ylcarbamoyl)-2,2,3-trimethylcyclopentanecarboxylic acid;
N-(benzo[d]thiazol-2-yl)-3-chlorobenzamide;
N-(benzo[d]thiazol-2-yl)-4-bromo-l-methyl-lH-pyrazole-3-carboxamide;
N-(benzo[d]thiazol-2-yl)-4-chloro-2-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)-3-methoxybenzamide;
N-(benzo[d]thiazol-2-yl)-4-methoxy-3-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)-2,6-dichIorobenzamide; methyl 3-(benzo[d]thiazol-2-yIcarbamoyl)-5-nitrobenzoate;
N-(benzo[d]thiazol-2-yl)-2-methyl-3-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)-2-chlorobenzamide;
N-(benzo[d]thiazol-2-yI)-3-iodobenzamide; l-allyl-N-(benzo[d]thiazol-2-yl)-4-hydroxy-2-oxo-l,2-dihydroquinoline-3-carboxamide;
N-(benzo[d]thiazol-2-yl)-4-hydroxy-l-methyl-2-oxo-l,2-dihydroquinoline-3-carboxamide;
N-(benzo[d]thiazol-2-yl)-3,4-dichlorobenzamide;
N-(benzo[d]thiazol-2-yl)-4-chloro-l-methyl-lH-pyrazole-3-carboxamide;
3-(benzo[d]thiazol-2-yIcarbamoyl)-l,2,2-trimethylcyclopentanecarboxylic acid;
N-(benzo[d]thiazol-2-yl)-l-ethyl-4-hydroxy-2-oxo-l,2-dihydroquinoline-3-carboxamide;
N-(benzo[d]thiazoI-2-yl)-4-(5-ethylpyridin-2-yl)benzamide;
N-(benzo[d]thiazol-2-yl)-2-chloro-4-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)-3-methyl-4-nitrobenzamide;
N-(benzo[d]thiazol-2-yl)cyclohexanecarboxamide;
N-(benzo[d]thiazol-2-yl)-2-chloro-5-nitrobenzamide; methyl 6-(benzo[d]thiazol-2-ylcarbamoyl)picolinate;
N-(benzo[d]thiazol-2-yl)-5-bromofuran-2-carboxamide;
N-(benzo[d]thiazol-2-yl)-l-butyl-4-hydroxy-2-oxo-l,2-dihydroquinoline-3-carboxamide;
N-(benzo[d]thiazol-2-yl)-4-(4-pentylcyclohexyl)benzamide;
N-(benzo[d]thiazol-2-yl)-4-(5-pentylpyridin-2-yl)benzamide;
4-(benzo[d]thiazol-2-ylcarbamoyl)phenyl octanoate; N-(benzo[d]thiazol-2-yl)-4-hexylbenzamide; N-(benzo[d]thiazol-2-yl)-4-(pentyloxy)benzamide; N-(benzo[d]thiazol-2-yl)-2-chloronicotinamide; N-(benzo[d]thiazol-2-yl)-4-(4-propylcyclohexyl)benzamide; l-allyl-N-(benzo[d]thiazol-2-yI)-4-hydroxy-2-oxo-l,2-dihydroquinoline-3-carboxamide; N-(benzo[d]thiazol-2-yl)-4-(5-propylpyridin-2-yl)benzamide; N-(benzo[d]thiazol-2-yl)-5-bromonicotinamide; N-(benzo[d]thiazol-2-yl)-4-(hexyloxy)benzamide; N-l,3-benzothiazol-2-yl-4'-methoxybiphenyl-4-carboxamide; N-(benzo[d]thiazol-2-yl)-4-isopropylbenzamide; N-(benzo[d]thiazoI-2-yl)-2-(dimethylamino)benzamide; (R)-N-(benzo[d]thiazol-2-yl)azetidine-2-carboxamide; N-(benzo[d]thiazol-2-yl)piperidine-4-carboxamide; N-(6-methoxybenzo[d]thiazol-2-yl)-lH-indole-2-carboxamide, or a pharmaceutically acceptable salt thereof.
24. A method of treating cell proliferative diseases or conditions comprising administering to a patient an effective amount of a pharmaceutical composition according to claim 1.
25. The method according to claim 24 wherein the cell proliferative diseases are cancers.
26. A method of inhibiting HIV in a cell comprising contacting the cell with a pharmaceutical composition according to any one of claim 1.
27. A method of inhibiting the spread of HIV in a cell population comprising contacting a cell infected with HIV that is a member of the cell population that also comprises uninfected cells with a pharmaceutical composition according to any one of claim 1.
28. A method of treating HIV in a patient comprising administering a pharmaceutical composition according to any one of claim 1.
29. A compound of the formula (III):
Figure imgf000076_0001
or a pharmaceutically acceptable salt thereof, wherein Ri is Ci-Ce alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, -aryl-W-aryl, -aryl-W-heterocyclyl, or heterocyclyl-W-aryl, wherein W is a bond, -0-, -S02-, or -C(=0)-; R2 is H, Cι-C6 alkyl, or is linked to a carbon of Ri through a carbonyl group; R4 and R6 are independently H, halogen, C(0)R7, NR8R9, nitro, Cι-6-alkyl, Ci.5-alkoxy, 0CF3, CF3, aryl, -C1-6-alkyl-aryi, heteroaryl, -C1-6-alkyl-heteroaryl, C(0)NR8R9, C(0)C(0)NR8R9, Cι-C6 alkyl-C(0)-NH-, NR8R9-S02- or Rι0-S02-;
R7 is hydrogen, Cι-6-alkyl, Ci-e-alkoxy, C(Z)-Rn where Z is CH2 or 0, heteroaryl, aryl, or a group of the formula
Figure imgf000076_0002
wherein n is 1 to 5 and each Rι2 is the same or different and is Ci-e-alkyl, hydroxy, halogen, nitro, oxo, amino, halo-Cι-6-aIkyl, Ci.6-alkoxy, halo-d-e-alkoxy, or cyano, NHC(0)-C1-6-alkyl, NHC(0)-C2.6-alkylene, C{0)-0-C1-6-aIkyl, or C(0)-aryl; R8 and R9 are independently hydrogen, or Ci-C6-alkyl; Rio is Cι-6-alkyl, Cι.6-alkyl-aryl, aryl, or heteroaryl; Rii is Ci-e-alkyl, Cι.6-alkyl-aryl, aryl, or NR8R9; with the proviso that R and R6 are not simultaneously hydrogen; and wherein each one of the alkyl, aryl, heteroaryl, or heterocyclyl of the above groups is optionally substituted with one or more groups selected from Cι.8-alkyl, C2-C6 alkenyl, hydroxy, halogen, nitro, oxo, amino, monoalkylamino, dialkylamino, halo-Cι.8-alkyl, Cι.8-alkoxy, halo-Ci-s-alkoxy, cyano, NHC(0)-C1-8-alkyi, NHC(0)-cycloalkyl, NHC(0)-C2.5-alkenyl, NHC(O)- aryl-C(0)-0-Ci-8-alkyl, C(0)-0-R13, -0-C(0)-Ci-C8 alkyl, or C(0)-aryl, wherein Ri3 is H or CrC8 alkyl, and two substituents on aryl, together with the atoms to which they are attached, optionally form a dioxane ring; provided that the compound is not: N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide; N-(5- methoxythiazolo[5,4-b]pyridin-2-yl)-4-methylbenzamide; or 4-chloro-N-(5-methoxythiazolo[5,4-b]pyridin- 2-yl)benzamide.
30. The compound of claim 29 wherein Ri is aryl.
31. The compound of claim 30 wherein Ri is phenyl, optionally substituted with 1, 2, or 3 groups independently selected from halogen, halo-CrCe alkyl, cyano, -N-C(0)-Cι-C6 alkyl, nitro, Cι-C6 alkoxy, and Cι-C6 alkyl.
32. The compound of claim 29 wherein Ri is furanyl or thiophene, which are optionally substituted with 1, 2, or 3 groups independently selected from halogen, halo-CrC6 alkyl, cyano, -N- C(0)-Cι-C6 alkyl, nitro, CrC6 alkoxy, and CrC6 alkyl.
33. The compound of claim 31 wherein R6 is hydrogen, and R is Cι-6-alkoxy.
34. The compound of claim 32 wherein R6 is hydrogen, and R4 is Ci-6-alkoxy.
35. A compound selected from the group consisting of: 3-methoxy-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide; N-(6-methoxybenzo[d]thiazol-2-yl)-3-methylbenzamide; 2-fluoro-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide; 2-methoxy-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide; 4-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)benzamide; N-(benzo[d]thiazol-2-yl)-2-(dimethylamino)benzamide; N-(6-methoxybenzo[d]thiazol-2-yl)-2,4-dimethylbenzamide; N-(benzo[d]thiazol-2-yl)-4-isopropylbenzamide;
(R)-N-(benzo[d]thiazol-2-yl)azetidine-2-carboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)piperidine-4-carboxamide;
N-(benzo[d]thiazol-2-yl)piperidine-4-carboxamide;
(R)-N-(6-methoxybenzo[d]thiazol-2-yl)indoline-2-carboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)indoline-2-carboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)isobutyramide;
N-(6-methoxybenzo[d]thiazol-2-yl)pivalamide;
N-(6-methoxybenzo[d]thiazol-2-yl)cyclobutanecarboxamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-2-(l-methyl-lH-indol-2-yl)acetamide;
3-fluoro-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-3-methylthiophene-2-carboxamide;
3-chloro-N-(6-methoxybenzo[d]thiazol-2-yl)thiophene-2-carboxamide; l-(4-cyanophenyl)-3-(6-methoxybenzo[d]thiazol-2-yl)urea;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)thiophene-2-carboxamide;
2,4-dichloro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
3-fluoro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
3-chloro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-3-methylthiophene-2-carboxamide;
3-chloro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)thiophene-2-carboxamide;
2,6-difluoro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
3,4-difluoro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-4-(trifluoromethyl)benzamide;
4-cyano-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
4-acetamido-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-4-nitrobenzamide;
4-methoxy-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)furan-2-carboxamide;
4-fluoro-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)benzamide;
N-(6-methoxybenzo[d]thiazol-2-yl)-lH-indole-2-carboxamide; and pharmaceutically acceptable salts thereof.
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