WO2019094732A1 - Inhibiteurs de protéine de liaison à un élément de réponse d'amp cyclique - Google Patents

Inhibiteurs de protéine de liaison à un élément de réponse d'amp cyclique Download PDF

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WO2019094732A1
WO2019094732A1 PCT/US2018/060048 US2018060048W WO2019094732A1 WO 2019094732 A1 WO2019094732 A1 WO 2019094732A1 US 2018060048 W US2018060048 W US 2018060048W WO 2019094732 A1 WO2019094732 A1 WO 2019094732A1
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optionally substituted
compound
alkyl
alkenyl
creb
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PCT/US2018/060048
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Ching-Shih Chen
Chia-Hsien Wu
I-Shan Hsieh
Po-Hsien Huang
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Academia Sinica
National Cheng Kung University
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Definitions

  • CREB cyclic- AMP response element-binding protein
  • CBP transcriptional co-activator
  • inhibitors for example, CHW-71, disrupt the interaction between CREB and CBP, leading to the proteasomal degradation of CREB and/or CBP and the downregulation of an array of CREB target gene products.
  • diseases associated with the binding of CREB to CBP e.g. , proliferative disease, or inflammatory disease
  • CREB cyclic-AMP response element-binding protein
  • the compounds are useful in treating and/or preventing diseases associated with the binding of CREB to CREB-binding protein (CBP) and/or the CREB-CBP pathway, e.g. , proliferative disease, or inflammatory disease, in a subject in need thereof.
  • CBP CREB-binding protein
  • each of R 1 , R 2 , R 3 , R 4 , and R 5 is independently H, halogen, alkylhalogen, C 1-6 alkyl, Ci-6 alkenyl, C 1-6 alkynyl, carbocyclyl, cycloalkenyl, heterocyclyl, -OH, alkoxyl, -NH 2 , alkylamino, amide, sulfonamide, urea, -CN, -NO2, trifluoromethyl, aryl, heteroaryl, -SH, - OSO2R, -S0 2 NR'R", -OC(0)R', C(0)OR, COR, or CONR'R", or two of R 1 , R 2 , R 3 , R 4 , or R 5 together with the atoms to which they are attached are combined to form an optionally substituted, 5- or 6-membered aryl or optionally substituted heterocyclic or heteroaryl ring;
  • X is -C- or -N-;
  • A is -NR'- or -0-
  • n 0 or 1 ;
  • a and R 5 are joined together with the atoms to which they are attached to form a optionally substituted heterocyclic ring;
  • Ring B is aryl, 5- or 6-membered heteroaryl, or monocyclic or bicyclic 5-10 membered heterocyclyl, each of which is optionally substituted by H, halogen, alkylhalogen, Ci-6 alkyl, Ci-6 alkenyl, Ci-6 alkynyl, carbocyclyl, cycloalkenyl, heterocyclyl, -OH, alkoxyl, - NH 2 , alkylamino, amide, sulfonamide, urea, cyano, nitro, trifluoromethyl, aryl, heteroaryl, - SH, -S0 2 NR'R", -OC(0)R', C(0)OR, COR, or CONR'R";
  • R is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R' is H, acyl, Ci-6 alkyl, Ci-6 alkenyl, or Ci-6 alkynyl;
  • R" is H, acyl, Ci-6 alkyl, Ci-6 alkenyl, or Ci-6 alkynyl.
  • exemplary compounds of Formula (I) include but are not limited to:
  • Exemplary compounds of Formula (I) include, but are not limited to:
  • a is 0, 1, 2, 3, 4, or 5;
  • each instance of R a is independently H, halogen, alkylhalogen, C 1-6 alkyl, C 1-6 alkenyl, Ci-6 alkynyl, carbocyclyl, cycloalkenyl, heterocyclyl, -OH, alkoxyl, -NH 2 , alkylamino, amide, sulfonamide, urea, cyano, nitro, trifluoromethyl, aryl, heteroaryl, -SH, -S0 2 NR'R", - OC(0)R', C(0)OR, COR, or CONR'R", wherein R, R' , and R" are as defined in Formula (I).
  • compositions including a compound described herein, and optionally a pharmaceutically acceptable excipient.
  • a pharmaceutical composition described herein includes a
  • a pharmaceutical composition described herein further comprises an additional pharmaceutical agent.
  • the pharmaceutical compositions may be useful in modulating (e.g., inhibiting) the binding of CREB to CBP in a subject, biological sample, tissue, or cell; in treating a disease (e.g. , a proliferative disease) in a subject in need thereof; or in preventing a disease in a subject in need thereof.
  • the disease is a disease associated with the CREB -CBP pathway. In certain embodiments, the disease associated with binding of CREB to CBP. In certain embodiments, the disease is a proliferative disease (e.g., cancer), or an inflammatory disease. In certain embodiments, the disease is cancer. In certain embodiments, the disease is lung cancer, breast cancer, leukemia, acute lymphoblastic leukemia, lymphoma, Burkitt' s lymphoma, melanoma, multiple myeloma, Ewing' s sarcoma, osteosarcoma, brain cancer, ovarian cancer, neuroblastoma, or colorectal cancer.
  • the disease is lung cancer, breast cancer, leukemia, acute lymphoblastic leukemia, lymphoma, Burkitt' s lymphoma, melanoma, multiple myeloma, Ewing' s sarcoma, osteosarcoma, brain cancer, ovarian cancer, neuroblastoma
  • the subject is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the cell is in vitro. In certain embodiments, the cell is in vivo. In certain embodiments, the subject is a human patient with a proliferative disease. In certain embodiments, the subject is a human patient having cancer. In certain embodiments, the subject is a human patient having triple-negative breast cancer. In certain embodiments, the subject is a human patient having lung cancer. In certain embodiments, the subject is a human patient having an inflammatory disease. In certain embodiments, the subject is a human patient having pancreatic fibrosis or liver fibrosis. In certain embodiments, the subject is a human patient having lung cancer, breast cancer, leukemia, acute
  • lymphoblastic leukemia lymphoma, Burkitt' s lymphoma, melanoma, multiple myeloma, Ewing's sarcoma, osteosarcoma, brain cancer, ovarian cancer, neuroblastoma, or colorectal cancer.
  • kits including a container with a compound or pharmaceutical composition described herein.
  • a kit described herein may include a single dose or multiple doses of the compound or pharmaceutical composition.
  • the described kits may be useful in inhibiting the binding of CREB to CBP in a subject, biological sample, tissue, or cell, in treating a disease associated with the CREB-CBP pathway in a subject in need thereof, in preventing a disease associated with the CREB-CBP pathway in a subject in need thereof, in treating a disease (e.g. , proliferative disease, inflammatory disease) in a subject in need thereof, and/or in preventing a disease (e.g. , proliferative disease, inflammatory disease) in a subject in need thereof.
  • a disease e.g. , proliferative disease, inflammatory disease
  • kits described herein further includes instructions for using the compound or pharmaceutical composition included in the kit.
  • a kit described herein includes compounds described herein, or a pharmaceutically acceptable salt, co- crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, or a pharmaceutical composition described herein, and instructions for using the compound or pharmaceutical composition included in the kit.
  • the present disclosure provides methods of modulating (e.g. , inhibiting) the binding of CREB to CBP in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.
  • the present disclosure provides methods of modulating (e.g. , inhibiting) the binding of CREB to CBP in a biological sample, tissue, or cell, the methods comprising contacting the biological sample, tissue, or cell with an effective amount of a compound or pharmaceutical composition described herein.
  • the compound being administered or used to the subject or biological sample selectively inhibits the binding of CREB to CBP.
  • a compound, pharmaceutical composition, method, use, or kit is referred to as “selectively,” “specifically,” or “competitively” inhibiting the binding of CREB to CBP
  • the compound, pharmaceutical composition, method, use, or kit inhibits the binding of CREB to CBP to a greater extent (e.g.
  • not less than 2-fold not less than 5-fold, not less than 10-fold, not less than 30-fold, not less than 100-fold, not less than 1,000-fold, or not less than 10,000-fold; and/or: not more than 2- fold, not more than 5-fold, not more than 10-fold, not more than 30-fold, not more than 100- fold, not more than 1,000-fold, or not more than 10,000-fold) than inhibiting the binding of CREB to a different protein.
  • Another aspect of the present disclosure relates to methods of treating a disease in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.
  • the present disclosure provides methods of preventing a disease in a subject in need thereof, the methods comprising administering to the subject a
  • Another aspect of the present disclosure relates to methods of inhibiting the binding of CREB to CBP in a subject in need thereof, the methods comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein.
  • Another aspect of the present disclosure relates to methods of inhibiting the binding of CREB to CBP in a biological sample, tissue, or cell, the methods comprising contacting the biological sample, tissue, or cell with an effective amount of a compound or pharmaceutical composition described herein.
  • the present disclosure provides compounds and pharmaceutical compositions described herein for use in a method of the disclosure (e.g., a method of inhibiting the binding of CREB to CBP, a method of treating a disease (e.g., a proliferative disease), or a method of preventing a disease (e.g., a proliferative disease).
  • a method of the disclosure e.g., a method of inhibiting the binding of CREB to CBP, a method of treating a disease (e.g., a proliferative disease), or a method of preventing a disease (e.g., a proliferative disease).
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al.,
  • ⁇ - ⁇ is intended to encompass, Ci, C 2 , C 3 , C 4 , C5, C 6 , Ci-6, Ci-5, Ci ⁇ , Ci- 3 , Ci- 2 , C 2 -6, C2-5, C2- , C2-3, C3-6, C3-5, C 3 ⁇ , C4-6, C4-5, and C5-6.
  • aliphatic includes both saturated and unsaturated, straight chain (i.e. , unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups.
  • aliphatic is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
  • alkyl includes straight, branched and cyclic alkyl groups.
  • alkyl alkenyl
  • alkynyl alkynyl
  • lower alkyl is used to indicate those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-6 aliphatic carbon atoms. In yet other
  • the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-4 carbon atoms.
  • Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl, vinyl, allyl, n-butyl, sec- butyl, isobutyl, tert-butyl, cyclobutyl, -CH 2 -cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert- pentyl, cyclopentyl, -CH 2 -cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH 2 -cyclohexyl moieties and the like, which again, may bear one or more substituents.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2- propynyl (propargyl), 1-propynyl, and the like.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“O-io alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("O-s alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-5 alkyl”).
  • an alkyl group has 1 to 4 carbon atoms ("Ci ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of Ci-6 alkyl groups include methyl (O), ethyl (C2), propyl (C3) (e.g. , n-propyl, isopropyl), butyl (C 4 ) (e.g.
  • alkyl groups include n-heptyl (C 7 ), n- octyl (Cs), and the like.
  • each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g. , halogen, such as F).
  • the alkyl group is an unsubstituted Cuo alkyl (such as unsubstituted Ci- ⁇ alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g.
  • the alkyl group is a substituted Cuo alkyl (such as substituted C 1-6 alkyl, e.g. , -CF3, Bn).
  • alkylhalogen refers to an alkyl group substituted with halogen.
  • alkylamino refers to an alkyl group substituted with an amine group.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2-20 alkenyl”).
  • an alkenyl group has 2 to 10 carbon atoms ("C2-10 alkenyl”).
  • an alkenyl group has 2 to 9 carbon atoms ("C2-9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms ("C2-5 alkenyl"). In some
  • an alkenyl group has 2 to 4 carbon atoms ("C2- alkenyl").
  • an alkenyl group has 2 to 3 carbon atoms ("C2-3 alkenyl").
  • an alkenyl group has 2 carbon atoms ("C2 alkenyl”).
  • the one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2-A alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C 6 ), and the like.
  • alkenyl examples include heptenyl (C 7 ), octenyl (Cs), octatrienyl (Cs), and the like.
  • each instance of an alkenyl group is independently optionally substituted, i.e. , unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents.
  • the alkenyl group is unsubstituted C2-10 alkenyl.
  • the alkenyl group is substituted C2-10 alkenyl.
  • a C C double bond for which the
  • ma y be an (E)- or (Z)- double bond.
  • Alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C2-20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms ("C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2 ⁇ alkynyl”). In some
  • an alkynyl group has 2 to 3 carbon atoms ("C2-3 alkynyl").
  • an alkynyl group has 2 carbon atoms ("C2 alkynyl").
  • the one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2- alkynyl groups as well as pentynyl (C5), hexynyl (C 6 ), and the like.
  • alkynyl examples include heptynyl (C 7 ), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e. , unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-10 alkynyl.
  • Carbocyclyl or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C3-10 carbocyclyl") and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 8 ring carbon atoms ("C3-8 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”).
  • a carbocyclyl group has 5 to 10 ring carbon atoms ("C5-10 carbocyclyl").
  • Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ),
  • C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-lH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated.
  • Carbocyclyl also includes ring systems wherein the carbocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclic ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently optionally substituted, i.e.,
  • the carbocyclyl group is unsubstituted C3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is substituted C3-10 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6 cycloalkyl").
  • a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-10 cycloalkyl").
  • C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5).
  • C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C 4 ).
  • Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (Cs).
  • each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents.
  • the cycloalkyl group is unsubstituted C3-10 cycloalkyl.
  • the cycloalkyl group is substituted C3-10 cycloalkyl.
  • Heterocyclyl or “heterocyclic” refers to a radical of a 3- to 10-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered heterocyclyl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclic ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclic ring, or ring systems wherein the heterocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such instances, the number of ring members continue to designate the number of ring members in the
  • heterocyclic ring system Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a "substituted heterocyclyl”) with one or more substituents.
  • each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a "substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl").
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl").
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7- membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5- membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Aryl refers to a radical of a monocyclic or polycyclic (e.g. , bicyclic or tricyclic) 4n+2 aromatic ring system (e.g. , having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-14 aryl").
  • an aryl group has six ring carbon atoms ("C6 aryl”; e.g. , phenyl).
  • an aryl group has ten ring carbon atoms ("Cio aryl"; e.g.
  • an aryl group has fourteen ring carbon atoms ("Ci 4 aryl”; e.g. , anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently optionally substituted, i.e. , unsubstituted (an "unsubstituted aryl") or substituted (a
  • substituted aryl with one or more substituents.
  • the aryl group is unsubstituted Ce-i4 aryl.
  • the aryl group is substituted C 6 -i4 aryl.
  • Aralkyl is a subset of alkyl and aryl and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. In certain embodiments, the aralkyl is optionally substituted benzyl. In certain embodiments, the aralkyl is benzyl. In certain embodiments, the aralkyl is optionally substituted phenethyl. In certain embodiments, the aralkyl is phenethyl.
  • Heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g. , having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g. , indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e. , either the ring bearing a heteroatom (e.g. , 2-indolyl) or the ring that does not contain a heteroatom (e.g. , 5- indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently optionally substituted, i.e.
  • the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Heteroaralkyl is a subset of alkyl and heteroaryl and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.
  • Unsaturated or “partially unsaturated” refers to a group that includes at least one double or triple bond.
  • a “partially unsaturated” ring system is further intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g. , aryl or heteroaryl groups).
  • saturated refers to a group that does not contain a double or triple bond, i.e. , contains all single bonds.
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, which are divalent bridging groups, are further referred to using the suffix -ene, e.g. , alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g.
  • substituted or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, "substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, "substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
  • substituted whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g.
  • a carbon or nitrogen atom is replaced with a permissible substituent, e.g. , a substituent which upon substitution results in a stable compound, e.g. , a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the substituent is a carbon atom substituent.
  • the substituent is a nitrogen atom substituent.
  • the substituent is an oxygen atom substituent.
  • the substituent is a sulfur atom substituent.
  • each instance of is, independently, selected from Ci-10 alkyl, Ci-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-ioalkenyl, heteroC2-ioalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6 -i4 aryl, and 5-14 membered heteroaryl, or two groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkyl, alkynyl, heteroCi-10 alkyl, heteroC2-ioalkenyl, heteroC2-ioalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6 -i4 aryl, and 5-14 membered heteroaryl, or two groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered hetero
  • each instance of R bb is, independently, selected from hydrogen, -OH, -OR aa ,
  • each instance of R cc is, independently, selected from hydrogen, Ci-10 alkyl, Ci-10 perhaloalkyl, C 2 -io alkenyl, C 2 -io alkynyl, heteroCi-10 alkyl, heteroC 2 -io alkenyl, heteroC 2 -io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6 -i4 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R ee is, independently, selected from C 1-6 alkyl, C 1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6alkenyl, heteroC 2 -6 alkynyl, C3-10
  • each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R ff is, independently, selected from hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6alkyl, heteroC 2 -6alkenyl, heteroC 2 -6alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6 -io aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
  • heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • a "counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
  • An anionic counterion may be monovalent (i.e., including one formal negative charge).
  • An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent.
  • Exemplary counterions include halide ions (e.g. , F , CI “ , Br “ , ⁇ ), NO3 , C10 4 " , OH “ , H 2 P0 4 , HC03 ⁇ HS0 4 , sulfonate ions (e.g.
  • Exemplary counterions which may be multivalent include C03 2- , HP0 4 2_ , P0 4 3_ , B 4 07 2_ , S0 4 2_ , S 2 03 2_ , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • Halo or "halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), or iodine (iodo, -I).
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR 2121 , -N(R CC ) 2 , -CN,
  • the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an "amino protecting group").
  • heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R aa , R bb , R cc and R dd are as defined herein.
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t- butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)] methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l
  • TBOC 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l- methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benz
  • Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7, 8-pentamethylchroman-6-sulfonamide (Pmc), methanes
  • Ts p-toluenesulfonamide
  • Mtr 2,
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N- benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2- one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5- triazacyclohexan-2-one, 1 -substituted
  • Dpp diphenylphosphinamide
  • Mpt dimethylthiophosphinamide
  • diphenylthiophosphinamide Ppt
  • dialkyl phosphoramidates dibenzyl phosphoramidate, diphenyl phosphoramidate
  • benzenesulfenamide o-nitrobenzenesulfenamide
  • Nps 2,4- dinitrobenzenesulfenamide
  • pentachlorobenzenesulfenamide 2-nitro-4- methoxybenzenesulfenamide
  • triphenylmethylsulfenamide triphenylmethylsulfenamide
  • 3-nitropyridinesulfenamide Npys
  • a "leaving group” is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule.
  • a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502).
  • Exemplary leaving groups include, but are not limited to, halo (e.g. , chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g.
  • a “hydrocarbon chain” refers to a substituted or unsubstituted divalent alkyl, alkenyl, or alkynyl group.
  • a hydrocarbon chain includes (1) one or more chains of carbon atoms immediately between the two radicals of the hydrocarbon chain; (2) optionally one or more hydrogen atoms on the chain(s) of carbon atoms; and (3) optionally one or more substituents ("non-chain substituents," which are not hydrogen) on the chain(s) of carbon atoms.
  • a chain of carbon atoms consists of consecutively connected carbon atoms ("chain atoms”) and does not include hydrogen atoms or heteroatoms.
  • a non-chain substituent of a hydrocarbon chain may include any atoms, including hydrogen atoms, carbon atoms, and heteroatoms.
  • hydrocarbon chain -C A H(C B H 2 C C H 3 )- includes one chain atom C A , one hydrogen atom on C A , and non-chain substituent -(C B H 2 C C H 3 ).
  • C x hydrocarbon chain wherein x is a positive integer, refers to a hydrocarbon chain that includes x number of chain atom(s) between the two radicals of the hydrocarbon chain. If there is more than one possible value of x, the smallest possible value of x is used for the definition of the hydrocarbon chain.
  • -CH(C 2 Hs)- is a Ci hydrocarbon chain
  • a C3-10 hydrocarbon chain refers to a hydrocarbon chain where the number of chain atoms of the shortest chain of carbon atoms immediately between the two radicals of the hydrocarbon chain is 3, 4, 5, 6, 7, 8, 9, or 10.
  • a hydrocarbon chain may be saturated (e.g. , -(CH 2 ) 4 -).
  • the hydrocarbon chain is substituted (e.g. , -CH(C 2 Hs)- and -CF2-). Any two substituents on the hydrocarbon chain may be joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring.
  • ⁇ is a C 3 hydrocarbon chain wherein one chain atom is replaced with an oxygen atom.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci ⁇ alkyl) 4 " salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds described herein may be prepared, e.g. , in crystalline form, and may be solvated. Suitable solvates include
  • solvates and further include both stoichiometric solvates and non-stoichiometric solvates.
  • the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
  • Solvate encompasses both solution-phase and isolatable solvates.
  • Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is associated with water.
  • the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R x H 2 0, wherein R is the compound, and x is a number greater than 0.
  • a given compound may form more than one type of hydrate, including, e.g. , monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1 , e.g.
  • hemihydrates R-0.5 H 2 0
  • polyhydrates x is a number greater than 1, e.g. , dihydrates (R-2 H 2 0) and hexahydrates (R-6 H 2 0)).
  • tautomers refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g. , a single bond to a double bond, a triple bond to a single bond, or vice versa).
  • the exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e. , the reaction providing a tautomeric pair) may catalyzed by acid or base.
  • Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
  • isomers compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers”. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers”.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimpo sable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • polymorphs refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
  • prodrugs refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Ci-Cs alkyl, d-Cs alkenyl, C 2 -C 8 alkynyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds described herein may be preferred.
  • small molecule refers to molecules, whether naturally-occurring or artificially created (e.g. , via chemical synthesis) that have a relatively low molecular weight.
  • a small molecule is an organic compound (i.e. , it contains carbon).
  • the small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g. , amines, hydroxyl, carbonyls, and heterocyclic rings, etc.).
  • functional groups e.g. , amines, hydroxyl, carbonyls, and heterocyclic rings, etc.
  • the molecular weight of a small molecule is not more than about 1,000 g/mol, not more than about 900 g/mol, not more than about 800 g/mol, not more than about 700 g/mol, not more than about 600 g/mol, not more than about 500 g/mol, not more than about 400 g/mol, not more than about 300 g/mol, not more than about 200 g/mol, or not more than about 100 g/mol.
  • the molecular weight of a small molecule is at least about 100 g/mol, at least about 200 g/mol, at least about 300 g/mol, at least about 400 g/mol, at least about 500 g/mol, at least about 600 g/mol, at least about 700 g/mol, at least about 800 g/mol, or at least about 900 g/mol, or at least about 1,000 g/mol. Combinations of the above ranges (e.g. , at least about 200 g/mol and not more than about 500 g/mol) are also possible.
  • the small molecule is a therapeutically active agent such as a drug (e.g. , a molecule approved by the U.S.
  • the small molecule may also be complexed with one or more metal atoms and/or metal ions.
  • the small molecule is also referred to as a "small organometallic molecule.”
  • Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents.
  • the small molecule is a drug.
  • the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R.
  • small molecule drug refers to a small molecule that has been approved by a governmental agency (e.g., FDA) for administering to a subject (e.g., human or non-human animal), or a radical of such a small molecule.
  • the term “inhibit” or “inhibition” in the context of enzymes, for example, in the context of CREB, refers to a reduction in the binding of CREB to CBP. In some embodiments, the term refers to a reduction of the level of binding of CREB to CBP, e.g. , to a level that is statistically significantly lower than an initial level binding of CREB to CBP, which may, for example, be a baseline level of binding of CREB to CBP.
  • the term refers to a reduction of the level of binding of CREB to CBP, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of binding of CREB to CBP.
  • a compound, pharmaceutical composition, method, use, or kit When a compound, pharmaceutical composition, method, use, or kit is referred to as “selectively,” “specifically,” or “competitively” inhibiting the binding of CREB to CBP, the compound, pharmaceutical composition, method, use, or kit inhibits the binding of to a greater extent (e.g. , not less than 2-fold, not less than 5-fold, not less than 10-fold, not less than 30-fold, not less than 100-fold, not less than 1,000-fold, or not less than 10,000-fold; and/or: not more than 2-fold, not more than 5-fold, not more than 10-fold, not more than 30- fold, not more than 100-fold, not more than 1,000-fold, or not more than 10,000-fold) than inhibiting the binding of CREB to a different protein.
  • a greater extent e.g. , not less than 2-fold, not less than 5-fold, not less than 10-fold, not less than 30-fold, not less than 100-fold, not less than 1,000-fold, or not more
  • composition and “formulation” are used interchangeably.
  • a "subject" to which administration is contemplated refers to a human (i.e. , male or female of any age group, e.g. , pediatric subject (e.g. , infant, child, or adolescent) or adult subject (e.g. , young adult, middle-aged adult, or senior adult)) or non-human animal.
  • the non-human animal is a mammal (e.g. , primate (e.g. , cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g. , cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g.
  • the non-human animal is a fish, reptile, or amphibian.
  • the non-human animal may be a male or female at any stage of development.
  • the non-human animal may be a transgenic animal or genetically engineered animal.
  • a "patient" refers to a human subject in need of treatment of a disease.
  • the subject may also be a plant.
  • the plant is a land plant.
  • the plant is a non-vascular land plant.
  • the plant is a vascular land plant.
  • the plant is a seed plant.
  • the plant is a cultivated plant.
  • the plant is a dicot.
  • the plant is a monocot. In certain embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, e.g. , maize, corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, the plant is a legume, e.g. , a bean plant, e.g. , soybean plant. In some embodiments, the plant is a tree or shrub.
  • tissue samples such as tissue sections and needle biopsies of a tissue
  • cell samples e.g. , cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
  • Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g. , obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein.
  • treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease.
  • treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g. , in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • prevent refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease.
  • the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.
  • an "effective amount" of a compound described herein refers to an amount sufficient to elicit the desired biological response.
  • An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactic treatment.
  • an effective amount is the amount of a compound described herein in a single dose.
  • an effective amount is the combined amounts of a compound described herein in multiple doses.
  • a “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a prophylactically effective amount of a compound described herein is an amount effective to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • cyclic-AMP response element-binding protein refers to a nuclear transcription factor activated by phosphorylation at Serl33 by multiple kinases. Once phosphorylated, CREB enters the nucleus and binds the transcriptional co-activator, CREB- binding protein (CBP), to initiate CREB -dependent transcriptional activation of genes related to the regulation of cell differentiation, proliferation and survival.
  • CBP CREB-binding protein
  • a "proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology;
  • a proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g. , metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix
  • proliferative diseases include cancers (i.e. , "malignant neoplasms"), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases).
  • malignant neoplasms e.g., "malignant neoplasms”
  • benign neoplasms e.g., angiogenesis
  • inflammatory diseases e.g., IL-12, IL-12, and autoimmune diseases.
  • autoimmune diseases include cancers (i.e. , "malignant neoplasms"), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases).
  • “Triple-negative breast cancer” refers to cancer that tests negative for estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 (HER2).
  • HER2 human epidermal growth factor receptor 2
  • cancer refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See, e.g. , Stedman 's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990.
  • Exemplary cancers include, but are not limited to, hematological malignancies. Additional exemplary cancers include, but are not limited to, lung cancer (e.g.
  • kidney cancer e.g., nephroblastoma, a.k.a. Wilms' tumor, renal cell carcinoma
  • acoustic neuroma e.g., adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g. , lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g. , cholangiocarcinoma); bladder cancer; breast cancer (e.g.
  • adenocarcinoma of the breast papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast
  • brain cancer e.g. , meningioma, glioblastomas, glioma (e.g. , astrocytoma,
  • adenocarcinoma adenocarcinoma
  • Ewing's sarcoma ocular cancer (e.g. , intraocular melanoma,
  • retinoblastoma familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g. , stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g. , head and neck squamous cell carcinoma, oral cancer (e.g. , oral squamous cell carcinoma), throat cancer (e.g. , laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); heavy chain disease (e.g.
  • gastric cancer e.g. , stomach adenocarcinoma
  • GIST gastrointestinal stromal tumor
  • germ cell cancer e.g. , head and neck squamous cell carcinoma, oral cancer (e.g. , oral squamous cell carcinoma), throat cancer (e.g. , laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer
  • liver cancer e.g. , hepatocellular cancer (HCC), malignant hepatoma); leiomyosarcoma (LMS); mastocytosis (e.g. , systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g.
  • PV polycythemia vera
  • EMT essential thrombocytosis
  • AMM agnogenic myeloid metaplasia
  • MF myelofibrosis
  • CML chronic myelocytic leukemia
  • CTL chronic neutrophilic leukemia
  • HES hypereosinophilic syndrome
  • neuroblastoma neurofibroma (e.g. , neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g.
  • gastroenteropancreatic neuroendocrine tumor GEP-NET
  • carcinoid tumor carcinoid tumor
  • osteosarcoma e.g., bone cancer
  • ovarian cancer e.g. , cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma
  • papillary adenocarcinoma pancreatic cancer
  • pancreatic cancer e.g. , pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors
  • penile cancer e.g.
  • MPNST chondrosarcoma, fibrosarcoma, myxosarcoma
  • sebaceous gland carcinoma small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g. , seminoma, testicular embryonal carcinoma); thyroid cancer (e.g. , papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g. , Paget' s disease of the vulva).
  • testicular cancer e.g. , seminoma, testicular embryonal carcinoma
  • thyroid cancer e.g. , papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer
  • urethral cancer urethral cancer
  • vaginal cancer e.g. , Paget' s disease of the vulva
  • inflammatory disease refers to a disease caused by, resulting from, or resulting in inflammation.
  • inflammatory disease may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and/or T-lymphocytes leading to abnormal tissue damage and/or cell death.
  • An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes.
  • Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, pancreatic fibrosis, liver fibrosis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g.
  • FIG. 1 includes diagrams showing activity of putative CREB inhibitors determined bya luciferase reporter assay.
  • MDA-MB-23 cells were seeded into 12- well plates (1 x 105 cells/well) and transfected with the CRE reporter plasmids (CCS-002L, Qiagen, Valencia, CA) for 48 hours. After 24 hours, cells were treated with ASE (i) and 71 CHW-series compounds at the 5 ⁇ for another 48 hours. The pRenilla lucif erase plasmid was used as the internal control for normalization. The transcriptional activity for each compound was determined by adding D-luciferin to cell lysates, and the bioluminescence signal was detected with a microplate luminometer (Promega, Madison, WI). # denotes the lucif erase activity > 150%.
  • FIG. 2 is a chart showing in vitro efficacies of representative compounds relative to that of AS-E in inhibiting the viability of MDA-MB-231 cells after 72 hours of treatment by the compounds as indicated in 5% FBS -containing medium determined by MTT assays, of the in vitro derivatives of the compound library, relative to AS-E, in.
  • FIG. 3 is a photo showing the ability of ASE versus CHW-10 and CHW-71 to disrupt the association of CREB with CBP as determined by co-immunoprecipitation analysis.
  • 2 x 106 cells of MDA-MB-231 cells were seeding in 15cm culture dish in DMEM culture medium with 10% FBS for 24 hours then treated with DMSO (D*), AS-E (I, 5 ⁇ ), CHW- 10 (2.5 ⁇ ), or CHW-71 (2.5 ⁇ ) for 72 hours.
  • Cells were harvested by using PBS and lysed with lysis buffer (20mM Tris-HCl pH 7.5, 150mM NaCl, 10% Triton X-100, ImM PMSF, and ImM Na3V04) for 30 minutes at 4 °C.
  • the protein samples were incubated with protein A/G agarose beads (Santa Cruz Biotechnology, Inc, Santa Cruz, CA) to remove nonspecific binding. Equal amount of the protein samples were incubated with agarose beads conjugated with rabbit anti-CBP antibodies (Cell Signaling Technology, Inc., Danvers, MA) overnight.
  • Agarose beads were washed three times with wash buffer (20mM Tris-HCl pH 7.5, 150mM NaCl, 0.5% Triton X-100) and resuspended in SDS sample buffer for immunoblotting analysis by using antibodies against CBP, CREB, b-catenin, p53, and ⁇ - actin.
  • wash buffer (20mM Tris-HCl pH 7.5, 150mM NaCl, 0.5% Triton X-100
  • SDS sample buffer for immunoblotting analysis by using antibodies against CBP, CREB, b-catenin, p53, and ⁇ - actin.
  • Nonspecific IgG (Santa Cruz Biotechnology, Inc, Santa Cruz, CA) was used in the immunoprecipitation step as a negative control.
  • FIG. 4 is a photo showing the concentration-dependent suppressive effect of CHW-71 (left) versus shRNA-mediated knockdown of CREB or CBP (right) on the
  • Left panel a chart showing tumor volume change in the course of treatment.
  • Right panel a phone showing tumor volumes in mice treated with the compound at the indicated doses.
  • FIG. 6 is a photo showing the concentration-dependent suppressive effect of CHW-71 on the expression/phosphorylation of gpl30, EGFR, c-Jun, Jak2, and Stat3 in two lung cancer cell lines as determined by Western blot analysis.
  • FIG. 7 is a schematic illustration of an exemplary process for inducing acute pancreatic fibrosis in a mouse model
  • FIGs. 8A to 8B include diagrams showing therecovery of intensive cerulean-induction showed mild to severe pancreatic fibrosis in KC mice, but not in the wild type mice or unstimulated KC mice.
  • FIG. 8A KC mice treated with or without cerulein resolved fibrosis differently.
  • FIG. 8B Wild-type mice treated with cerulein showed maintained pancreatic acinar architecture with no signs of fibrosis.
  • FIGs. 9A to 9B include diagrams showing that administration of CHW-71 via 25 mg/kg i.p. (FIG. 9A); and 100 mg/kg p.o. (FIG. 9B) decreased the percentage of area of fibrosis regions in the acute pancreatitis model.
  • FIG. 10 is a photo showing that CHW-71 inhibits the CREB and fibroblast makers expression in LX2 cells.
  • FIG. 11 is a photo showing that CHW-71 induces LX-2 cells senescence via a STAT3-dependent mechanism.
  • CHW-71 -induced SA-P-Gal activities were as an indication for LX2 senescence as endogenous lysosomal beta-galactosidase exists specifically in senescent cells.
  • FIG. 12 is a photo showing the effects of exemplary compound CHW-71 on the phosphorylation/expression levels of CBP, CREB, gpl30, EGFR, c-jun, JAK2, Stat3 as well as CREB downstream targets CyclinA, Cyclin Dl, and Bcl-2 in tumor lysates from nude mice-bearing MDA-MB-231 subcutaneous tumors and treated with vehicle, compound CHW-71 at 50 mpk, or compound CHW-71 at 100 mpk as determined by Western blot analysis.
  • FIGs. 13A and 13B include diagrams showing the effects of compound CHW-71 via 100 mg/kg p.o. (FIGs. 13A and 13B) on mice in an acute pancreatitis model, including decreased percentage of area of fibrosis regions.
  • FIG. 13A and FIG.13B shows the decreased percentage of area of fibrosis regions.
  • Described herein are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.
  • compounds of Formula (I), and pharmaceutically acceptable salts thereof are inhibitors of CREB binding to CBP and are useful in modulating (e.g. , inhibiting) the binding of CREB to CBP in a subject, biological sample, tissue, or cell.
  • the compounds may be useful in treating or preventing a disease (e.g.
  • compositions, kits, and uses including a compound described herein.
  • One aspect of the present disclosure relates to the compounds described herein.
  • the compounds described herein are inhibitors of CREB.
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, L, A, Ring B, and n are defined herein.
  • X is -C-. In some embodiments, X is -N-.
  • R 1 is H.
  • R 1 is halogen (e.g. , F, CI, Br, or I).
  • R 1 is alkylhalogen (e.g. , -CH 2 (halogen) (e.g. , - CH 2 C1)).
  • R 1 is Ci-6 alkyl (e.g. , Me, Et, n-propyl).
  • R is C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, cycloalkenyl, or heterocyclyl.
  • R 1 is -OH.
  • R 1 is alkoxyl (e.g. , -OMe). In some embodiments, R 1 is -NH 2 , alkylamino, amide, sulfonamide, urea, -CN, -NO2, trifluoromethyl, aryl, heteroaryl, -SH, -S0 2 NR'R", -OC(0)R' , C(0)OR, COR, or CONR'R", or two of R 1 , R 2 , R 3 , R 4 , or R 5 together with the atoms to which they are attached are combined to form an optionally substituted, 5- or 6-membered aryl or optionally substituted heterocyclic or heteroaryl ring.
  • each of R 1 , R 2 , R 3 , R 4 , and R 5 is independently H, halogen, alkylhalogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, cycloalkenyl, heterocyclyl, -OH, alkoxyl, -NH 2 , alkylamino, amide, sulfonamide, urea, -CN, -NO2, trifluoromethyl, aryl, heteroaryl, -SH, -OSO2R, -S0 2 NR'R", -OC(0)R' , C(0)OR, COR, or CONR'R", or two of R 1 , R 2 , R 3 , R 4 , or R 5 together with the atoms to which they are attached are combined to form an optionally substituted, 5- or 6-membered aryl or optionally substituted heterocyclic or hetero
  • R 2 is H.
  • R 2 is halogen (e.g. , F, CI, Br, or I).
  • R 2 is alkylhalogen.
  • R 2 is Ci-6 alkyl (e.g. , Me, Et, n-Propyl).
  • R 2 is C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, cycloalkenyl, or heterocyclyl.
  • R 2 is -OH.
  • R 2 is alkoxyl (e.g. , -OMe).
  • R 2 is -NH 2 , alkylamino, amide, sulfonamide, urea, -CN, -NO2, trifluoromethyl, aryl, heteroaryl, -SH, -S0 2 NR'R", - OC(0)R', C(0)OR, COR, or CONR'R", or two of R 1 , R 2 , R 3 , R 4 , or R 5 together with the atoms to which they are attached are combined to form an optionally substituted, 5- or 6- membered aryl or optionally substituted heterocyclic or heteroaryl ring.
  • R 3 is H.
  • R 3 is halogen (e.g., F, CI, Br, or I).
  • R 3 is alkylhalogen.
  • R 3 is Ci-6 alkyl (e.g. , Me, Et, n-propyl).
  • R 3 is Ci- ⁇ alkenyl, C 1-6 alkynyl, carbocyclyl, cycloalkenyl, or heterocyclyl.
  • R 3 is -OH.
  • R 3 is alkoxyl (e.g., -OMe).
  • R 3 is -NH 2 , alkylamino, amide, sulfonamide, urea, -CN, -NO2, trifluoromethyl, aryl, heteroaryl, -SH, -S0 2 NR'R", - OC(0)R', C(0)OR, COR, or CONR'R", or two of R 1 , R 2 , R 3 , R 4 , or R 5 together with the atoms to which they are attached are combined to form an optionally substituted, 5- or 6- membered aryl or optionally substituted heterocyclic or heteroaryl ring.
  • R 4 is H.
  • R 4 is halogen (e.g. , F, CI, Br, or I). In some embodiments, R 4 is alkylhalogen. In some embodiments, R 4 is Ci-6 alkyl (e.g. , Me, Et, n-Propyl). In some embodiments, R 4 is Ci-6 alkenyl, Ci-6 alkynyl, carbocyclyl, cycloalkenyl, or heterocyclyl. In some embodiments, R 4 is -OH. In some embodiments, R 4 is alkoxyl (e.g. , -OMe).
  • R 4 is halogen (e.g. , F, CI, Br, or I). In some embodiments, R 4 is alkylhalogen. In some embodiments, R 4 is Ci-6 alkyl (e.g. , Me, Et, n-Propyl). In some embodiments, R 4 is Ci-6 alkenyl, Ci-6 alkynyl, carbocyclyl, cycloalkeny
  • R 4 is -NH 2 , alkylamino, amide, sulfonamide, urea, -CN, -N0 2 , trifluoromethyl, aryl, heteroaryl, -SH, -S0 2 NR'R", - OC(0)R', C(0)OR, COR, or CONR'R", or two of R 1 , R 2 , R 3 , R 4 , or R 5 together with the atoms to which they are attached are combined to form an optionally substituted, 5- or 6- membered aryl or optionally substituted heterocyclic or heteroaryl ring.
  • R 5 is H.
  • R 5 is halogen (e.g. , F, CI, Br, or I).
  • R 5 is alkylhalogen.
  • R 5 is Ci-6 alkyl (e.g. , Me, Et, n-propyl).
  • R 5 is Ci-6 alkenyl, Ci-6 alkynyl, carbocyclyl, cycloalkenyl, or heterocyclyl.
  • R 5 is -OH.
  • R 5 is alkoxyl (e.g., -OMe).
  • R 5 is Ci-6 alkoxyl.
  • R 5 is -NH 2 , alkylamino, amide, sulfonamide, urea, -CN, -N0 2 , trifluoromethyl, aryl, heteroaryl, -SH, -S0 2 NR'R", -OC(0)R' , C(0)OR, COR, or CONR'R", or two of R 1 , R 2 , R 3 , R 4 , or R 5 together with the atoms to which they are attached are combined to form an optionally substituted, 5- or 6-membered aryl or optionally substituted heterocyclic or heteroaryl ring.
  • R 5 is -C(0)OR.
  • R 5 is - C(0)OH.
  • R 5 is -OH, -C(0)OH, or Ci_ 6 alkoxyl.
  • R 5 is -OS0 2 R, where R is optionally substituted Ci-6 alkyl or optionally substituted aryl.
  • R 5 is -OS0 2 (Me) or -OS0 2 (phenyl).
  • R 5 is H, halogen, alkylhalogen, Ci-6 alkyl, Ci-6 alkenyl, Ci-6 alkynyl, carbocyclyl, cycloalkenyl, heterocyclyl, -OH, alkoxyl, -NH 2 , alkylamino, amide,
  • R 1 , R 2 , R 3 , R 4 , or R 5 together with the atoms to which they are attached are combined to form an optionally substituted, 5- or 6-membered aryl or optionally substituted heterocyclic or heteroaryl ring.
  • R 1 and R 2 , together with the atoms to which they are attached are combined to form an optionally substituted phenyl ring.
  • R 1 and R 2 , together with the atoms to which they are attached are combined to form an unsubstituted phenyl ring.
  • R 2 and R 3 together with the atoms to which they are attached are combined to form an optionally substituted phenyl ring.
  • R 3 and R 4 together with the atoms to which they are attached are combined to form an optionally substituted phenyl ring.
  • R 4 and R 5 together with the atoms to which they are attached are combined to form an optionally substituted phenyl ring.
  • two of R 1 , R 2 , R 3 , R 4 , or R 5 together with the atoms to which they are attached are combined to form an optionally substituted, heterocyclic or heteroaryl ring.
  • R 1 and R 2 together with the atoms to which they are attached are combined to form an optionally substituted, heterocyclic ring.
  • R 4 and R 5 together with the atoms to which they are attached are combined to form an optionally substituted, heterocyclic ring.
  • R 1 and R 2 together with the atoms to which they are attached are combined to form an optionally substituted, heteroaryl ring, (e.g. , optionally substituted pyridyl ring).
  • R 4 and R 5 together with the atoms to which they are attached are combined to form an optionally substituted, heteroaryl ring (e.g. , optionally substituted pyridyl ring).
  • A is -NR'- (e.g. , -NH-).
  • A is -0-. In some embodiments, A is -NR'- and n is 1.
  • n is 0. In some embodiments, n is 1.
  • a and R 5 are joined together with the atoms to which they are attached to form an optionally substituted heterocyclic ring. In some embodiments, A and R 5 are joined together with the atoms to which they are attached to form a 6- 10 membered, optionally substituted heterocyclic ring containing oxygen, nitrogen, and/or sulfur heteroatoms. In some embodiments, A and R 5 are joined together with the atoms to which they are attached to form a 6- 10 membered, optionally substituted
  • a and R 5 are joined together with the atoms to which they are attached to form an optionally
  • Ring B is aryl (e.g. , phenyl). In some embodiments, Ring B is benzyl. In some embodiments, Ring B is 5- or 6-membered heteroaryl, or monocyclic or bicyclic 5- 10 membered heterocyclyl. In some embodiments, Ring B is optionally substituted pyridine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted morpholine, optionally substituted pyrrole, or optionally substituted triazolopyridine.
  • Ring B is optionally substituted by H, halogen, alkylhalogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, cycloalkenyl, heterocyclyl, -OH, alkoxyl, -NH 2 , alkylamino, amide, sulfonamide, urea, cyano, nitro, trifluoromethyl, aryl, heteroaryl, -SH, -S0 2 NR'R", -OC(0)R', C(0)OR, COR, or CONR'R".
  • Ring B is optionally substituted by -N0 2 .
  • Ring B is optionally substituted by -alkylhalogen.
  • Ring B is o tionally substituted by -CF 3 .
  • Ring B is of the formula:
  • R is hydrogen. In some embodiments, R is optionally substituted acyl. In some embodiments, R is optionally substituted alkyl (e.g. , substituted or unsubstituted C 1-6 alkyl). In certain embodiments, R is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C 2 -6 alkenyl). In certain
  • R is substituted or unsubstituted alkynyl (e.g. , substituted or unsubstituted C 2 -6 alkynyl).
  • R is substituted or unsubstituted carbocyclyl (e.g. , substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system).
  • R is substituted or unsubstituted heterocyclyl (e.g.
  • R is substituted or unsubstituted aryl (e.g. , substituted or unsubstituted, 6- to 10-membered aryl).
  • R is substituted or unsubstituted heteroaryl (e.g.
  • R' is H. In certain embodiments, R' is acyl. In certain embodiments, R' is Ci- ⁇ alkyl. In certain embodiments, R' is C 1-6 alkenyl. In certain embodiments, R' is C 1-6 alkynyl.
  • R" is H. In certain embodiments, R" is acyl. In certain embodiments, R" is C 1-6 alkyl. In certain embodiments, R" is Ci- ⁇ alkenyl. In certain embodiments, R" is C 1-6 alkynyl.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
  • a pharmaceutically acceptable excipient In certain embodiments, a pharmaceutical
  • composition described herein comprises a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions described herein are useful in treating and/or preventing diseases associated with the binding of CREB to CBP and/or the binding of CREB to CBP (e.g. , proliferative diseases (e.g. , cancer, inflammatory diseases)).
  • the pharmaceutical compositions described herein are useful in treating and/or preventing cancer or an inflammatory disease.
  • the compound described herein is provided in an effective amount in the pharmaceutical composition.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • a therapeutically effective amount is an amount effective for inhibiting the binding of CREB to CBP.
  • a therapeutically effective amount is an amount effective for treating a disease (e.g. , a disease associated with the CREB-CBP pathway).
  • a therapeutically effective amount is an amount effective for inhibiting the binding of CREB to CBP and treating a disease (e.g.
  • a prophylactically effective amount is an amount effective for inhibiting the binding of CREB to CBP.
  • a prophylactically effective amount is an amount effective for preventing or keeping a subject in need thereof in remission of a disease (e.g. , a disease associated with the binding of CREB to CBP (e.g. , proliferative disease)).
  • a prophylactically effective amount is an amount effective for inhibiting the binding of CREB to CBP, and preventing a disease (e.g. , a disease associated with binding of CREB to CBP (e.g. , proliferative disease)).
  • the effective amount is an amount effective for inhibiting the binding of CREB to CBP by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the binding of CREB to CBP by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%.
  • the subject is an animal.
  • the animal may be of either sex and may be at any stage of development.
  • the subject described herein is a human.
  • the subject is a non-human animal.
  • the subject is a mammal.
  • the subject is a non-human mammal.
  • the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • the subject is a companion animal, such as a dog or cat.
  • the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat.
  • the subject is a zoo animal.
  • the subject is a research animal, such as a rodent (e.g. , mouse, rat), dog, pig, or non-human primate.
  • the animal is a genetically engineered animal.
  • the animal is a transgenic animal (e.g. , transgenic mice and transgenic pigs).
  • the subject is a fish or reptile.
  • the cell is present in vitro. In certain embodiments, the cell is present in vivo.
  • compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e. , the "active ingredient") into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a "unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.
  • compositions described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • crospovidone cross-linked poly(vinyl-pyrrolidone)
  • sodium carboxymethyl starch sodium starch glycolate
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. , acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. , bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g.
  • natural emulsifiers e.g. , acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin
  • colloidal clays e.g. , bentonite (aluminum silicate
  • stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol
  • carbomers e.g. , carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer
  • carrageenan cellulosic derivatives (e.g. , carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
  • polyoxyethylene sorbitan monolaurate Tween ® 20
  • polyoxyethylene sorbitan Tween ® 60
  • polyoxyethylene sorbitan monooleate Tween ® 80
  • sorbitan monopalmitate Span ® 40
  • sorbitan monostearate Span ® 60
  • sorbitan tristearate Span ® 65
  • glyceryl monooleate sorbitan monooleate
  • sorbitan monooleate (Span ® 80), polyoxyethylene esters (e.g.
  • polyoxyethylene monostearate Myrj ® 45
  • polyoxyethylene hydrogenated castor oil polyethoxylated castor oil
  • polyoxymethylene stearate polyoxymethylene stearate
  • Solutol ® sucrose fatty acid esters
  • polyethylene glycol fatty acid esters e.g. , Cremophor ®
  • polyoxyethylene ethers e.g.
  • polyoxyethylene lauryl ether (Brij ® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic ® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
  • Exemplary binding agents include starch (e.g. , cornstarch and starch paste), gelatin, sugars (e.g. , sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. , acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,
  • starch e.g. , cornstarch and starch paste
  • sugars e.g. , sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.
  • natural and synthetic gums e.g. , acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol
  • methylcellulose methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum ® ), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • the preservative is an antioxidant.
  • the preservative is a chelating agent.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g. , sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g.
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT),
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyro gen- free water, isotonic s
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g.
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates described herein are mixed with solubilizing agents such as Cremophor ® , alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S. P., and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial -retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d)
  • disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate
  • solution retarding agents such as paraffin
  • absorption accelerators such as quaternary ammonium compounds
  • wetting agents such as, for example, cetyl alcohol and glycerol monostearate
  • absorbents such as kaolin and bentonite clay
  • lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.
  • the dosage form may include a buffering agent.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active ingredient can be in a micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g. , tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating agents examples include polymeric substances and waxes.
  • Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required.
  • the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices.
  • Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin.
  • conventional syringes can be used in the classical mantoux method of intradermal administration.
  • Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable.
  • Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions.
  • Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers.
  • Such compositions are conveniently in the form of dry powders for
  • a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling
  • solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
  • Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
  • the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
  • the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
  • Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient.
  • Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical
  • compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation .
  • compositions described herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • compositions provided herein can be administered by any route, including enteral (e.g. , oral), parenteral, intravenous, intramuscular, intra-arterial,
  • intramedullary intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • Specifically contemplated routes are oral administration, intravenous administration (e.g. , systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct
  • the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.
  • any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is one dose per day.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is two doses per day.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is three doses per day.
  • the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell.
  • the duration between the first dose and last dose of the multiple doses is three months, six months, or one year.
  • the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
  • a dose (e.g. , a single dose, or any dose of multiple doses) described herein includes independently between 0.1 ⁇ g and 1 ⁇ g, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein.
  • a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.
  • Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a compound or composition, as described herein, can be administered in any combination.
  • the compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g. , activity (e.g. , potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in inhibiting the binding of CREB to CBP in a subject, biological sample, tissue, or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject, biological sample, tissue, or cell.
  • additional pharmaceutical agents that improve their activity (e.g. , activity (e.g. , potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in inhibiting the binding of CREB to CBP in a subject, biological sample, tissue, or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in
  • a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.
  • the compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g. , combination therapies.
  • Pharmaceutical agents include therapeutically active agents.
  • Pharmaceutical agents also include prophylactically active agents.
  • Pharmaceutical agents include small organic molecules such as drug compounds (e.g. , compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
  • drug compounds e.g. , compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)
  • CFR Code of Federal Regulations
  • peptides proteins
  • carbohydrates monosaccharides
  • the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g. , proliferative disease, inflammatory disease).
  • a disease e.g. , proliferative disease, inflammatory disease.
  • Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent.
  • the additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional
  • the additional pharmaceutical agents include, but are not limited to, antiproliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, and a combination thereof.
  • the additional pharmaceutical agent is an anti-proliferative agent (e.g. , anti-cancer agent). In certain embodiments, the additional pharmaceutical agent is an anti-leukemia agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ADE, Adriamycin RDF (doxorubicin hydrochloride), Ambochlorin (chlorambucil), ARRANON (nelarabine), ARZERRA (ofatumumab), BOSULIF (bosutinib), BUSULFEX (busulfan), CAMPATH (alemtuzumab), CERUBIDINE (daunorubicin hydrochloride), CLAFEN
  • the additional pharmaceutical agent is an anti- lymphoma agent. In certain embodiments, the additional pharmaceutical agent is
  • ABITREXATE metalhotrexate
  • ABVD ABVE
  • ABVE-PC ABVE-PC
  • ADCETRIS brentuximab vedotin
  • ADRIAMYCIN PFS doxorubicin hydrochloride
  • ADRIAMYCIN RDF ADRIAMYCIN RDF
  • BELEODAQ belinostat
  • BEXXAR tositumomab and iodine I 131 tositumomab
  • BICNU carmustine
  • BLENOXANE bleomycin
  • CARMUBRIS carmustine
  • CHOP CHOP
  • CLAFEN cyclophosphamide
  • COPP COPP-ABV
  • CVP CVP
  • CYTOXAN cyclophosphamide
  • DEPOCYT liposomal cytarabine
  • DTIC-DOME diacarbazine
  • EPOCH FOLEX
  • the additional pharmaceutical agent is REVLIMID (lenalidomide), DACOGEN (decitabine ), VIDAZA (azacitidine ), CYTOSAR-U (cytarabine), IDAMYCIN (idarubicin ), CERUBIDINE
  • the additional pharmaceutical agent is ABITREXATE (methotrexate), ABRAXANE
  • paclitaxel albumin- stabilized nanoparticle formulation AC, AC-T, ADE, ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRUCIL (fluorouracil), AFINITOR (everolimus), AFINITOR DISPERZ (everolimus), ALDARA (imiquimod), ALIMTA (pemetrexed disodium), AREDIA (pamidronate disodium), AREVIIDEX (anastrozole), AROMAS IN (exemestane), AVASTIN (bevacizumab), BECENUM (carmustine), BEP, BICNU
  • CYFOS ifosfamide
  • CYRAMZA ramucirumab
  • KEYTRUDA pembrolizumab
  • KYPROLIS carbfilzomib
  • LIPODOX doxorubicin hydrochloride liposome
  • LUPRON leuprolide acetate
  • LUPRON DEPOT leuprolide acetate
  • LUPRON DEPOT-3 MONTH leuprolide acetate
  • LUPRON DEPOT-4 MONTH leuprolide acetate
  • LUPRON DEPOT-PED leuprolide acetate
  • MEGACE megestrol acetate
  • MEKINIST trametinib
  • METHAZOLASTONE temozolomide
  • PERJETA pertuzumab
  • PLATINOL cisplatin
  • PLATINOL-AQ cisplatin
  • POMALYST pomalidomide
  • prednisone a prednisone
  • PROLEUKIN aldesleukin
  • PROLIA denosumab
  • PROVENGE pulseucel-t
  • REVLIMID lasalidomide
  • RUBIDOMYCIN unorubicin hydrochloride
  • SPRYCEL dasatinib
  • STIVARGA regorafenib
  • SUTENT sininib malate
  • SYLATRON peginterferon alfa-2b
  • SYLVANT sinuximab
  • TAXOL paclitaxel
  • TAXOTERE thalidomide
  • TAC TAFINLAR
  • TARABINE PFS cytarabine
  • TARCEVA erlotinib hydrochloride
  • TASIGNA nilotinib
  • TAXOL paclitaxel
  • etoposide TORISEL (temsirolimus), TPF, TRISENOX (arsenic trioxide), TYKERB (lapatinib ditosylate), VECTIBIX (panitumumab), VEIP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VEPESID (etoposide), VIADUR (leuprolide acetate), VIDAZA (azacitidine), VINCASAR PFS (vincristine sulfate),
  • VOTRIENT pazopanib hydrochloride
  • WELLCOVORIN leucovorin calcium
  • XALKORI crizotinib
  • XELODA capecitabine
  • XELOX XGEVA
  • XOFIGO radium 223 dichloride
  • XTANDI enzalutamide
  • YERVOY ipilimumab
  • ZALTRAP ziv- aflibercept
  • ZELBORAF vemurafenib
  • ZOLADEX goserelin acetate
  • the additional pharmaceutical agent is a binder or inhibitor of the binding of CREB to CBP.
  • the additional pharmaceutical agent is a protein kinase inhibitor (e.g. , tyrosine protein kinase inhibitor).
  • the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g. , DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g. , taxanes and vinca alkaloids), hormone receptor
  • epigenetic or transcriptional modulators e.g. , DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors
  • antimitotic drugs e.g. , taxanes and vinca alkaloids
  • modulators e.g. , estrogen receptor modulators and androgen receptor modulators
  • cell signaling pathway inhibitors e.g. , tyrosine protein kinase inhibitors
  • modulators of protein stability e.g. , proteasome inhibitors
  • Hsp90 inhibitors glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation.
  • the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g. , stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.
  • kits e.g. , pharmaceutical packs
  • the kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g. , a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g. , a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a
  • the pharmaceutical composition or compound described herein in some embodiments, are combined to form one unit dosage form.
  • kits including a first container comprising a compound or pharmaceutical composition described herein.
  • the kits are useful for treating a disease (e.g. , proliferative disease, inflammatory disease) in a subject in need thereof.
  • the kits are useful for preventing a disease (e.g. , proliferative disease, inflammatory disease) in a subject in need thereof.
  • a disease e.g. , proliferative disease, inflammatory disease
  • kits are useful for inhibiting the binding of CREB to CBP in a subject, biological sample, tissue, or cell.
  • kits described herein further includes instructions for using the compound or pharmaceutical composition included in the kit.
  • a kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA).
  • the information included in the kits is prescribing information.
  • the kits and instructions provide for treating a disease (e.g. , proliferative disease, inflammatory disease) in a subject in need thereof.
  • the kits and instructions provide for preventing a disease (e.g. , proliferative disease, inflammatory disease) in a subject in need thereof.
  • a disease e.g. , proliferative disease, inflammatory disease
  • kits and instructions provide for modulating (e.g. , inhibiting) the binding of CREB to CBP in a subject, biological sample, tissue, or cell.
  • a kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
  • the compounds described herein are capable of modulating (e.g. , reversibly modulating or irreversibly modulating) the binding of CREB to CBP.
  • the present disclosure thus also provides methods of modulating (e.g. , inhibiting) the binding of CREB to CBP in a subject, biological sample, tissue, or cell.
  • the present disclosure further provides methods for the treatment of a wide range of diseases, such as diseases associated with the binding of CREB to CBP and/or diseases associated with the binding of CREB to CBP, proliferative diseases, and inflammatory diseases in a subject in need thereof.
  • the present disclosure provides methods of modulating (e.g. , inhibiting) the binding of CREB to CBP in a subject in need thereof, the methods comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein.
  • methods of interfering with the binding of CREB to CBP in a subject comprising: contacting cells expressing CREB to CBP with an effective amount of a compound or pharmaceutical composition described herein.
  • the contacting step is performed by administering the compound or the pharmaceutical composition to a subject in need thereof.
  • the subject has, is suspected of having, or is at risk for a disease associated with the CREB-CBP pathway.
  • the present disclosure provides methods of modulating (e.g. , inhibiting) the binding of CREB to CBP in a biological sample, tissue, or cell, the methods comprising contacting the biological sample, tissue, or cell with an effective amount of a compound or pharmaceutical composition described herein.
  • the binding of CREB to CBP in a subject, biological sample, tissue, or cell is inhibited by a compound, pharmaceutical composition, kit, use, or method described herein by at least 1%, at least 3%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.
  • the binding of CREB to CBP in a subject, biological sample, tissue, or cell is inhibited by a compound, pharmaceutical composition, kit, use, or method described herein by not more than 1%, not more than 3%, not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, or not more than 90%.
  • the binding of CREB to CBP in a subject, biological sample, tissue, or cell is selectively inhibited by the compound, pharmaceutical composition, kit, use, or method.
  • the binding of CREB in a subject, biological sample, tissue, or cell is selectively inhibited by the compound, pharmaceutical composition, kit, use, or method, compared to the binding of a different protein.
  • the binding of CREB to CBP in a subject, biological sample, tissue, or cell is selectively inhibited by the compound, pharmaceutical composition, kit, use, or method, compared to the binding of CREB to a different protein.
  • the binding of CREB to CBP described herein in a subject, biological sample, tissue, or cell is reversibly inhibited by the compound, pharmaceutical composition, kit, use, or method.
  • the binding of CREB to CBP described herein in a subject, biological sample, tissue, or cell is irreversibly inhibited by the compound, pharmaceutical composition, kit, use, or method.
  • Another aspect of the present disclosure relates to methods of inhibiting the binding of CREB to CBP in a subject in need thereof, the methods comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein.
  • Another aspect of the present disclosure relates to methods of inhibiting the binding of CREB to CBP in a biological sample, tissue, or cell, the methods comprising contacting the biological sample, tissue, or cell with an effective amount of a compound or
  • composition described herein e.g. , contacting the biological sample, tissue, or cell in vivo or in vitro.
  • the contacting of the biological sample, tissue, or cell with an effective amount of a compound or pharmaceutical composition described herein is in vitro.
  • a disease to be treated with a compound or pharmaceutical composition described herein is a disease associated with the binding of CREB to CBP.
  • the disease is associated with the CREB-CBP pathway.
  • the disease is a proliferative disease.
  • the proliferative disease is cancer.
  • the proliferative disease is lung cancer.
  • the proliferative disease is non- small cell lung cancer, breast cancer, colorectal cancer, pancreatic cancer, gastric cancer, or cervical cancer.
  • the disease is lung cancer, breast cancer, leukemia, acute lymphoblastic leukemia, lymphoma, Burkitt' s lymphoma, melanoma, multiple myeloma, Ewing' s sarcoma, osteosarcoma, brain cancer, ovarian cancer, neuroblastoma, or colorectal cancer.
  • the proliferative disease is triple-negative breast cancer.
  • the disease is an inflammatory disease.
  • the inflammatory disease is pancreatic fibrosis or liver fibrosis.
  • the present disclosure provides the compounds described herein for use in a method described herein (e.g., a method of inhibiting the binding of CREB to CBP, a method of interfering with the binding of CREB to CBP, a method of treating a disease (e.g., a proliferative disease), or a method of preventing a disease (e.g., a proliferative disease)).
  • the present disclosure provides the compounds described herein for use in treating or preventing a proliferative disease in a subject.
  • the present disclosure provides the compounds described herein, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, or a pharmaceutical composition thereof, for use in treating or preventing a proliferative disease in a subject.
  • the present disclosure provides the pharmaceutical compositions described herein for use in a method described herein (e.g., a method of inhibiting the binding of CREB to CBP, a method of interfering with the binding of CREB to CBP, a method of treating a disease (e.g., a proliferative disease), or a method of preventing a disease (e.g., a proliferative disease).
  • a method described herein e.g., a method of inhibiting the binding of CREB to CBP, a method of interfering with the binding of CREB to CBP, a method of treating a disease (e.g., a proliferative disease), or a method of preventing a disease (e.g., a proliferative disease).
  • Example 1 Identification of exemplary CREB inhibitor compounds via screening of a focused compound library
  • An exemplary compound library consisting of 71 compounds was developed (CHW- 1 - CHW71; Table 1) for assessing their abilities to inhibit CREB-mediated transcription.
  • Exemplary compounds of Formula (I) include, but are not limited to, the compounds of Table 1: Table 1. Structures of CHWl - CHW71 in the compound library
  • MTT assays indicate that CHW-71, CHW-52, CHW-10, and CHW-23 exhibited higher potencies relative to the positive control AS-E (i) in suppressing the viability of MDA- MB-231 cells (FIG. 2).
  • the ICso values were: CHW-71, 2 ⁇ ; CHW-52, 2 ⁇ ; CHW-10, 2.5 ⁇ ; AS-E (i), 5 ⁇ .
  • CHW-10, CHW-52, and CHW-71 were chosen for further testing of whether they were CREB inhibitors.
  • Microwave assisted synthesis was carried out in sealed tubes with a CEM Discover SP system (CEM Corporation, Matthews, NC, USA). Purity of the final compounds were determined with an Hitachi 2000 series HPLC system using C-18 column (Luca 5 ⁇ -08(2) 100A ⁇ . 4.60 mm x 250 mm) using mobile phase A-water containing 0.1% formic acid 10 mmol NH 4 OAc and mobile phase B- methanol. Elution condition, at 0 min phase A 40% + phase B 60%; at 20 min phase A 0% + phase B 100%; at 60 min phase A 0% + phase B 100%. The flow-rate was 0.75 mL/min, and the injection volume was 5 ⁇ h. The system operated at 25 °C. Peaks were detected at 210 nm. Purity of all the tested compounds was found to be >95% by HPLC analysis unless otherwise stated.
  • Example 1 Evidence that CHW-10 and CHW-71 are CREB inhibitors - Validation of the ability of CHW-10 and CHW-71 to disrupt the complex formation of CREB with CBP
  • TNBC Triple-negative breast cancer
  • CHW-71 was effective in inhibiting the proliferation of MDA-MB-231 cells, in part, by blocking the expression of glycoprotein 130 (gpl30) and epidermal growth factor receptor (EGFR), leading the inhibition of the IL-6-Jak2-Stat3 signaling pathway (FIG. 4, left).
  • This down-regulation was mediated via a CREB/CBP- dependent mechanism as shRNA-mediated knockdown of CREB or CBP mimicked the effect of CHW-71 on all relevant biomarkers (right).
  • CHW-71 on signaling targets is not cell line- or cell type-specific
  • CHW-71 was also effective in suppressing the expression of the aforementioned key biomarkers, including CREB, CBP, EGFR, gpl30, p-Stat3, and cyclin Al, in H1975 and A549 lung cancer cells (FIG. 6). This finding indicates that the effect of these CREB inhibitors on signaling targets was not cell line- or cell type-specific.
  • CHW-71 inhibits the CREB and fibroblast makers expression in LX2 hepatic stellate cells.
  • CHW-71-induced LX-2 cells senescence could be mediated via a STAT3-dependent mechanism.
  • Example 3 In vivo efficacy of Compound CHW-71 in nude mice bearing MDA-MB-231 xenografts via oral gavage.
  • C. Western blot analysis was conducted to analyze the effects of treatment using exemplary compound CHW-71 on the
  • the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects described herein, is/are referred to as comprising particular elements and/or features, certain embodiments described herein or aspects described herein consist, or consist essentially of, such elements and/or features.

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Abstract

L'invention concerne des composés de formule (I), et des sels pharmaceutiquement acceptables de ceux-ci. Les composés selon l'invention sont utiles dans le traitement de maladies associées à la liaison de CREB à la protéine de liaison CREB (CBP) et/ou à la voie CREB-CBP (par exemple, des maladies prolifératives, par exemple le cancer (par exemple, le cancer du poumon ou le cancer du sein), et une maladie inflammatoire (par exemple, une fibrose pancréatique ou une fibrose hépatique)). La présente invention concerne également des compositions pharmaceutiques, des kits, des méthodes et des utilisations comprenant ou employant un desdits composés.
PCT/US2018/060048 2017-11-10 2018-11-09 Inhibiteurs de protéine de liaison à un élément de réponse d'amp cyclique WO2019094732A1 (fr)

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US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels

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US11919887B2 (en) 2019-12-06 2024-03-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels

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