WO2011082400A2 - Modulators of immunoinhibitory receptor pd-1, and methods of use thereof - Google Patents
Modulators of immunoinhibitory receptor pd-1, and methods of use thereof Download PDFInfo
- Publication number
- WO2011082400A2 WO2011082400A2 PCT/US2011/020046 US2011020046W WO2011082400A2 WO 2011082400 A2 WO2011082400 A2 WO 2011082400A2 US 2011020046 W US2011020046 W US 2011020046W WO 2011082400 A2 WO2011082400 A2 WO 2011082400A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- hydrogen
- alkyl
- aryl
- methyl
- Prior art date
Links
- 0 CC(C)c1nc(*)c(*)c(*)n1 Chemical compound CC(C)c1nc(*)c(*)c(*)n1 0.000 description 4
- JXRGUPLJCCDGKG-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1S(Cl)(=O)=O)=O Chemical compound [O-][N+](c(cc1)ccc1S(Cl)(=O)=O)=O JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 3
- XJKJHILCYUUVSJ-UHFFFAOYSA-N COc(cc1)cnc1N Chemical compound COc(cc1)cnc1N XJKJHILCYUUVSJ-UHFFFAOYSA-N 0.000 description 1
- YMAXPRGVRYPONZ-UHFFFAOYSA-N COc(cc1)cnc1NS(c(cc1)ccc1N)(=O)=O Chemical compound COc(cc1)cnc1NS(c(cc1)ccc1N)(=O)=O YMAXPRGVRYPONZ-UHFFFAOYSA-N 0.000 description 1
- XWYHRMOVAFFFCC-UHFFFAOYSA-N COc(cc1)cnc1NS(c(cc1)ccc1[N+]([O-])=O)(=O)=O Chemical compound COc(cc1)cnc1NS(c(cc1)ccc1[N+]([O-])=O)(=O)=O XWYHRMOVAFFFCC-UHFFFAOYSA-N 0.000 description 1
- GYAXOMJLDKJSGB-UHFFFAOYSA-N COc1ccnc(NS(c(cc2)ccc2N)(=O)=O)n1 Chemical compound COc1ccnc(NS(c(cc2)ccc2N)(=O)=O)n1 GYAXOMJLDKJSGB-UHFFFAOYSA-N 0.000 description 1
- BNWAKYPMZDSXTB-UHFFFAOYSA-N COc1ccnc(NS(c(cc2)ccc2[N+]([O-])=O)(=O)=O)n1 Chemical compound COc1ccnc(NS(c(cc2)ccc2[N+]([O-])=O)(=O)=O)n1 BNWAKYPMZDSXTB-UHFFFAOYSA-N 0.000 description 1
- YNXLSFXQTQKQEF-UHFFFAOYSA-N COc1nc(N)ncc1 Chemical compound COc1nc(N)ncc1 YNXLSFXQTQKQEF-UHFFFAOYSA-N 0.000 description 1
- VACCAVUAMIDAGB-UHFFFAOYSA-N Cc1nnc(NS(c(cc2)ccc2N)(=O)=O)[s]1 Chemical compound Cc1nnc(NS(c(cc2)ccc2N)(=O)=O)[s]1 VACCAVUAMIDAGB-UHFFFAOYSA-N 0.000 description 1
- SGXOZJHNXADHDF-UHFFFAOYSA-N Cc1nnc(NS(c(cc2)ccc2O)(=O)=O)[s]1 Chemical compound Cc1nnc(NS(c(cc2)ccc2O)(=O)=O)[s]1 SGXOZJHNXADHDF-UHFFFAOYSA-N 0.000 description 1
- FQCUWNIOHQUHIF-UHFFFAOYSA-N Nc(cc1)ccc1S(Nc1nnc(-c2ccccc2)[s]1)(=O)=O Chemical compound Nc(cc1)ccc1S(Nc1nnc(-c2ccccc2)[s]1)(=O)=O FQCUWNIOHQUHIF-UHFFFAOYSA-N 0.000 description 1
- ATEAASNFYTUARU-UHFFFAOYSA-N Nc(cc1)ccc1S(Nc1nnc[s]1)(=O)=O Chemical compound Nc(cc1)ccc1S(Nc1nnc[s]1)(=O)=O ATEAASNFYTUARU-UHFFFAOYSA-N 0.000 description 1
- UHZHEOAEJRHUBW-UHFFFAOYSA-N Nc1nnc(-c2ccccc2)[s]1 Chemical compound Nc1nnc(-c2ccccc2)[s]1 UHZHEOAEJRHUBW-UHFFFAOYSA-N 0.000 description 1
- QUKGLNCXGVWCJX-UHFFFAOYSA-N Nc1nnc[s]1 Chemical compound Nc1nnc[s]1 QUKGLNCXGVWCJX-UHFFFAOYSA-N 0.000 description 1
- XAAKAMVNDJQIGI-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1S(Nc1nnc(-c2ccccc2)[s]1)(=O)=O)=O Chemical compound [O-][N+](c(cc1)ccc1S(Nc1nnc(-c2ccccc2)[s]1)(=O)=O)=O XAAKAMVNDJQIGI-UHFFFAOYSA-N 0.000 description 1
- MLNZDSSSKGMPHQ-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1S(Nc1nnc[s]1)(=O)=O)=O Chemical compound [O-][N+](c(cc1)ccc1S(Nc1nnc[s]1)(=O)=O)=O MLNZDSSSKGMPHQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
Definitions
- One aspect of the present invention relates to compounds that selectively modulate the activity of the immunoinhibitory receptor PD-1.
- one aspect of the invention relates to a compound of formula I:
- A is aryl, heteroaryl or biaryl
- Figure 3 depicts the results of validation testing of sulfamonomethoxine and sulfamethizole using wild type, PD-1 , and PD- -/- " T cells. Responses of PD-1 and PD- ⁇ -/- "
- PD-1 T cells are cultured with a proliferative stimulus (anti-CD3) plus either PD-L2-Ig or a negative control Ig fusion protein.
- PD-1 T cells proliferate less and produce lower amounts of cytokines when cultured with PD-L2-Ig as compared to the negative control Ig fusion protein because PD-1 -ligands deliver an inhibitory signal through PD-1.
- Compounds of interest will modulate this inhibitory
- a compound was considered to be a potential agonist if it reduced T cell function in the presence of PD-L2Ig relative to controls ( Figure 1, compound 4).
- the present invention relates to any one of the
- the present invention relates to any one of the
- R 12 is hydrogen or alkyl.
- aralkylcarbonyl heteroarylcarbonyl, heterocyclylalkylcarbonyl, aralkylcarbonyl, heteroaralkylcarbonyl, alkyloxycarbonyl, haloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl,
- heteroaralkyl halo, haloalkyl, cyano, nitro, -N(R 1 )R , -CH 2 N(R 1 )R ,
- One aspect of the invention relates to a compound, or a pharmaceutically acceptable salt, solvate, enantiomer or stereoisomer thereof, selected from the group consisting of
- pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids.
- inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid
- organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic,
- Certain compounds of the invention and their salts may exist in more than one crystalline form (i.e., polymorph); the present invention includes each of the crystal forms and mixtures thereof.
- exemplary pro-drugs upon cleavage release a corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of this invention include but are not limited to carboxylic acid substituents (e.g., -(CH 2 )C(0)OH or a moiety that contains a carboxylic acid) wherein the free hydrogen is replaced by (Ci-C 4 )alkyl, (C 2 - Ci 2 )alkanoyloxy-methyl, (C 4 -Cc))l-(alkanoyloxy)ethyl, 1 -methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyl-oxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1 - (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alk
- the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly or by intramuscular injection).
- the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (for example, as a sparingly soluble salt).
- one aspect of the invention relates to the use of compounds of the invention (e.g., those of formula I) in combination with at least one other anti-inflammatory or immunosuppressant agent.
- compounds of the invention e.g., those of formula I
- at least one other anti-inflammatory or immunosuppressant agent e.g., those of formula I
- therapeutic agents that can be used in
- a therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms in a patient.
- Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) and the ED 50 (effective dose for 50% maximal response).
- the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between MTD and ED 50 .
- the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
- the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
- the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
- the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. In the treatment of crises, the administration of an acute bolus or an infusion approaching the MTD may be required to obtain
- Dosage intervals can also be determined using the MEC value.
- Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% until the desired amelioration of symptoms is achieved.
- the effective local concentration of the drug may not be related to plasma concentration.
- the dosage ranges from about 0.0001 to 100 mg/kg, and more usually 0.01 to 5 mg/kg, of the host body weight.
- dosages can be 0.3 mg/kg body weight, 1 mg/kg body weight, 3 mg/kg body weight, 5 mg/kg body weight or 10 mg/kg body weight or within the range of 1-10 mg/kg.
- An exemplary treatment regime entails administration once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every three to 6 months.
- PD-1 is also expressed on B cells, macrophages and dendritic cells. Far less is know about PD-1 function on B cells, macrophages and DC. However, PD-1 also can inhibit responses of B cells and macrophages. Therefore, PD-1 antagonist and agonist compounds have the potential to modulate responses of any PD-1 expressing cell. For example, in certain embodiments, compounds of the invention which are PD-1 antagonists may be used to enhance B cell or macrophage responses.
- compounds of the invention can be combined with an immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), and cells transfected with genes encoding immune stimulating cytokines.
- an immunogenic agent such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), and cells transfected with genes encoding immune stimulating cytokines.
- tumor vaccines include peptides of melanoma antigens, such as peptides of gplOO, MAGE antigens, Trp-2,
- PD-1 blocking compounds of the invention can also be used in combination with bispecific antibodies that target Fc alpha or Fc gamma receptor-expressing effectors cells to tumor cells (see, e.g., U.S. Pat. Nos. 5,922,845 and 5,837,243).
- Bispecific antibodies can be used to target two separate antigens.
- anti-Fc receptor/anti tumor antigen e.g., Her-2/neu
- bispecific antibodies have been used to target macrophages to sites of tumor. This targeting may more effectively activate tumor specific responses.
- the T cell arm of these responses may be augmented by the use of PD-1 blockade.
- antigen may be delivered directly to DCs by the use of bispecific antibodies which bind to tumor antigen and a dendritic cell specific cell surface marker.
- HSV-II, and CMV, Epstein Barr virus adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus .
- compounds of the invention can be co-administered with one or more other therapeutic agents, e.g., a cytotoxic agent, a radiotoxic agent or an immunosuppressive agent.
- the compound can be linked to the agent or can be administered separate from the agent. In the latter case (separate administration), the compound can be administered before, after or concurrently with the agent or can be co-administered with other known therapies, e.g., an anti-cancer therapy, e.g., radiation.
- aliphatic refers to compounds and/or groups which are linear or branched, but not cyclic (also known as “acyclic” or “open-chain” groups).
- hydrocarbon refers to an organic compound consisting entirely of hydrogen and carbon.
- alkylene moiety e.g., methylene
- aryl as used herein means a phenyl group, naphthyl, phenanthrenyl, or anthracenyl group.
- the aryl groups of the present invention can be optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluroralkylsulfonyl, alkenylsulfony
- arylene is art-recognized, and as used herein pertains to a bidentate moiety obtained by removing two hydrogen atoms of an aryl ring, as defined above.
- hydroxy as used herein means an -OH group.
- haloalkoxy as used herein means an alkoxy group, as defined herein, wherein at least one hydrogen is replaced with a halogen, as defined herein.
- Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
- fluoroalkyloxy is likewise defined.
- arylthio as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through a sulfur.
- heteroarylthio is likewise defined.
- triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, /?-toluenesulfonyl, methanesulfonyl, and
- oxy refers to a -O- group.
- alkylcarbonyloxy as used herein means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
- amino refers to -NH 2 and substituted derivatives thereof wherein one or both of the hydrogens are independently replaced with substituents selected from the group consisting of alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carbocyclylcarbonyl,
- treatment includes partial or total destruction of the undesirable proliferating cells with minimal destructive effects on normal cells.
- a desired mechanism of treatment of unwanted rapidly proliferating cells, including cancer cells, at the cellular level is apoptosis.
- the specificity of the effects of sulfamonomethoxine and sulfamethizole were assessed by comparing responses of wild type, PD-1 C , and PD-1 "7" T cells.
- the effects of sulfamonomethoxine and sulfamethizole were evaluated over a range of compound concentrations (dilution series from 16 nM to 80 ⁇ ) and analyzed their effects on T cell proliferation and cytokine production.
- the 2D structure and data from the primary screen are shown in Figure 2.
- a secondary screen demonstrated the specificity of
- T Cell Culture Assay T cells were added to tissue culture wells coated with plate- bound anti-CD3 (8 ⁇ / ⁇ 1) plus either 3 ⁇ g/ml PD-L2Ig or control Ig fusion protein. Cells were added at 1 x 10 5 cells/well in 100 of media. Drug or media control was added in 100 ⁇ . Plates were incubated for up to 96 hours. Supernatants were harvested at various times for cytokine analyses. In some experiments, T cells were labeled with CFSE to assess T cell proliferation, as will be discussed below.
- the IFN-y ELISA Assay is a sandwich ELISA based on an R& D systems IFN- ⁇ kit.
- the kit included the capture and biotinylated detection antibody. A secondary antibody was still required for measurement of the levels of IFN- ⁇ cytokine.
- This assay used an anti-IFN- ⁇ as the capture antibody.
- the IFN- ⁇ in the supernatant of T cells (PD- 1 or PD- 1 KO) incubated with and without drug would be incubated with the capture antibody.
- a detection antibody, anti-IFN- ⁇ conjugated with biotin would be added to bind to the IFN- ⁇ .
- Streptavidin conjugated to IR 800 Dye was used to visualize the interaction. Biotin on the detection antibody would bind to the streptavidin on the dye conjugate. The IR 800 Dye could then be detected by a plate reader.
Abstract
Disclosed are an assay to identify modulators of the PD-1 :PD-L pathway and PD-1 :PD-L pathway modulators, e.g., compounds and pharmaceutical compositions thereof. Methods for treating diseases influenced by modulation of the PD-1 :PD-L pathway such as, for example, autoimmune diseases, inflammatory disorders, allergies, transplant rejection, cancer, immune deficiency, and other immune system-related disorders, are also disclosed.
Description
Modulators of Immunoinhibitory Receptor PD-1,
and Methods of Use Thereof
RELATED APPLICATIONS
This application claims the benefit of priority to United States Provisional Patent Application serial number 61/292,020, filed January 4, 2010; the contents of which are hereby incorporated by reference.
BACKGROUND
The programmed death PD-1 receptor and PD-L1 ligand pathway is part of the B7:CD28 family of co-stimulatory pathways. Ligation of PD-1 by either of its ligands, PD- Ll and PD-L2, during TCR signaling inhibits TCR-mediated proliferation and cytokine production (34-38). Although PD-1 is inducibly expressed on T cells following their activation, the effects of PD-1 ligation on T cells can be seen as early as 2 hrs after activation (39). It has also been shown that PD-1 can inhibit primary and secondary T cell responses (40, 41).
Interest in the PD-1 :PD-L pathway has grown with the discovery that it can regulate the balance between stimulatory and inhibitory signals that regulate and maintain peripheral tolerance and the control of antimicrobial immunity. The induction and maintenance of T cell tolerance requires the PD-1 receptor and its ligands PD-L1 and PD-L2. This pathway regulates several tolerance checkpoints. First, this pathway regulates the initial decision between T cell activation versus anergy. Second, there is a limiting of the effector T cell responses. Third, nonhematopoietic expression of PD-L1 controls T cells response. In addition, this pathway also controls the development, maintenance and function of induced regulatory T cells. In turn, this will protect tissues from auto-immune damage. This pathway also has a role in autoimmune diseases and chronic infections.
Antibodies have been used to modulate the PD-1 :PD-L pathway. For example, US Patent Application No. 2009/0217401 (Korman; Alan J. et al.), hereby incorporated by reference in its entriety, describes isolated monoclonal antibodies, particularly human monoclonal antibodies, that specifically bind to PD-1 with high affinity.
SUMMARY
One aspect of the present invention relates to compounds that selectively modulate the activity of the immunoinhibitory receptor PD-1. For example, one aspect of the invention relates to a compound of formula I:
I
or a pharmaceutically acceptable salt, solvate, enantiomer or stereoisomer thereof, wherein independently for each occurrence,
A is aryl, heteroaryl or biaryl;
B is aryl, heteroaryl or biaryl;
X is -N(R)-, -C(R)2-, -O- or -S-;
R is hydrogen or alkyl; and
Y is -S(=0)2-, -S(=0)- or -C(=0)-.
Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention (e.g., a compound of formula I, or a pharmaceutically acceptable salt, solvate, enantiomer or stereoisomer thereof), and one or more
pharmaceutically acceptable carriers. A pharmaceutical composition of the invention may also comprise a second therapeutic agent. Such pharmaceutical compositions of the invention can be administered in accordance with a method of the invention (for example, as part of a therapeutic regimen for treatment or prevention of autoimmune diseases or infections). In one embodiment, the invention relates to a packaged pharmaceutical comprising a therapeutically effective amount of the compound or composition. In one embodiment, the invention relates to a packaged pharmaceutical comprising a
prophylactically effective amount of the compound or composition.
Another aspect of the invention relates to a method of modulating the PD-1 :PD-L pathway in a cell comprising the step of contacting a cell with a compound of the present invention, or administering a compound of the present invention to a subject in need thereof. Such methods can be used to ameliorate any condition, such as an autoimmune disease, transplant rejection, infectious diseases and/or cancer, which is caused by or potentiated by the activity of the PD-1 :PD-L pathway.
Another aspect of the invention relates to a method of treating or preventing specific disorders in which the immunoinhibitory receptor PD-1 plays a part, for example, in autoimmune diseases, graft rejection, infections and/or cancer. Modulation of this pathway can be used, for example, as immunotherapy and/or for treating or preventing autoimmune diseases, graft rejection, infections and/or cancer. In certain embodiments, such methods
comprise the step of administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the invention.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 depicts schema of potential effects of candidate molecules.
Figure 2 depicts the screening results for sulfamonomethoxine and sulfamethizole, showing rescue of IFN-γ production above the negative control wells on the plate.
Figure 3 depicts the results of validation testing of sulfamonomethoxine and sulfamethizole using wild type, PD-1 , and PD- -/-" T cells. Responses of PD-1 and PD-Γ -/-"
(KO) T cells over a range of compound concentrations (0 to 10,000 nM) are shown.
Specificity is shown by block of PD-1 mediated inhibition in PD-1 Tg cells only when PD-
L2 was present. Furthermore, there was no effect on PD-Γ " T cells. Specific effects are seen above 400 nM in rescuing T cells from PD-1 mediated inhibition of IFN- γ production.
Figure 4 depicts the results of structure-activity relationship testing of a compound of the invention (top). In the middle graph, the KO data are represented by the darker, flat line; Tg data are represented by the lighter, variable, top line. In the bottom graph, the KO data are represented by the darker, top, flat line; Tg data are represented by the lighter, bottom line. Error bars indicate ±1 standard deviation.
Figure 5 depicts the results of structure-activity relationship testing of a compound of the invention (top). In the middle graph, the KO data are represented by the darker, flat line; Tg data are represented by the lighter, variable, top line. In the bottom graph, the KO data are represented by the darker, flat line; Tg data are represented by the lighter, slightly variable line. Error bars indicate ±1 standard deviation.
Figure 6 depicts the results of structure-activity relationship testing of a compound of the invention (top). In the middle graph, the KO data are represented by the darker, flat line; Tg data are represented by the lighter, variable, top line. In the bottom graph, the KO data are represented by the darker, flat line; Tg data are represented by the lighter, slightly variable line. Error bars indicate ±1 standard deviation.
DETAILED DESCRIPTION
One aspect of the invention relates to compounds that block the function of a key immune inhibitory pathway that restrains anti-microbial immune responses during chronic infection. This pathway, consisting of the immunoinhibitory receptor PD-1 and its two ligands PD-L1 and PD-L2, has become an attractive therapeutic target because it has a significant role in controlling the responses of T lymphocytes in a number of infectious
diseases for which no cures are yet available. PD-1 mediated inhibitory signals
downregulate T cell responses and facilitate microbial persistence. Modulation of this pathway during chronic viral infection can reinvigorate virus-specific T cells and lead to pathogen control in animal models. For example, the PD-1 :PD-L pathway inhibits T cell responses in several emerging/re-emerging human infectious diseases (including Hepatitis C, Helicobacter pylori). In addition, this inhibitory pathway restrains anti-tumor immune responses. Specifically, expression of PD-1 ligands on tumor cells has been shown to inhibit T cell tumor immunity in animal models and high PD-L1 expression on tumors in humans is associated with poor prognosis. The PD-1 :PD-L pathway also controls self- reactive T cells and protects against autoimmune diseases. In addition, the pathway regulates graft reactive T cells following organ transplantation. It follows that antagonists of the PD-1 :PD-L pathway can be used to enhance anti-microbial and anti-tumor immune responses, and agonists of the PD-1 :PD-L pathway can be used to treat autoimmune diseases and graft rejection.
SCREENING OF COMPOUNDS
In vitro assays to test for compounds that interfere with the PD-1 function have been developed. These assays utilize unique mouse strains to specifically identify PD-1 -specific effects. For example, a transgenic mouse that constitutively expresses PD-1 on T cells (PD- lc) has been developed (43). It has recently been disclosed that PD-1C T cells are very susceptible to signaling through PD-1, as measured by a decrease in T cell proliferation and cytokine production. These PD-1 T cells can be used to assess the functional effects of small molecules. A PD-1 deficient mouse (PD-Γ ") has also been developed (44), and T cells from such mice will serve as useful controls for in vitro as well as in vivo studies.
In certain embodiments, PD-1 T cells are cultured with a proliferative stimulus (anti-CD3) plus either PD-L2-Ig or a negative control Ig fusion protein. PD-1 T cells proliferate less and produce lower amounts of cytokines when cultured with PD-L2-Ig as compared to the negative control Ig fusion protein because PD-1 -ligands deliver an inhibitory signal through PD-1. Compounds of interest will modulate this inhibitory
-/- interaction in wild type and PD-1 T cells, but not in PD- " cells. Thus, compounds which are antagonists will block PD-1 inhibitory function and lead to increased T cell responses
-/- by wild type and PD-1 T cells, but will not affect PD- " T cells. Conversely, compounds which are agonists will deliver an inhibitory signal, and reduce T cell responses by wild type and PD-1C T cells, but not PD-1_/" T cells.
Because it is believed that PD-1 can inhibit cytokine (IFN-γ) production to a greater extent than T cell proliferation in a number of situations (36, 44), in certain embodiments IFN-γ production was chosen as the readout, using a bead-based fluorescent ELISA assay. These beads have a broad dynamic range (about 1 pg/mL to about 5 ng/mL), robust detection of cytokines from complex solutions (including culture media), minimal time requirement (about 3 hours from start to finish), and homogeneous format (no washing required).
Thus, for an initial screen of test compounds, one can culture PD-1 T cells with plate-bound anti-CD3, PD-L2Ig (or control Ig) plus test compounds in a 384 well format assay. Tissue culture supernatants can then be assayed for IFN-γ production using beads together with high throughput flow cytometry. PD-1 T cells proliferate less and produce lower amounts of cytokines when cultured with PDL2-Ig as compared to the negative control Ig fusion protein because PD-L2 delivers an inhibitory signal through PD-1.
A compound was considered to be potential antagonist if it blocked PD-1 inhibitory effects (Figure 1, compound 3). Such an antagonist leads to increased T cell function in the presence of PD-L2Ig as compared to control Ig fusion protein. Toxic compounds will decrease T cell responses in the presence of Ig control or PD-L2Ig (Figure 1, compound 2). Compounds that generally increase IFN-γ regardless of the PD-L2:PD-1 interaction, were eliminated as well (Figure 1, compound 1).
A compound was considered to be a potential agonist if it reduced T cell function in the presence of PD-L2Ig relative to controls (Figure 1, compound 4). In certain
embodiments, cut offs for screening-positive hits were set as an effect that is greater than 3 standard deviations from control (e.g. in Figure 1, compound 3 would be a screening positive for a potential antagonist).
Any compound of interest can be screened according to the present invention.
Suitable test compounds include small organic compounds. Small organic compounds include a wide variety of organic molecules, such as sulfonamides, heterocyclics, aromatics, alicyclics, aliphatics and combinations thereof, comprising steroids, antibiotics, enzyme inhibitors, ligands, hormones, drugs, alkaloids, opioids, terpenes, porphyrins, toxins, catalysts, as well as combinations thereof.
COMPOUNDS
I
or a pharmaceutically acceptable salt, solvate, enantiomer or stereoisomer thereof, wherein independently for each occurrence,
A is aryl, heteroaryl or biaryl;
B is aryl, heteroaryl or biaryl;
X is -N(R)-, -C(R)2-, -O- or -S-;
R is hydrogen or alkyl; and
Y is -S(=0)2-, -S(=0)- or -C(=0)-.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein X is -N(R)-. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein X is -N(H)-. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein X is -N(CH3)-. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein X is -C(H)2-. In certain
embodiments, the present invention relates to any one of the aforementioned compounds, wherein X is -0-. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein X is -S-.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein Y is -S(=0)2-. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein Y is -S(=0)-. In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein Y is -C(=0)-.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein X is -N(R)-; and Y is -S(=0)2-. In certain
embodiments, the present invention relates to any one of the aforementioned compounds, wherein X is -N(R)-; and Y is -C(=0)2-.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein A is heteroaryl, arylheteroaryl or heteroarylheteroaryl.
In certain embodiments, the present invention relates to any one of the
R1 to R5 are independently selected from the group consisting of hydrogen, alkyl, heterocyclyl, aryl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl, halo, haloalkyl, cyano, nitro, -N(R12)R13, -CH2N(R12)R13, -CH2CH2N(R12)R13, -CH2CH2CH2N(R12)R13, -OR12, -CH2OR12, -CH2CH2OR12 and -CH2CH2CH2OR12 ; R12 is hydrogen, alkyl, haloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl, formyl, alkylcarbonyl, haloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heterocyclylalkylcarbonyl, aralkylcarbonyl, heteroaralkylcarbonyl, alkyloxycarbonyl, haloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heterocyclylalkyloxycarbonyl,
aralkyloxycarbonyl, heteroaralkyloxycarbonyl and amido; and R13 is hydrogen or alkyl.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R1 is hydrogen.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R2 is hydrogen.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R3 is hydrogen.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R4 is hydrogen. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R4 is hydrogen, methyl, phenyl or methoxy.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R5 is hydrogen.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R12 is hydrogen. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R12 is alkyl. In
certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R12 is methyl.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R13 is hydrogen. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R13 is alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R13 is methyl.
In certain embodiments, the present invention relates to any one of the
R2
R4 ^ to R5 are independently selected from the group consisting of hydrogen, alkyl, aryl, -OR12, -CH2OR12, -CH2CH2OR12 and -CH2CH2CH2OR12; and R12 is hydrogen or alkyl.
In certain embodiments, the present invention relates to any one of the
R2
R4 ; R1 , R2, R3 and R5 are hydrogen; R4 is hydrogen, alkyl, aryl, -OR12,
-CH2OR12, -CH2CH2OR12 and -CH2CH2CH2OR12; and R12 is hydrogen or alkyl.
In certain embodiments, the present invention relates to any one of the
R1, R2, R3 and R5 are hydrogen; R4 is hydrogen, methyl, phenyl or methoxy.
In certain embodiments, the p
In certain embodiments, the present invention relates to any one of the
, § N R8 or ¾ N'N ; w is -S-, -O- or -N(R10)-; R6 to R9 are independently selected from the group consisting of hydrogen, alkyl, heterocyclyl, aryl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl, halo, haloalkyl, cyano, nitro,
-N(R12)R13, -CH2N(R12)R13, -CH2CH2N(R12)R13, -CH2CH2CH2N(R12)R13, -OR12,
-CH2OR12, -CH2CH2OR12 and -CH2CH2CH2OR12 ; R10 is hydrogen or alkyl; R12 is hydrogen, alkyl, haloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl, formyl, alkylcarbonyl, haloalkylcarbonyl, heterocyclylcarbonyl,
arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heterocyclylalkylcarbonyl,
aralkylcarbonyl, heteroaralkylcarbonyl, alkyloxycarbonyl, haloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heterocyclylalkyloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl and amido; and R13 is hydrogen or alkyl.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein W is -S-. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein W is -CH2-. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein W is -0-. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein W is -N(R)-. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein W is
-N(H)-. In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein W is -N(CH3)-.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R12 is hydrogen. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R12 is alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R12 is methyl.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R13 is hydrogen. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R13 is alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R13 is methyl.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein A is
; W is -S-; and R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, alkyloxy, alky loxy alkyl and aryl.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein A is
W is -S-; and R7 is hydrogen, alkyl, aryl, -OR12, -CH2OR12, -CH2CH2OR12 or -CH2CH2CH2OR12; and R12 is hydrogen or alkyl.
In certain embodiments, the present invention relates to any one of the
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein B is aryl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein B is substituted phenyl.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein B is
R1 to R5 are independently selected from the group consisting of hydrogen, alkyl, heterocyclyl, aryl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl, halo, haloalkyl, cyano, nitro, -N(R12)R13, -CH2N(R12)R13, -CH2CH2N(R12)R13, -CH2CH2CH2N(R12)R13, -OR12, -CH2OR12,
-CH2CH2OR12 and -CH2CH2CH2OR12 ; R10 is hydrogen or alkyl; R12 is hydrogen, alkyl, haloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl, formyl, alkylcarbonyl, haloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl,
aralkylcarbonyl, heteroarylcarbonyl, heterocyclylalkylcarbonyl, aralkylcarbonyl, heteroaralkylcarbonyl, alkyloxycarbonyl, haloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl,
heterocyclylalkyloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl and amido; and R13 is hydrogen or alkyl.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R1 is hydrogen.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R2 is hydrogen.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R3 is hydrogen. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R3 is -N(R12)R13, -CH2N(R12)R13, -CH2CH2N(R12)R13 or -CH2CH2CH2N(R12)R13. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R3 is -N(R12)R13. In certain embodiments, the present invention relates to any one of the
3 12 12 12
aforementioned compounds, wherein R is -OR , -CH2OR , -CH2CH2OR or
-CH2CH2CH2OR12. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R3 is -OR12.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R4 is hydrogen.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R5 is hydrogen.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R12 is hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl or amido. In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R12 is hydrogen. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R12 is alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R12 is methyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R12 is methylcarbonyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R12 is methyoxycarbonyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R12 is methylaminocarbonyl.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R13 is hydrogen. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R13 is alkyl. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R13 is methyl.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein R12 is hydrogen; and R13 is hydrogen. In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R12 is methyl; and R13 is hydrogen.
In certain embodiments, the present invention relates to any one of the
R3 is hydrogen, alkyl, heterocyclyl, aryl, heteroaryl, heterocyclylalkyl, aralkyl,
heteroaralkyl, halo, haloalkyl, cyano, nitro, -N(R1 )R , -CH2N(R1 )R ,
-CH2CH2N(R12)R13, -CH2CH2CH2N(R12)R13, -OR12, -CH2OR12, -CH2CH2OR12 and
-CH2CH2CH2OR12 ; R10 is hydrogen or alkyl; R12 is hydrogen, alkyl, haloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl, formyl, alkylcarbonyl, haloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heterocyclylalkylcarbonyl, aralkylcarbonyl, heteroaralkylcarbonyl, alkyloxycarbonyl, haloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl,
heteroaryloxycarbonyl, heterocyclylalkyloxycarbonyl, aralkyloxycarbonyl,
heteroaralkyloxycarbonyl and amido; and R13 is hydrogen or alkyl.
In certain embodiments, the present invention relates to any one of the
aforementioned compounds, wherein B is
; R1, R2, R4 and R5 are hydrogen; R3 is -N(R12)R13 or -OR12; and R13 is hydrogen or methyl.
In certain embodiments, the present invention relates to any one of the
R 3 is -N(R 12 )R 13 or -OR 12 ; R 12 is hydrogen, alkylcarbonyl, alkyloxycarbonyl or amido; and R13 is hydrogen or methyl.
In certain embodiments, the present invention relates to any one of the
One aspect of the invention relates to a compound, or a pharmaceutically acceptable salt, solvate, enantiomer or stereoisomer thereof, selected from the group consisting of
One aspect of the invention relates to a compound, or a pharmaceutically acceptable salt, solvate, enantiomer or stereoisomer thereof, selected from the group consisting of
In certain embodiments, the invention relates to any one of the aforementioned compounds and attendant definitions, wherein the compound is an modulator of the PD-1 :PD-L pathway.
In certain embodiments, the invention relates to any one of the aforementioned compounds and attendant definitions, wherein the compound is a PD-1 antagonist.
In certain embodiments, the invention relates to any one of the aforementioned compounds and attendant definitions, wherein the compound is a PD-1 agonist.
In certain embodiments, the invention relates to any one of the aforementioned compounds and attendant definitions, wherein the compound is a selective inhibitor of the PD-1 :PD-L1 pathway.
Many of the compounds of the invention may be provided as salts with
pharmaceutically compatible counterions (i.e., pharmaceutically acceptable salts). A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound or a prodrug of a
compound of this invention. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a subject. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, and succinic acids. Salts tend to be more soluble in water or other protic solvents than their corresponding free base forms. The present invention includes such salts.
Pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and also those formed with organic acids such as maleic acid. For example, acids commonly employed to form
pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β- hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene -2-sulfonate, mandelate and the like.
Suitable bases for forming pharmaceutically acceptable salts with acidic functional groups include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di alkyl-N-(hydroxy alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-
hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.
Certain compounds of the invention and their salts may exist in more than one crystalline form (i.e., polymorph); the present invention includes each of the crystal forms and mixtures thereof.
Certain compounds of the invention and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
Certain compounds of the invention may contain one or more chiral centers, and exist in different optically active forms. When compounds of the invention contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures thereof. The enantiomers may be resolved by methods known to those skilled in the art; for example, enantiomers may be resolved by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example, via enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support; suitable include chiral supports (e.g., silica with a bound chiral ligand) or in the presence of a chiral solvent. Where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step may be used to liberate the desired purified enantiomer. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
When a compound of the invention contains more than one chiral center, it may exist in diastereoisomeric forms. The diastereoisomeric compounds may be separated by methods known to those skilled in the art (for example, chromatography or crystallization) and the individual enantiomers may be separated as described above. The present invention includes the various diastereoisomers of compounds of the invention, and mixtures thereof. Compounds of the invention may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and/or geometric isomer of compounds of the invention, and mixtures thereof. Compounds of the invention
may exist in zwitterionic form. The present invention includes each zwitterionic form of compounds of the invention, and mixtures thereof.
As used herein the term "pro-drug" refers to an agent which is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form). Pro-drugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmacological compositions over the parent drug. An example, without limitation, of a pro-drug would be a compound of the present invention wherein it is administered as an ester (the "pro-drug") to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is metabolically hydrolyzed to the carboxylic acid once inside the cell where water solubility is beneficial. Pro-drugs have many useful properties. For example, a pro-drug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the drug. A pro-drug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.
Exemplary pro-drugs release an amine of a compound of the invention wherein the free hydrogen of an amine or alcohol is replaced by (Ci-C6)alkanoyloxymethyl, l-((Ci- Ce)alkanoyl-oxy)ethyl, 1 -methyl- l-((Ci-C6)alkanoyloxy)ethyl, (Ci-Ce)alkoxycarbonyl- oxymethyl, N-(Ci-C6)alkoxycarbonylamino-methyl, succinoyl, (Ci-C6)alkanoyl, a- amino(Ci-C4)alkanoyl, arylactyl and a-aminoacyl, or α-aminoacyl-a-aminoacyl wherein said a-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, -P(0)(OH)2, -P(0)(0(Ci-C6)alkyl)2 or glycosyl (the radical resulting from detachment of the hydroxyl of the hemiacetal of a carbohydrate).
Other exemplary pro-drugs upon cleavage release a corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of this invention include but are not limited to carboxylic acid substituents (e.g., -(CH2)C(0)OH or a moiety that contains a carboxylic acid) wherein the free hydrogen is replaced by (Ci-C4)alkyl, (C2- Ci2)alkanoyloxy-methyl, (C4-Cc))l-(alkanoyloxy)ethyl, 1 -methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyl-oxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1 - (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-
(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C2)alkylamino(C2-C3)alkyl (such as β-dimethylamino-ethyl), carbamoyl-(Ci-C2)alkyl, N,N-di(Ci-C2)-alkylcarbamoyl-(Ci- C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl.
GENERAL SYNTHETIC METHODS
Some of the general methods which were utilized to prepare the compounds disclosed in this application are described below.
iii
In one approach to the preparation of sulfonamides, an aryl, heteroaryl or biaryl amine (i) can be reacted with an aryl, heteroaryl or biaryl sufonyl chloride (ii) to yield the desired sulfonamides (iii). Further chemical manipulation can then be done on any substituents on the A and/or B rings, as well as on the N-H of the sulfonamide (e.g.
methylation). The synthesis of compounds other than sufonamides, such as amides, can be effected by using a different nucleophile or electrophile, such as using an acyl chloride (- C(=0)C1) instead of a sulfonyl chloride (ii).
In addition, it may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form. The term "chemically protected form," as used herein, pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions (i.e., they have been modified with a protecting group).
By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic
Synthesis (T. Green and P. Wuts, Wiley, 1991), and Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=0)Pv), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or
trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=0)CH3,-OAc).
For example, an aldehyde or ketone group may be protected as an acetal or ketal, respectively, in which the carbonyl group (C(=0)) is converted to a diether (C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
For example, an amine group may be protected, for example, as an amide (- NRC(=0)R) or a urethane (-NRC(=0)OR), for example, as: a methyl amide (- NHC(=0)CH3); a benzyloxy amide (-NHC(=0)OCH2C6H5NHCbz); as a t-butoxy amide (- NHC=(=0)OC(CH3)3,-NHBoc); a 2-biphenyl-2-propoxy amide (-
NHC(=0)OC(CH3)2C6H4C6H5NHBoc), as a 9-fluorenylmethoxy amide (-NHFmoc), as a 6- nitroveratryloxy amide (-NFiNvoc), as a 2-trimethylsilylethyloxy amide (-NHTeoc), as a 2,2,2-trichloroethyloxy amide (-NHTroc), as an allyloxy amide (-NHAlloc), as a 2- (phenylsulfonyl)ethyloxy amide (-NHPsec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical.
For example, a carboxylic acid group may be protected as an ester or an amide, for example, as: a benzyl ester; a t-butyl ester; a methyl ester; or a methyl amide.
For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; or an acetamidomethyl ether (-SCH2NHC(=0)CH3).
PHARMACEUTICAL COMPOSITIONS
One or more compounds of this invention can be administered to a human patient by themselves or in pharmaceutical compositions where they are mixed with suitable carriers or excipient(s) at doses to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions. For example, one aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound of formula I, or a pharmaceutically acceptable salt, solvate, enantiomer or stereoisomer thereof; and a pharmaceutically acceptable diluent or carrier.
Techniques for formulation and administration of the compounds of the instant application may be found in references well known to one of ordinary skill in the art, such as "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition.
Suitable routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including
intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
Alternatively, one may administer a compound in a local rather than a systemic manner, for example, via injection of the compound directly into an edematous site, often in a depot or sustained release formulation.
Furthermore, one may administer a compound in a targeted drug delivery system, for example, in a liposome coated with endothelial-cell-specific antibody.
The pharmaceutical compositions of the present invention may be manufactured, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants are used in the formulation appropriate to the barrier to be permeated. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or
polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical preparations which can be used orally include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.
For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
The compounds can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
Alternatively, the active ingredient may be in powder form for reconstitution before use with a suitable vehicle, e.g., sterile pyrogen-free water.
The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly or by intramuscular injection). Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (for example, as a sparingly soluble salt).
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethysulfoxide also may be employed. Additionally, the compounds may be delivered using a sustained-release system, such as semi-permeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
The pharmaceutical compositions may also comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to
calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers, such as polyethylene glycols.
COMBINATION THERAPY
In one aspect of the invention, a compound of the invention, or a pharmaceutically acceptable salt thereof, can be used in combination with another therapeutic agent to treat diseases such cancer and/or neurological disorders. For example, the additional agent can be a therapeutic agent that is art-recognized as being useful to treat the disease or condition being treated by the compound of the present invention. The additional agent also can be an agent that imparts a beneficial attribute to the therapeutic composition (e.g., an agent that affects the viscosity of the composition).
The combination therapy contemplated by the invention includes, for example, administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, and additional agent(s) in a single pharmaceutical formulation as well as administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, and additional agent(s) in separate pharmaceutical formulations. In other words, co-administration shall mean the administration of at least two agents to a subject so as to provide the beneficial effects of the combination of both agents. For example, the agents may be administered simultaneously or sequentially over a period of time.
The agents set forth below are for illustrative purposes and are not intended to be limited. The combinations, which are part of this invention, can be the compounds of the present invention and at least one additional agent selected from the lists below. The combination can also include more than one additional agent, e.g., two or three additional agents if the combination is such that the formed composition can perform its intended function.
For example, one aspect of the invention relates to the use of compounds of the invention (e.g., those of formula I) in combination with at least one other anti-inflammatory or immunosuppressant agent. Examples of therapeutic agents that can be used in
combination therapy are described in greater detail below in the section on uses of the compounds of the invention.
DOSAGE
As used herein, a "therapeutically effective amount" or "therapeutically effective dose" is an amount of a compound of the invention or a combination of two or more such compounds, which inhibits, totally or partially, the progression of the condition or
alleviates, at least partially, one or more symptoms of the condition. A therapeutically effective amount can also be an amount which is prophylactically effective. The amount which is therapeutically effective will depend upon the patient's size and gender, the condition to be treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount may be determined by methods known to those of skill in the art.
A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) and the ED50 (effective dose for 50% maximal response). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between MTD and ED50. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. In the treatment of crises, the administration of an acute bolus or an infusion approaching the MTD may be required to obtain a rapid response.
Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the kinase modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
Dosage intervals can also be determined using the MEC value. Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% until the desired amelioration of symptoms is achieved. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
For administration of a compounds of the invention, the dosage ranges from about 0.0001 to 100 mg/kg, and more usually 0.01 to 5 mg/kg, of the host body weight. For example dosages can be 0.3 mg/kg body weight, 1 mg/kg body weight, 3 mg/kg body weight, 5 mg/kg body weight or 10 mg/kg body weight or within the range of 1-10 mg/kg. An exemplary treatment regime entails administration once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every three to 6 months.
Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
A "therapeutically effective dosage" of a compound of the invention preferably results in a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. For example, for the treatment of tumors, a "therapeutically effective dosage" preferably inhibits cell growth or tumor growth by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects. The ability of a compound to inhibit tumor growth can be evaluated in an animal model system predictive of efficacy in human tumors. Alternatively, this property of a composition can be evaluated by examining the ability of the compound to inhibit, such inhibition in vitro by assays known to the skilled practitioner. A therapeutically effective amount of a therapeutic compound can decrease tumor size, or otherwise ameliorate symptoms in a subject. One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.
KITS
The compounds and compositions of the invention (e.g., compounds and compositions of formula I) may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Instructions for use may also be provided.
USES AND METHODS
As noted above, PD-1 is an immunoreceptor belonging to the CD28/CTLA-4 family which negatively regulates antigen receptor signaling by mechanisms that include recruitment of protein tyrosine phosphatases, SHP-1 or SHP-2, upon interacting with either of two ligands, PD-L1 or PD-L2. Because of the wide range of ligand distribution in the body, its biological significance pervades almost every aspect of immune responses including autoimmunity, tumor immunity, infectious immunity, transplantation immunity, allergy and immunological privilege.
The compounds, compositions and methods of the present invention have numerous in vitro and in vivo utilities involving, for example, detection of PD-1 or enhancement of immune response by modulation of PD-1. In certain embodiments, the compounds of the invention can be administered to cells in culture, in vitro or ex vivo, or to subjects, e.g., in vivo, to enhance immunity in a variety of situations. Accordingly, in one aspect, the invention provides a method of modifying an immune response in a subject comprising administering to the subject a compound of the invention such that the immune response in the subject is modified.
As used herein, the term "subject" is intended to include human and non-human animals. Non-human animals includes all vertebrates, e.g. mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles, although mammals are preferred, such as non-human primates, sheep, dogs, cats, cows and horses. In certain embodiments, subjects include human patients in need of enhancement of an immune response. The methods are suitable for treating human patients having a disorder that can be treated by augmenting the T-cell mediated immune response. In certain embodiments, the methods are suitable for treatment of cancer cells in vivo. To
achieve antigen-specific enhancement of immunity, the compounds of the invention can be administered together with an antigen of interest. When the compounds of the invention are administered together with another agent, they can be administered in any order or simultaneously.
The invention further provides methods for detecting the presence of human PD-1 in a sample, or measuring the amount of human PD-1, comprising contacting the sample, and a control sample, with a compound of the invention which specifically binds to human PD- 1 , under conditions that allow for formation of a complex between the compound and human PD-1. The formation of a complex is then detected, wherein a difference in complex formation between the sample compared to the control sample is indicative of the presence of human PD-1 in the sample.
In certain embodiments, the agonists of the invention can be used in circumstances where a reduction in the level of immune response may be desirable, for example, in certain types of allergy or allergic reactions (e.g., by inhibition of IgE production), autoimmune diseases (e.g., rheumatoid arthritis, type I diabetes mellitus, multiple sclerosis,
inflammatory bowel disease, Crohn's disease, and systemic lupus erythematosis), tissue, skin and organ transplant rejection, and graft-versus-host disease (GVHD). In addition, under certain circumstances it may be desirable to elicit or enhance a patient's immune response in order to treat an immune disorder or cancer. The disorders being treated or prevented by the disclosed methods include but are not limited to infections with microbes (e.g. bacteria), viruses (e.g., systemic viral infections such as influenza, viral skin diseases such as herpes or shingles), or parasites; and cancer (e.g., melanoma and prostate cancers).
In addition, under certain circumstances it may be desirable to elicit or enhance a patient's immune response in order to treat an immune disorder or cancer. The disorders being treated or prevented by the disclosed methods include but are not limited to infections with microbes (e.g. bacteria), viruses (e.g., systemic viral infections such as influenza, viral skin diseases such as herpes or shingles), or parasites; and cancer (e.g., melanoma and prostate cancers).
In certain embodiments, stimulation of immune responses with compounds of the invention which are antagonists of PD-1 enhances T cell responses. Thus, in some embodiments, compounds of the invention can be used to inhibit or reduce the
downregulatory activity associated with PD-1, e.g., the activity associated with
downregulation of TcR/CD28 -mediated immune response. For example, modulation of PD-
1/PD-L interaction with antagonizing compounds should lead to enhanced T cell proliferative responses, consistent with a downregulatory role for the PD-1 pathway in T responses.
PD-1 is also expressed on B cells, macrophages and dendritic cells. Far less is know about PD-1 function on B cells, macrophages and DC. However, PD-1 also can inhibit responses of B cells and macrophages. Therefore, PD-1 antagonist and agonist compounds have the potential to modulate responses of any PD-1 expressing cell. For example, in certain embodiments, compounds of the invention which are PD-1 antagonists may be used to enhance B cell or macrophage responses.
In certain embodiments, the compounds of the invention inhibit binding of PD-L to
PD-1 with an IC50 of, for example, less than 10 nM, less then 5 nM, or less than 1 nM. Inhibition of PD-L binding can be measured as described herein or using techniques known in the art.
Cancer
Blockade of PD-1 can enhance the immune response to cancerous cells in the patient. The ligand for PD-1, PD-L1, is upregulated in a variety of human cancers. The level of PD-L 1 expression correlates with prognosis: the higher the expression of PD-L 1, the poorer the prognosis. The interaction between PD-1 and PD-L1 contributes to the multiple barriers that prevent anti-tumor responses, and shields tumors from immune eradication. Signals through this pathway can decrease tumor infiltrating lymphocytes, decrease T-cell receptor mediated proliferation, and induce regulatory T cells, promoting immune evasion by the cancerous cells. Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 and the effect may be additive when the interaction of PD-1 with PD-L2 is blocked as well. Previous studies have shown that T-cell proliferation can be restored by inhibiting the interaction of PD-1 with PD-L1. In one aspect, the present invention relates to treatment of a subject using a compound of the invention, which is a PD- 1/PD-L 1 antagonist, such that growth of cancerous tumors is inhibited. A compound of the invention may be used alone to inhibit the growth of cancerous tumors. Alternatively, a compound of the invention may be used, e.g., in conjunction with other immunogenic agents, standard cancer treatments, or antibodies.
Accordingly, in one embodiment, the invention provides a method of inhibiting growth of tumor cells in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention.
For example, cancers whose growth may be inhibited using the compounds of the invention include cancers typically responsive to immunotherapy. Non-limiting examples of cancers for treatment include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormone refractory prostate adenocarcinoma), breast cancer, colon cancer and lung cancer (e.g. non-small cell lung cancer). Additionally, the invention includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the invention.
Examples of other cancers that may be treated using the methods of the invention include bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, hematopoietic cancers, such as acute myeloid leukemia (AML), and combinations of said cancers. The present invention is also useful for treatment of metastatic cancers, especially metastatic cancers that express PD-L1.
Optionally, compounds of the invention can be combined with an immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), and cells transfected with genes encoding immune stimulating cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gplOO, MAGE antigens, Trp-2,
MARTI and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.
In humans, some tumors have been shown to be immunogenic, such as melanomas. It is anticipated that by raising the threshold of T cell activation by PD-1 blockade, one may expect to activate tumor responses in the subject.
PD-1 blockade is likely to be most effective when combined with a vaccination protocol. Many experimental strategies for vaccination against tumors have been devised. In one of these strategies, a vaccine is prepared using autologous or allogeneic tumor cells. These cellular vaccines have been shown to be most effective when the tumor cells are transduced to express GM-CSF. GM-CSF has been shown to be a potent activator of antigen presentation for tumor vaccination.
The study of gene expression and large scale gene expression patterns in various tumors has led to the definition of so called tumor specific antigens. In many cases, these tumor specific antigens are differentiation antigens expressed in the tumors and in the cell from which the tumor arose, for example melanocyte antigens gplOO, MAGE antigens, and Trp-2. More importantly, many of these antigens can be shown to be the targets of tumor specific T cells found in the host. PD-1 blockade may be used in conjunction with a collection of recombinant proteins and/or peptides expressed in a tumor in order to generate an immune response to these proteins. These proteins are normally viewed by the immune system as self antigens and are therefore tolerant to them. The tumor antigens may also include the protein telomerase, which is required for the synthesis of telomeres of chromosomes and which is expressed in more than 85% of human cancers and in only a limited number of somatic tissues. (These somatic tissues may be protected from immune attack by various means). Tumor antigens may also be "neo-antigens" expressed in cancer cells because of somatic mutations that alter protein sequence or create fusion proteins between two unrelated sequences (e.g. bcr-abl in the Philadelphia chromosome), or idiotype from B cell tumors.
Other tumor vaccines may include the proteins from viruses implicated in human cancers such a Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). Another form of tumor specific antigen which may be used in conjunction with PD-1 blockade is purified heat shock proteins (HSP) isolated from the tumor tissue itself. These heat shock proteins contain fragments of proteins from the tumor cells and these HSPs are highly efficient at delivery to antigen presenting cells for eliciting tumor immunity.
Dendritic cells (DC) are potent antigen presenting cells that can be used to prime antigen- specific responses. DCs can be produced ex vivo and loaded with various protein and peptide antigens as well as tumor cell extracts. DCs may also be transduced by genetic means to express these tumor antigens as well. DCs have also been fused directly to tumor cells for the purposes of immunization. As a method of vaccination, DC immunization may be effectively combined with PD-1 blockade to activate more potent anti-tumor responses.
PD-1 blockade may also be combined with standard cancer treatments. For example, PD-1 blockade may be effectively combined with chemotherapeutic regimes. In these instances, it may be possible to reduce the dose of chemotherapeutic reagent administered. An example of such a combination is a compound of the invention in combination with decarbazine for the treatment of melanoma. Another example of such a combination is a compound of the invention in combination with interleukin-2 (IL-2) for the treatment of melanoma. The scientific rationale behind the combined use of PD-1 blockade and chemotherapy is that cell death, that is a consequence of the cytotoxic action of most chemotherapeutic compounds, should result in increased levels of tumor antigen in the antigen presentation pathway. Other combination therapies that may result in synergy with PD-1 blockade through cell death are radiation, surgery, and hormone deprivation. Each of these protocols creates a source of tumor antigen in the host. Angiogenesis inhibitors may also be combined with PD-1 blockade. Inhibition of angiogenesis leads to tumor cell death, which may feed tumor antigen into host antigen presentation pathways.
PD-1 blocking compounds of the invention can also be used in combination with bispecific antibodies that target Fc alpha or Fc gamma receptor-expressing effectors cells to tumor cells (see, e.g., U.S. Pat. Nos. 5,922,845 and 5,837,243). Bispecific antibodies can be used to target two separate antigens. For example anti-Fc receptor/anti tumor antigen (e.g., Her-2/neu) bispecific antibodies have been used to target macrophages to sites of tumor. This targeting may more effectively activate tumor specific responses. The T cell arm of these responses may be augmented by the use of PD-1 blockade. Alternatively, antigen may be delivered directly to DCs by the use of bispecific antibodies which bind to tumor antigen and a dendritic cell specific cell surface marker.
Tumors evade host immune surveillance by a large variety of mechanisms. Many of these mechanisms may be overcome by the inactivation of proteins which are expressed by the tumors and which are immunosuppressive. These include among others TGF-beta, IL- 10, and Fas ligand. Antibodies to each of these entities may be used in combination with
PD-1 antagonist compounds of the invention to counteract the effects of the immunosuppressive agent and favor tumor immune responses by the host.
Bone marrow transplantation is currently being used to treat a variety of tumors of hematopoietic origin. While graft versus host disease is a consequence of this treatment, therapeutic benefit may be obtained from graft vs. tumor responses. PD-1 blockade can be used to increase the effectiveness of the donor engrafted tumor specific T cells.
There are also several experimental treatment protocols that involve ex vivo activation and expansion of antigen specific T cells and adoptive transfer of these cells into subjects in order to antigen-specific T cells against tumor. Ex vivo activation in the presence of anti-PD-1 compounds of the invention may be expected to increase the frequency and activity of the adoptively transferred T cells.
Infectious Diseases
Other methods of the invention are used to treat subjects that have been exposed to particular toxins or pathogens. Accordingly, another aspect of the invention provides a method of treating an infectious disease in a subject comprising administering to the subject a compound of the invention which is a PD-1 antagonist, such that the subject is treated for the infectious disease.
Progressive chronic or persistent viral infections, such as HIV or HCV, cause significant morbidity and mortality. Both CD8 and CD4 T cells are critical in the immune response to chronic viral infections and long-term control of latent and reactivating viruses. It appears that CD8 T cells are the major effectors exerting viral control and that CD4 T cell "help" is essential for sustaining CD8 T cell function during chronic infection (1, 2).
Unfortunately, in many instances the host T cell response fails to effectively contain viral replication (3, 4), and such infections are associated with suppressed T cell immunity (5-7). Defining the mechanisms that lead to this loss of T cell function during chronic infections may provide new targets for therapeutic intervention and augmenting of antiviral responses. Pathways in the B7:CD28 family regulate the balance between stimulatory and inhibitory signals needed for effective immune responses to microbes, while maintaining self- tolerance (for recent reviews, see (8-11)). Recent studies indicate that the PD-1 :PD-L pathway (12, 13), has a central role in regulating the interplay between host defenses aimed at eradicating pathogenic microbes and microbial strategies that evolved to resist immune responses and persist in the host (14).
For example, a number of microorganisms that cause chronic infection appear to have exploited the PD-1 :PD-L pathway to evade host immune effector mechanisms and establish persistent infection (11, 13). Following an acute infection or vaccination, effective antiviral T cells acquire the ability to perform multiple effector functions upon antigen stimulation, including cytokine production, cytotoxicity, and proliferation. Chronic viral infections, in contrast, are often characterized by T cell dysfunction (1, 7). For example, during chronic LCMV infection, virus-specific CD8 T cells lose the ability to elicit effector functions in a progressive and hierarchical manner (4). T cell "exhaustion" has been observed in many chronic viral infections in both animal models and humans (including HIV, HBV, HCV) (5-7, 17, 23, 42). Thus, while the precise functional defects often differ, the general concept of T cell dysfunction appears to be a common feature of persisting infections.
The PD-1 :PD-L pathway contributes directly to T cell dysfunction and lack of viral control in established chronic infection. In vivo blockade of PD-1 :PD-L1 interactions in mice restored T cell function and enhanced viral control in mice with chronic LCMV infection (14). These observations were quickly extended to humans. PD-1 levels are elevated on HIV, HBV and HCV-specific T cells (16, 17, 19-22, 24-26). Blocking PD- 1 :PD-L interactions in vitro reversed exhaustion of HIV and HCV-specific CD8 and CD4 T cells and restored cytokine production and proliferation (16, 19-21, 26). Thus, both animal models and human studies indicate that PD-1 expression on virus-specific T cells may limit antiviral effectiveness by downregulating function and proliferation, and suggest a new therapeutic strategy for chronic viral infection. Blockade of the PD-1 :PD-L pathway has the potential to reinvigorate exhausted virus-specific T cells and improve T cells responses to therapeutic vaccination, leading to enhanced viral control (15).
Similar to its application to tumors as discussed above, PD-1 blockade can be used alone, or as an adjuvant, in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self-antigens. Examples of pathogens for which this therapeutic approach may be particularly useful, include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to HIV, Hepatitis (A, B, & C), Influenza,
Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa. PD-1 blockade is particularly useful against established chronic or persistent infections by agents such as HIV that present altered antigens over the course of the infections. These
novel epitopes are recognized as foreign at the time of anti-human PD-1 administration, thus provoking a strong T cell response that is not dampened by negative signals through PD-1.
Some examples of pathogenic viruses causing infections treatable by methods of the invention include HIV, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6,
HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus .
The PD-1 :PD-L pathway appears to have a key role in chronicity of bacterial infections. For example, during H. pylori infection, T cell responses are insufficient to clear bacteria, leading to persistent infection. Following exposure to H. pylori, PD-L1 is upregulated on human gastric epithelial cells in vitro or in vivo (33). Anti-PD-Ll blocking antibodies enhance T cell proliferation and IL-2 production in cultures of gastric epithelial cells exposed to H. pylori and CD4 T cells (32), suggesting that PD-L1 blockade may provide a means to improve T cell responses and pathogen control during H. pylori infection. Some examples of other pathogenic bacteria causing infections treatable by methods of the invention include chlamydia, rickettsial bacteria, mycobacteria,
staphylococci, streptococci, pneumonococci, meningococci and gonococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme
disease bacteria.
Some examples of pathogenic fungi causing infections treatable by methods of the invention include Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Pneumocystis carinii, Coccidioides immitis and Histoplasma capsulatum.
Some examples of pathogenic parasites causing infections treatable by methods of the invention include Entamoeba histolytica, Balantidium coli, Naegleriafowleri,
Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.
In all of the above methods, PD-1 modulation can be combined with other forms of immunotherapy such as cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), or bispecific antibody therapy, which provides for enhanced presentation of tumor antigens.
Autoimmune Reactions
Compounds of the invention, which are PD-1/PD-L1 agonists, may be used to treat autoimmune diseases, as studies in disease models indicate that the PD-1 :PDL pathway is involved in a number of different autoimmune diseases. For example, the PD-1 receptor has been demonstrated to play a role in the development of diabetes. Using a nonobese diabetic (NOD) mouse model it has been demonstrated that blockade of PD-1 receptor, or PD-Ll, but not PD-L2 ligands accelerates onset of diabetes. There are a higher percentage of mice developing diabetes than in the control animals. This may be due to the role of PD-1 :PDL1 interactions in limiting T cell mediation of autoimmune B cell destruction or controlling the balance between pathogenic effector T cells and protective regulatory T cells. Several studies suggest that PD-1 :PD-L1 may mediate apoptosis of activated T cells. These data could provide the rationale for potential therapeutic use of agonists of the PD-1 :PD-L pathway in the treatment of autoimmune diseases, such as diabetes (45).
PD-Ll is expressed in parenchymal cells, and non-hematopoietic expression of PD- Ll was demonstrated to be able to protect against autoimmune diabetes using bone marrow chimeras where mice lacking both PD-Ll and PD-L2 were compared with mice lacking either PD-Ll or PD-L2. This study shows PD-Ll /PD-L2 expression on APCs is insufficient to prevent early onset diabetes that develops in PDL1/PDL2 knockout mice. Therefore, PD- Ll expression on tissues is a critical mediator of peripheral T cell tolerance. This finding supports the idea that the exploitation of the PDl :PD-L pathway by therapeutic intervention can be used to treat autoimmune disease (40).
The PD-1 :PD-L1 pathway also has a role in the regulation of experimental autoimmune encephalomyelitis (EAE). EAE mouse models are used to investigate the autoimmune disease, multiple sclerosis. In this study myelin oligodendrocyte glycoprotein (MOG) was used to induce EAE in mice. MOG induces an immune response that attacks cells of the central nervous system of the mouse. It is reported that after immunization with MOG, expression of PD-1 and PD-Ll, but not PD-L2, increased in cells of the central nervous system. Also blockade of the PD-1 receptor by antibodies, leads to accelerated and more severe EAE disease progression. It has been suggested that this result supports the idea that the PD-1 :PD-L pathway regulates peripheral tolerance. This result also supports
the idea that this pathway could be important in the treatment of many autoimmune diseases (45). The therapeutic potential of this pathway in autoimmune disease is illustrated by a study in which ES cell derived-DCs engineered to have high expression of PD-L1 and myelin antigen could ameliorate EAE and diminish infiltration of the spinal cord by macrophages and T cells (47).
Induction of anti-tumor responses using tumor cell and peptide vaccines reveals that many anti-tumor responses involve anti-self reactivities (depigmentation observed in anti- CTLA-4+GM-CSF-modified B 16 melanoma in van Elsas et al. supra; depigmentation in Trp-2 vaccinated mice; autoimmune prostatitis evoked by TRAMP tumor cell vaccines; and melanoma peptide antigen vaccination and vitilago observed in human clinical trials.
Therefore, it is possible to consider using compounds of the invention in
conjunction with various self proteins in order to devise vaccination protocols to efficiently generate immune responses against these self proteins for disease treatment. For example, Alzheimers disease involves inappropriate accumulation of Αβ peptide in amyloid deposits in the brain; antibody responses against amyloid are able to clear these amyloid deposits.
Other self proteins may also be used as targets such as IgE for the treatment of allergy and asthma, and TNFa for rheumatoid arthritis. Finally, antibody responses to various hormones may be induced by the use of a compound of the invention. Neutralizing antibody responses to reproductive hormones may be used for contraception. Neutralizing antibody response to hormones and other soluble factors that are required for the growth of particular tumors may also be considered as possible vaccination targets.
Analogous methods as described above for the use of compounds of the invention can be used for induction of therapeutic autoimmune responses to treat patients having an inappropriate accumulation of other self-antigens, such as amyloid deposits, including Αβ in Alzheimer's disease, cytokines such as TNFa, and IgE.
Additionally, PD-1 has been found to play a role in graft- versus-host disease (Blazar et al J Immuno 2003, 171 : 1272-7). For example, bone marrow transplantation is currently being used to treat a variety of tumors of hematopoietic origin. While graft versus host disease is a consequence of this treatment, therapeutic benefit may be obtained from graft vs. tumor responses. PD-1 modulation can be used to increase the effectiveness of the donor engrafted tumor specific T cells.
PD-1 also regulates alloimmune responses and graft rejection following solid organ transplantation (Yang et al. Circulation 2008; 117:660-9). For example, PD-1 blockade
leads to rapid expansion of graft reactive T cells and graft loss (Koehn et al J Immunol 2008; 181 : 5313-22).
It follows that one aspect of the invention related to a method for suppressing, treating, or preventing graft rejection accompanying the transplantation of an organ, or a portion thereof, or a tissue in a subject, the method comprising administering a
therapeutically effective amount of a compound or pharmaceutical composition of the invention to the subject. In certain embodiments, the present invention relates to any one of the aforementioned methods, wherein wherein the transplantation is allotransplantation. In certain embodiments, the present invention relates to any one of the aforementioned methods, wherein the transplantation is xenotransplantation. In certain embodiments, the present invention relates to any one of the aforementioned methods, wherein the organ is the liver, heart, kidney, lung, pancreas. In certain embodiments, the present invention relates to any one of the aforementioned methods, wherein the tissue is the skin, cornea, or bone tissue.
Another aspect of the invention relates to a method for enhancing the effect of at least one immunosuppressive agent on the suppression, treatment, or prevention of graft rejection accompanying the transplantation of an organ, or a portion thereof, or a tissue in a subject, the method comprising administering a therapeutically effective amount of a compound or pharmaceutical composition of the invention to the subject. In certain embodiments, the present invention relates to any one of the aforementioned methods, wherein the at least one immunosuppressive agent is selected from the group consisting of azathioprine, adrenocortical steroid, mizoribine, mycophenolate mofetil, leflunomide, sirolimus, deoxyspergualin, FTY720, abatacept, belatacept, an anti-CTLA antibody, cyclosporin, and tacrolimus (FK-506).
Vaccines
Compounds of the invention may be used to stimulate antigen-specific immune responses by coadministration of a compound of the invention with an antigen of interest (e.g., a vaccine). Accordingly, in another aspect the invention provides a method of enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) the antigen; and (ii) a compound of the invention, such that an immune response to the antigen in the subject is enhanced. The antigen can be, for example, a tumor antigen, a viral antigen, a bacterial antigen or an antigen from a pathogen. Non-limiting examples of such antigens include those discussed in the sections above, such as the tumor antigens (or
tumor vaccines) discussed above, or antigens from the viruses, bacteria or other pathogens described above.
Co-Administration with Other Therapeutic Agents
As previously described, compounds of the invention can be co-administered with one or more other therapeutic agents, e.g., a cytotoxic agent, a radiotoxic agent or an immunosuppressive agent. The compound can be linked to the agent or can be administered separate from the agent. In the latter case (separate administration), the compound can be administered before, after or concurrently with the agent or can be co-administered with other known therapies, e.g., an anti-cancer therapy, e.g., radiation. Such therapeutic agents include, among others, anti-neoplastic agents such as doxorubicin (adriamycin), cisplatin, bleomycin sulfate, carmustine, chlorambucil, decarbazine and cyclophosphamide hydroxyurea which, by themselves, are only effective at levels which are toxic or subtoxic to a patient. Cisplatin is intravenously administered as a 100 mg/dose once every four weeks and adriamycin is intravenously administered as a 60-75 mg/ml dose once every 21 days. Co-administration of the compound of the present invention with chemotherapeutic agents provides two anti-cancer agents which operate via different mechanisms which yield a cytotoxic effect to human tumor cells. Such co-administration can solve problems due to development of resistance to drugs or a change in the antigenicity of the tumor cells which would render them unreactive with the antibody.
DEFINITIONS
For convenience, certain terms employed in the specification, examples, and appended claims are collected here. All definitions, as defined and used herein, supersede dictionary definitions, definitions in documents incorporated by reference, and/or ordinary meanings of the defined terms.
The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.
The phrase "and/or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with "and/or" should be construed in the same fashion, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and/or" clause, whether related or unrelated to those
elements specifically identified. Thus, as a non-limiting example, a reference to "A and/or B", when used in conjunction with open-ended language such as "comprising" can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
As used herein in the specification and in the claims, "or" should be understood to have the same meaning as "and/or" as defined above. For example, when separating items in a list, "or" or "and/or" shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of." "Consisting essentially of," when used in the claims, shall have its ordinary meaning as used in the field of patent law.
As used herein in the specification and in the claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a non- limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently "at least one of A and/or B") can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts
of the method is not necessarily limited to the order in which the steps or acts of the method are recited.
In the claims, as well as in the specification above, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of and "consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.
The terms "co-administration" and "co-administering" refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time varied administration (administration of one or more therapeutic agents at a time different from that of the administration of an additional therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent at the same time.
The term "solvate" refers to a pharmaceutically acceptable form of a specified compound, with one or more solvent molecules, that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with solvents such, for example, water (to form the hydrate), isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or acetone. Also included are formulations of solvate mixtures such as a compound of the invention in combination with two or more solvents.
The definition of each expression, e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the 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.
The term "substituted" is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein below. The permissible substituents may be one or more and the same or
different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
The term "lower" when appended to any of the groups listed below indicates that the group contains less than seven carbons (i.e., six carbons or less). For example "lower alkyl" refers to an alkyl group containing 1-6 carbons, and "lower alkenyl" refers to an alkyenyl group containing 2-6 carbons.
The term "unsaturated," as used herein, pertains to compounds and/or groups which have at least one carbon-carbon double bond or carbon-carbon triple bond.
The term "aliphatic," as used herein, pertains to compounds and/or groups which are linear or branched, but not cyclic (also known as "acyclic" or "open-chain" groups).
The term "cyclic," as used herein, pertains to compounds and/or groups which have one ring, or two or more rings (e.g., spiro, fused, bridged).
The term "aromatic" refers to a planar or polycyclic structure characterized by a cyclically conjugated molecular moiety containing 4n+2 electrons, wherein n is the absolute value of an integer. Aromatic molecules containing fused, or joined, rings also are referred to as bicyclic aromatic rings. For example, bicyclic aromatic rings containing heteroatoms in a hydrocarbon ring structure are referred to as bicyclic heteroaryl rings.
The term "hydrocarbon" as used herein refers to an organic compound consisting entirely of hydrogen and carbon.
For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and
Physics, 67th Ed., 1986-87, inside cover.
The term "heteroatom" as used herein is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
The term "alkyl" means an aliphatic or cyclic hydrocarbon radical containing from 1 to 20, 1 to 15, or 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 2-methylcyclopentyl, and 1-cyclohexylethyl.
The term "alkenyl" as used herein means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
The term "alkynyl" as used herein means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
The term "alkylene," is art-recognized, and as used herein pertains to a bidentate moiety obtained by removing two hydrogen atoms of an alkyl group, as defined above.
The term "carbocyclyl" as used herein means monocyclic or multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbons containing from 3 to 12 carbon atoms that is completely saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system (e.g., phenyl).
Examples of carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1- cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl and 2-cyclopentenylmethyl.
The term "heterocyclyl", as used herein include non-aromatic, ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, which can be completely saturated or which can contain one or more units of unsaturation, for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system, and have 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur. For purposes of exemplification, which should not be construed as limiting the scope of this invention, the following are examples of heterocyclic rings: azepines, azetidinyl, morpholinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, quinicludinyl, thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl. The heterocyclyl groups of the invention are substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluroralkylsulfonyl,
alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluroralkoxysulfonyl, alkenyloxysulfonyl, alkynyloxysulfony, aminosulfonyl, sulfuric acid, alkylsulfmyl,
haloalkylsulfinyl, fluroralkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl, fluroralkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfiny, aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkylcarbonyl,
alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, fluroralkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluroralkoxysulfonyloxy,
alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, haloalkylsulfinyloxy, fluroralkylsulfinyloxy, alkenylsulfinyloxy, alkynylsulfmyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy, fluroralkoxysulfinyloxy, alkenyloxysulfinyloxy,
alkynyloxysulfinyloxy, aminosulfinyloxy, amino, amido, aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl, phosphoryl, silyl, silyloxy, and any of said substituents bound to the heterocyclyl group through an alkylene moiety (e.g., methylene).
The term "aryl," as used herein means a phenyl group, naphthyl, phenanthrenyl, or anthracenyl group. The aryl groups of the present invention can be optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluroralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluroralkoxysulfonyl, alkenyloxysulfonyl, alkynyloxysulfony, aminosulfonyl, sulfinic acid, alkylsulfinyl, haloalkylsulfinyl, fluroralkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl, fluroralkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfiny, aminosulfinyl, formyl, alkylcarbonyl,
haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, fluroralkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluroralkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, haloalkylsulfinyloxy, fluroralkylsulfinyloxy, alkenylsulfinyloxy, alkynylsulfmyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy, fluroralkoxysulfinyloxy, alkenyloxysulfinyloxy,
alkynyloxysulfinyloxy, aminosulfinyloxy, amino, amido, aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl, phosphoryl, silyl, silyloxy, and any of said substituents bound to the heterocyclyl group through an alkylene moiety (e.g., methylene).
The term "arylene," is art-recognized, and as used herein pertains to a bidentate moiety obtained by removing two hydrogen atoms of an aryl ring, as defined above.
The term "arylalkyl" or "aralkyl" as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aralkyl include, but are not limited to, benzyl, 2-phenylethyl, 3- phenylpropyl, and 2-naphth-2-ylethyl.
The term "heteroaryl" as used herein include aromatic ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, and have 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur. For purposes of exemplification, which should not be construed as limiting the scope of this invention: azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl,
benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl or tropanyl. The heteroaryl groups of the invention are substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, fluroralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluroralkoxysulfonyl, alkenyloxysulfonyl,
alkynyloxysulfony, aminosulfonyl, sulfinic acid, alkylsulfinyl, haloalkylsulfinyl, fluroralkylsulfinyl, alkenylsulfinyl, alkynylsulfmyl, alkoxysulfinyl, haloalkoxysulfinyl, fluroralkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfiny, aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy,
fluroralkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluroralkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfmyloxy, haloalkylsulfinyloxy, fluroralkylsulfinyloxy, alkenylsulfinyloxy, alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy, fluroralkoxysulfinyloxy, alkenyloxysulfinyloxy, alkynyloxysulfinyloxy, aminosulfinyloxy, amino, amido, aminosulfonyl, aminosulfmyl, cyano, nitro, azido, phosphinyl, phosphoryl, silyl, silyloxy, and any of said substituents bound to the heteroaryl group through an alkylene moiety (e.g., methylene).
The term "heteroarylene," is art-recognized, and as used herein pertains to a bidentate moiety obtained by removing two hydrogen atoms of a heteroaryl ring, as defined above.
The term "heteroarylalkyl" or "heteroaralkyl" as used herein means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heteroarylalkyl include, but are not limited to, pyridin- 3-ylmethyl and 2-(thien-2-yl)ethyl.
The term "biaryl," as used herein means an aryl-substituted aryl, an aryl-substituted heteroaryl, a heteroaryl-substituted aryl or a heteroaryl-substituted heteroaryl, wherein aryl and heteroaryl are as defined herein. Representative examples include 4-(phenyl)phenyl and 4-(4-methoxyphenyl)pyridinyl.
The term "halo" or "halogen" means -CI, -Br, -I or -F.
The term "haloalkyl" means an alkyl group, as defined herein, wherein at least one hydrogen is replaced with a halogen, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
The term "fluoroalkyl" means an alkyl group, as defined herein, wherein some or all of the hydrogens are replaced with fluorines.
The term "hydroxy" as used herein means an -OH group.
The term "alkoxy" as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. The terms "alkyenyloxy", "alkynyloxy", "carbocyclyloxy", and "heterocyclyloxy" are likewise defined.
The term "haloalkoxy" as used herein means an alkoxy group, as defined herein, wherein at least one hydrogen is replaced with a halogen, as defined herein. Representative
examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy. The term "fluoroalkyloxy" is likewise defined.
The term "aryloxy" as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen. The term "heteroaryloxy" as used herein means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen. The terms "heteroaryloxy" is likewise defined.
The term "arylalkoxy" or "arylalkyloxy" as used herein means an arylalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen. The term "heteroarylalkoxy" is likewise defined. Representative examples of aryloxy and heteroarylalkoxy include, but are not limited to, 2-chlorophenylmethoxy, 3-trifluoromethyl- phenylethoxy, and 2,3-dimethylpyridinylmethoxy.
The term "sulfhydryl" or "thio" as used herein means a -SH group.
The term "alkylthio" as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur. Representative examples of alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, and hexylthio. The terms "haloalkylthio", "fluoroalkylthio", "alkyenylthio", "alkynylthio",
"carbocyclylthio", and "heterocyclylthio" are likewise defined.
The term "arylthio" as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through a sulfur. The term "heteroarylthio" is likewise defined.
The term "arylalkylthio" or "aralkylthio" as used herein means an arylalkyl group, as defined herein, appended to the parent molecular moiety through a sulfur. The term "heteroarylalkylthio" is likewise defined.
The term "sulfonyl" as used herein refers to -S(=0)2- group.
The term "sulfonic acid" as used herein refers to -S(=0)2OH.
The term "alkylsulfonyl" as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl. The terms "haloalkylsulfonyl", "fluororalkylsulfonyl",
"alkenylsulfonyl", "alkynylsulfonyl", "carbocyclylsulfonyl", "heterocyclylsulfonyl", "arylsulfonyl", "aralkylsulfonyl", "heteroarylsulfonyl" and "heteroaralkylsulfonyl" are likewise defined.
The term "alkoxysulfonyl" as used herein means an alkoxy group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
Representative examples of alkoxysulfonyl include, but are not limited to,
methoxysulfonyl, ethoxysulfonyl and propoxy sulfonyl. The terms "haloalkoxysulfonyl", ' 'fluroralkoxy sulfonyl", ' 'alkeny loxy sulfonyl' ' , ' 'alkyny loxy sulfonyl",
"carbocyclyloxysulfonyl", "heterocyclyloxysulfonyl", "aryloxysulfonyl",
"aralkyloxysulfonyl", "hetero aryloxysulfonyl" and "heteroaralkyloxysulfonyl" are likewise defined.
The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, /?-toluenesulfonyl, methanesulfonyl, and
nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, /?-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
The term "aminosulfonyl" as used herein means an amino group, as defined herein, appended to the parent molecular moiety through a sulfonyl group.
The term "sulfmyl" as used herein refers to -S(=0)- group. Sulfmyl groups are as defined above for sulfonyl groups. The term "sulfuric acid" as used herein refers to - S(=0)OH.
The term "oxy" refers to a -O- group.
The term "carbonyl" as used herein means a -C(=0)- group.
The term "thiocarbonyl" as used herein means a -C(=S)- group.
The term "formyl" as used herein means a -C(=0)H group.
The term "alkylcarbonyl" as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1- oxopropyl, 2,2-dimethyl-l-oxopropyl, 1-oxobutyl, and 1-oxopentyl. The terms
"haloalkylcarbonyl", "fluoroalkylcarbonyl", "alkeny lcarbonyl", "alkynylcarbonyl", "carbocyclylcarbonyl", "heterocyclylcarbonyl", "arylcarbonyl", "aralkylcarbonyl", "heteroarylcarbonyl", and "heteroaralkylcarbonyl" are likewise defined.
The term "carboxy" as used herein means a -C02H group.
The term "alkoxycarbonyl" as used herein means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined
herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl. The terms
"haloalkoxycarbonyl", "fluoroalkoxycarbonyl", "alkenyloxycarbonyl",
"alkynyloxycarbonyl", "carbocyclyloxycarbonyl", "heterocyclyloxycarbonyl",
"aryloxycarbonyl", "aralkyloxycarbonyl", "heteroaryloxycarbonyl", and
"heteroaralkyloxycarbonyl" are likewise defined.
The term "alkylcarbonyloxy" as used herein means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. The terms "haloalkylcarbonyloxy", "fluoroalkylcarbonyloxy", "alkenylcarbonyloxy", "alkynylcarbonyloxy",
"carbocyclylcarbonyloxy", "heterocyclylcarbonyloxy", "arylcarbonyloxy",
"aralkylcarbonyloxy", "heteroarylcarbonyloxy", and "heteroaralkylcarbonyloxy" are likewise defined.
The term "alkylsulfonyloxy" as used herein means an alkylsulfonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. The terms "haloalkylsulfonyloxy", "fluroralkylsulfonyloxy", "alkenylsulfonyloxy",
"alkynylsulfonyloxy", "carbocyclylsulfonyloxy", "heterocyclylsulfonyloxy",
' 'arylsulfony loxy ", ' 'aralky lsulfony loxy ", ' 'heteroarylsulfony loxy ",
' 'heteroaralky lsulfony loxy ", ' 'haloalkoxy sulfony loxy ' ' , ' 'fluroralkoxy sulfony loxy ", ' 'alkenyloxy sulfony loxy ", ' 'alkyny loxy sulfony loxy ", ' 'carbocy cly loxy sulfony loxy ", "heterocyclyloxysulfonyloxy", "aryloxysulfonyloxy", "aralkyloxysulfonyloxy",
"heteroaryloxysulfonyloxy" and "heteroaralkyloxysulfonyloxy" are likewise defined.
The term "amino" as used herein refers to -NH2 and substituted derivatives thereof wherein one or both of the hydrogens are independently replaced with substituents selected from the group consisting of alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carbocyclylcarbonyl,
heterocyclylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl,
heteroaralkylcarbonyl and the sufonyl and sulfmyl groups defined above; or when both hydrogens together are replaced with an alkylene group (to form a ring which contains the nitrogen). Representative examples include, but are not limited to methylamino, acetylamino, and dimethylamino.
The term "amido" as used herein means an amino group, as defined herein, appended to the parent molecular moiety through a carbonyl.
The term "cyano" as used herein means a -C≡N group.
The term "nitro" as used herein means a -N02 group.
The term "azido" as used herein means a -N3 group.
The term "phosphinyl" or "phosphino" as used herein includes -PH3 and substituted derivatives thereof wherein one, two or three of the hydrogens are independently replaced with substituents selected from the group consisting of alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy, haloalkoxy, fluoroalkyloxy, alkenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, and amino.
The term "phosphoryl" as used herein refers to -P(=0)OH2 and substituted derivatives thereof wherein one or both of the hydroxyls are independently replaced with substituents selected from the group consisting of alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy, haloalkoxy, fluoroalkyloxy, alkenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, and amino.
The term "silyl" as used herein includes H3Si- and substituted derivatives thereof wherein one, two or three of the hydrogens are independently replaced with substitutuents selected from alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. Representative examples include trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM).
The term "silyloxy" as used herein means a silyl group, as defined herein, is appended to the parent molecule through an oxygen atom.
The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, /?-toluenesulfonyl and
methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations.
The term "treating" as used herein, encompasses the administration and/or application of one or more compounds described herein, to a subject, for the purpose of
providing prevention of or management of, and/or remedy for a condition. "Treatment" for the purposes of this disclosure, may, but does not have to, provide a cure; rather,
"treatment" may be in the form of management of the condition. When the compounds described herein are used to treat unwanted proliferating cells, including cancers,
"treatment" includes partial or total destruction of the undesirable proliferating cells with minimal destructive effects on normal cells. A desired mechanism of treatment of unwanted rapidly proliferating cells, including cancer cells, at the cellular level is apoptosis.
The term "preventing" as used herein includes either preventing or slowing the onset of a clinically evident disease progression altogether or preventing or slowing the onset of a preclinically evident stage of a disease in individuals at risk. This includes prophylactic treatment of those at risk of developing a disease.
The term "subject" for purposes of treatment includes any human or animal subject who has been diagnosed with, has symptoms of, or is at risk of developing a disorder. For methods of prevention the subject is any human or animal subject. To illustrate, for purposes of prevention, a subject may be a human subject who is at risk of or is genetically predisposed to obtaining a disorder characterized by unwanted, rapid cell proliferation, such as cancer. The subject may be at risk due to exposure to carcinogenic agents, being genetically predisposed to disorders characterized by unwanted, rapid cell proliferation, and so on. Besides being useful for human treatment, the compounds described herein are also useful for veterinary treatment of mammals, including companion animals and farm animals, such as, but not limited to dogs, cats, horses, cows, sheep, and pigs.
The term "modulate" (and grammatical equivalents) refers to an increase or decrease in activity. In particular embodiments, the term "increase" or "enhance" (and grammatical equivalents) means an elevation by at least about 25%, 50%>, 75%, 2-fold, 3-fold, 5-fold, 10-fold, 15-fold, 20-fold or more. In particular embodiments, the terms "decrease" or
"reduce" (and grammatical equivalents) means a diminishment by at least about 25%, 40%, 50%, 60%, 75%, 80%, 85%, 90%, 95%, 98% or more. In some embodiments, the indicated activity, substance or other parameter is not detectable.
The term "immune response" refers to the action of, for example, lymphocytes, antigen presenting cells, phagocytic cells, granulocytes, and soluble macromolecules produced by the above cells, the liver or mucosal barriers (including antibodies, cytokines, and complement) that results in selective damage to, destruction of, or elimination from the human body of invading pathogens, cells or tissues infected with pathogens, cancerous
cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.
As used herein, "hyperproliferative disease" refers to conditions wherein cell growth is increased over normal levels. For example, hyperproliferative diseases or disorders include malignant diseases (e.g., esophageal cancer, colon cancer, biliary cancer) and non- malignant diseases (e.g., atherosclerosis, benign hyperplasia, benign prostatic hypertrophy).
As used herein, "about" or "comprising essentially of mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" or "comprising essentially of can mean within 1 or more than 1 standard deviation per the practice in the art. Alternatively, "about" or "comprising essentially of can mean a range of up to 20%. Furthermore, particularly with respect to biological systems or processes, the terms can mean up to an order of magnitude or up to 5-fold of a value. When particular values are provided in the application and claims, unless otherwise stated, the meaning of "about" or "comprising essentially of should be assumed to be within an acceptable error range for that particular value.
EXEMPLIFICATION
The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.
Chemical names used below were generated using ChemDraw Ultra version 11.0. Preparation of N-(5-methyl- 1 ,3 ,4-thiadiazol-2-yl)-4-(methylamino)benzenesulfonamide
To a solution of 5-methyl-l,3,4-thiadiazol-2-amine (20g, 5.8mmol) in pyridine (19mL, 11.6mmol) and DCM (lOOmL) was added 4-nitrobenzene-l-sulfonyl chloride
(25.6g, 8.69mmol) in DCM (50mL). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid (9g). The solid was purified by column chromatography to give N-(5-methyl-l,3,4-thiadiazol-2-yl)-4- nitrobenzenesulfonamide. MS (ESI) m/z 301 [M+H]+.
To a solution of N-(5-methyl-l,3,4-thiadiazol-2-yl)-4-nitrobenzenesulfonamide (300mg, lmmol) in EtOH (8.6mL) was added Fe (336 mg, 6 mmol) followed by cone. HC1 (2 drops) and H20 (4.3mL). The reaction was heated to reflux for three hours. Fe was removed by filtration. The filtrate was evaporated to give a solid. The solid was purified by column chromatography to give 4-amino-N-(5 -methyl- 1,3, 4-thiadiazol-2- yl)benzenesulfonamide (300mg, 100%). 1H NMR (300Hz, DMSO-d6) δ ppm 13.61 (s, 1H), 7.41 (d, 2H), 6.56 (d, 2H), 5.89 (s, 1H), 2.43 (s, 3H). MS (ESI) m/z 271 [M+H]+.
To a solution of 4-amino-N-(5-methyl-l,3,4-thiadiazol-2-yl)benzenesulfonamide (200mg, 0.74mmol) in DMF (2mL) was added Mel (0.74mmol). The mixture was stirred at RT for two days. The solvent was removed under reduced pressure to give a solid. The resulting crude product was purified by column chromatography to give N-(5-methyl-l,3,4- thiadiazol-2-yl)-4-(methylamino)benzenesulfonamide (60mg, 30%). 1H NMR (300Hz, DMSO-d6) δ ppm 7.42 (d, 2H), 6.48 (d, 2H), 6.21 (s, 1H), 2.66 (d, 3H), 2.36 (s, 3H). MS (ESI) m z 307.3 [M+Na]+.
Preparation of N-(4-(N-(5-methyl-l, 3, 4-thiadiazo -2-yl)sulfamoyl)phenyl)acetamide
To a solution of 4-amino-N-(5-methyl-l,3,4-thiadiazol-2-yl)benzenesulfonamide (200mg, 0.74mmol) in pyridine (2mL) was added AcCl (58mg, 0.74mmol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give N-(4-(N-(5-methyl-l,3,4- thiadiazol-2-yl)sulfamoyl)phenyl)acetamide (70mg, 30.3%). 1H NMR (300Hz, DMSO-d6) 5 ppm 13.89 (s, 1H),10.31 (s, 1H), 7.75 (s, 4H), 2.49 (s, 3H), 2.11 (s, 3H). MS (ESI) m/z 311.0 [M-H]~.
Preparation o Methyl 4-(N-(5-methyl-l,3,4-thiadiazol-2-yl)sulfamoyl)phenylcarbamate
To a solution of 4-amino-N-(5-methyl-l,3,4-thiadiazol-2-yl)benzenesulfonamide (200mg, 0.74mmol) in pyridine (2mL) was added methyl chloro formate (70mg, 0.74mmol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give methyl 4-(N-(5 -methyl- 1, 3, 4-thiadiazol-2-yl)sulfamoyl)phenylcarbamate (80mg, 32.9%). 1H NMR (300Hz, DMSO-d6) δ ppm 10.04 (s, 1H), 7.68 (d, 2H), 7.56 (d, 2H), 3.68 (s, 3H), 2.43 (s, 3H). MS (ESI) m/z 351.1 [M+Na]+.
Preparatio -(5-methyl- 1 ,3 ,4-thiadiazol-2-yl)-4-(3-methylureido)benzenesulfonamide
To a solution of 4-amino-N-(5-methyl-l,3,4-thiadiazol-2-yl)benzenesulfonamide
(200mg, 0.74mmol) in pyridine (2mL) was added methylcarbamic chloride (69mg,
0.74mmol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give N-(5-methyl-l ,3,4-thiadiazol-2-yl)-4-(3-methylureido)benzenesulfonamide (50mg, 20.6%>). 1H NMR (300Hz, DMSO-d6) δ ppm 13.89 (s, 1H),8.94 (s, 1H), 7.62 (d, 2H), 7.53 (d, 2H), 6.14 (s, 1H), 2.64 (s, 3H), 2.45 (s, 3H). MS (ESI) m/z 326.1 [M-H]".
To a solution of cone. H2S04 (0.3g) in H20 (lmL) was added 4-amino-N-(5-methyl- l,3,4-thiadiazol-2-yl)benzenesulfonamide (200g, 0.74mmol) followed by a solution of NaN02 (5 lmg, 0.74mmol) in water (0.5mL). The mixture was heated to reflux for five minutes. The solvent was added into chilled water and filtered. Dry the filter cake and give 4-hydroxy-N-(5 -methyl- 1, 3, 4-thiadiazol-2-yl)benzenesulfonamide (95mg, 47.5%). 1H NMR (300Hz, DMSO-d6) δ ppm 13.78 (s, 1H), 10.34 (s, 1H), 7.60 (d, 2H), 6.85 (d, 2H), 2.23 (s, 3H). MS (ESI) m z 269.8 [M-H]".
reparation of 6-Amino-N-(5-methyl-l,3,4-thiadiazol-2-yl)pyridine-3-sulfonam
To a solution of 5-methyl-l,3,4-thiadiazol-2-amine (lOOmg, 0.799mmol) in pyridine (5ml) was added 6-chloropyridine-3-sulfonyl chloride (200mg, 0.94mmol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give 6-chloro-N-(5-methyl- l,3,4-thiadiazol-2-yl)pyridine-3-sulfonamide (25mg, 10.7%). 1H NMR (300Hz, DMSO- d6) δ ppm 8.62 (s, 1H), 8.05 (d, 2H), 7.55 (d, 2H), 2.44 (s, 3H). MS (ESI) m/z 288.9 [M-
H]-.
The mixture of 6-chloro-N-(5-methyl-l,3,4-thiadiazol-2-yl)pyridine-3-sulfonamide (45mg, 0.155mmol) in NH3 H20 (lOmL) was heated at HO C for two days. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give amino-N-(5-methy 1-1, 3, 4-thiadiazol-2-yl)pyridine-3 -sulfonamide (26mg, 61.9%). 1H NMR (300Hz, DMSO-d6) δ ppm 8.21 (s, 1H), 7.57 (d, 2H), 6.46 (s, 2H), 6.40 (d, 2H), 2.37 (s, 3H). MS (ESI) m/z 270.0 [M-H]".
Preparation of 4-Amino-N-(5-methyl-l,3,4-thiadiazol-2-yl)benzamide
(lOmL) was added 4-nitrobenzoyl chloride (3.3g, 17.37mmol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give N-(5 -methyl- 1,3, 4-thiadiazol-2-yl)-4- nitrobenzamide (834mg, 36.4%). MS (ESI) m/z 263.1 [M-H]"
To a solution of N-(5-methyl-l,3,4-thiadiazol-2-yl)-4-nitrobenzamide (478mg,
1.81mmol) in EtOH (9.6ml) was added Fe (608mg, 10.9mmol) followed by cone. HC1 (3 drops) and H20 (4.8mL). The reaction was heated to reflux for three hours. Fe was removed by filtration. The filtrate was evaporated to give a solid. The solid was purified by column chromatography to give 4-amino-N-(5 -methyl- 1, 3, 4-thiadiazol-2-yl)benzamide
(380 mg, 89.6%). lH NMR (300Hz, DMSO-d6) δ ppm 11.89 (s, 1H), 7.61 (d, 2H), 6.54 (d, 2H), 5.86 (s, 2H). MS (ESI) m/z 233 [M-H]~.
To a solution of NaH (O. lg, 4.33mmol) in THF (2mL) was added a solution of N-(5- methyl-l,3,4-thiadiazol-2-yl)-4-nitrobenzenesulfonamide (l .Og, 3.33mmol) in THF (8mL) followed by Mel (0.95g, 6.66mmol). The mixture was stirred at RT for two hours. The mixture was quenched by water. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give N-methyl-N-(5-methyl- l,3,4-thiadiazol-2-yl)-4-nitrobenzenesulfonamide (360mg, 34.6%). MS (ESI) m/z 327.3 [M+Na]+.
To a solution of N-methyl-N-(5-methyl-l,3,4-thiadiazol-2-yl)-4- nitrobenzenesulfonamide (200mg, 0.636mmol) in EtOH (4ml) was added Fe (214mg, 3.82mmol) followed by cone. HC1 (2 drops) and H20 (2mL).The reaction was heated to reflux for three hours. Fe was removed by filtration. The filtrate was evaporated to give a solid. The solid was purified by column chromatography to give 4-amino-N-methyl-N-(5- methyl-l,3,4-thiadiazol-2-yl)benzenesulfonamide (178 mg, 98%). 1H NMR (300Hz, DMSO-d6) δ ppm 7.43 (d, 2H), 6.57 (d, 2H), 5.91 (s, 2H), 3.57 (s, 3H), 2.45 (s, 3H). MS (ESI) m/z 307 [M+Na]+.
Preparation of 4-Amino-N-(l,3,4-thiadiazol-2-yl)benzenesulfonamide
To a solution of 1, 3, 4-thiadiazol-2-aminel (5.0g, 49.44mmol) in pyridine (130mL) was added 4-nitrobenzene-l-sulfonyl chloride (7.3g, 32.96mmol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give 4-nitro-N-(l,3,4-thiadiazol-2- yl)benzenesulfonamide (1.82g, 20%>).
To a solution of 4-nitro-N-(l,3,4-thiadiazol-2-yl)benzenesulfonamide (500mg, 1.7465mmol) in EtOH (lOmL) was added Fe (587mg, 10.4789mmol) followed by cone. HCl (5drops) and H20 (5mL). The reaction was heated to refiux for three hours. Fe was removed by filtration. The filtrate was evaporated to give a solid. The solid was purified by column chromatography to give 4-amino-N-(l,3,4-thiadiazol-2-yl)benzenesulfonamide (138 mg, 31%). 1H NMR (300Hz, DMSO-d6) δ ppm 8.64 (s, 1H), 7.40 (d, 2H), 6.56 (d, 2H), 5.85 (s, 2H). MS (ESI) m/z 254.9 [M-H]".
Preparation of 4-Amino-N-(5-phenyl-l,3,4-thiadiazol-2-yl)benzenesulfonamide
To a solution of 5-phenyl-l,3,4-thiadiazol-2-amine (1.5g, 8.4mmol) in pyridine (20mL) was added 4-nitrobenzene-l-sulfonyl chloride (930mg, 4.2mmol) followed by DMAP (69mg, 0.5462mmol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give 4-nitro-N-(5-phenyl-l,3,4-thiadiazol-2-yl)benzenesulfonamide (429mg, 31%). MS (ESI) m/z 361 [M-H]".
To a solution of 4-nitro-N-(5-phenyl-l,3,4-thiadiazol-2-yl)benzenesulfonamide (340mg, 0.938mmol) in EtOH (6.8mL) was added Fe (315mg, 5.629mmol) followed by cone. HCl (2 drops) and H20 (3.4mL). The reaction was heated to reflux for three hours. Fe was removed by filtration. The filtrate was evaporated to give a solid. The solid was purified by column chromatography to give 4-amino-N-(5 -phenyl- 1,3, 4-thiadiazol-2- yl)benzenesulfonamide (360 mg, 100%). 1H NMR (300Hz, DMSO-d6) δ ppm 7.80 (s, 2H), 7.53- 7.46 (m, 6H), 6.58 (s, 2H), 5.94 (s, 2H). MS (ESI) m z 331 [M-H]".
Preparation of 4-Amino-N-(5-(methoxymethyl)-l,3,4-thiadiazol-2-yl)benzenesulfonamide
To a solution of 5-(methoxymethyl)-l,3,4-thiadiazol-2-amine (500mg, 3.444mmol) in pyridine (5mL) was added 4-nitrobenzene-l-sulfonyl chloride (1.5g, 6.888mmol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give N-(5- (methoxymethyl)-l,3,4-thiadiazol-2-yl)-4-nitrobenzenesulfonamide (l .Og, 91%). MS (ESI) m/z 329 [M-H]~.
To a solution of N-(5-(methoxymethyl)-l,3,4-thiadiazol-2-yl)-4- nitrobenzenesulfonamide (300mg, 0.90843mmol) in EtOH (6ml) was added Fe (305mg, 5.45mmol) followed by cone. HC1 (3drops) and H20(3mL). The reaction was heated to reflux for three hours. Fe was removed by filtration. The filtrate was evaporated to give a solid. The solid was purified by column chromatography to give 4-amino-N-(5- (methoxymethyl)-l ,3,4-thiadiazol-2-yl)benzenesulfonamide (273 mg, 100%). 1H NMR (300Hz, DMSO-d6) δ ppm 7.40 (d, 2H), 6.56 (d, 2H), 5.87 (s, 2H), 4.53 (s, 2H), 3.32 (s, 3H). MS (ESI) m/z 301 [M+H]+.
Preparation of 4-Amino-N-(5-methylthiazol-2-yl)benzenesulfonamide
To a solution of 5-methylthiazol-2-amine (500mg, 4.38mmol) in pyridine (5mL) was added 4-nitrobenzene-l-sulfonyl chloride (1.65g, 5.26mmol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give N-(5-methylthiazol-2-yl)-4- nitrobenzenesulfonamide (325mg, impure).
To a solution of N-(5-methylthiazol-2-yl)-4-nitrobenzenesulfonamide (300mg,
1.0022mmol) in EtOH (6mL) was added Fe (337mg, 6.01mmol) followed by cone. HC1 (2drops) and H20 (3mL). The reaction was heated to reflux for three hours. Fe was removed by filtration. The filtrate was evaporated to give a solid. The solid was purified by column chromatography to give 4-amino-N-(5-methylthiazol-2-yl)benzenesulfonamide
(200 mg, 74%). 1H NMR (300Hz, DMSO-d6) δ ppm 7.40 (d, 1H), 6.85 (s, 0.5H), 6.56 (d, 1H), 5.79 (s, 1H), 2.15 (s, 1.5H). MS (ESI) m z 268 [M-H]".
reparation of 4-Amino-N-(4-methoxypyridin-2-yl)benzenesulfonamide
To a solution of 4-methoxypyridin-2-amine (500mg, 4.03mmol) in pyridine (5ml) was added 4-nitrobenzene-l-sulfonyl chloride (1.07g, 4.83mmol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give N-(4-methoxypyridin-2-yl)-4- nitrobenzenesulfonamide (210mg, %). MS (ESI) m/z 308 [M-H]~.
To a solution of N-(4-methoxypyridin-2-yl)-4-nitrobenzenesulfonamide (300mg, 0.9699mmol) in EtOH (6mL) was added Fe (326mg, 5.819mmol) followed by cone. HC1 (3 drops) and H20(3mL). The reaction was heated to reflux for three hours. Fe was removed by filtration. The filtrate was evaporated to give a solid. The solid was purified by column chromatography to give 4-amino-N-(4-methoxypyridin-2-yl)benzenesulfonamide (180 mg, 67%). 1H NMR (500Hz, DMSO-d6) δ ppm 7.78 (s, 1H), 7.48 (s, 2H), 6.56 (s, 3H), 6.42 (s, 1H), 3.37 (s, 3H). MS (ESI) m/z 280 [M+H]+.
Preparation of 4-Amino-N-(4-methoxypyrimidin-2-yl)benzenesulfonamide
To a solution of 4-methoxypyrimidin-2-amine (600mg, 4.79mmol) in pyridine (lOmL) was added 4-nitrobenzene-l-sulfonyl chloride (1.28g, 5.75mmol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give N-(4-methoxypyrimidin- 2-yl)-4-nitrobenzenesulfonamide (450mg, 30%). MS (ESI) m/z 309 [M-H]".
To a solution of N-(4-methoxypyrimidin-2-yl)-4-nitrobenzenesulfonamide (430mg, 1.3858mmol) in EtOH (9ml) was added Fe (465mg, 8.3148mmol) followed by cone. HC1 (3 drops) and H20 (4.5mL). The reaction was heated to reflux for three hours. Fe was removed by filtration. The filtrate was evaporated to give a solid. The solid was purified
by column chromatography to give 4-amino-N-(4-methoxypyrimidin-2- yl)benzenesulfonamide (190mg, 50%). IH NMR (300Hz, DMSO-d6) δ ppm 8.12 (s, 7.57 (d, 3H), 6.56 (d, 3H), 6.34 (s, 2H), 3.79 (s,3H). MS (ESI) m/z 303.0 [M+Na]+.
Preparation of 4-Amino-N- ( 2-methoxypyridin-4-yl)benzenesulfonamide
To a solution of 2-methoxypyridin-4-amine (lOOmg, 0.8055mmol) in pyridine (3mL) was added 4-nitrobenzene-l-sulfonyl chloride (214mg, 0.9667mmol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give N-(2-methoxypyridin-4- yl)-4-nitrobenzenesulfonamide MS (ESI) m/z 308 [M-H]~.
To a solution of N-(2-methoxypyridin-4-yl)-4-nitrobenzenesulfonamide (400mg, 1.2932mmol) in EtOH (8mL) was added Fe (435mg, 7.7595mmol) followed by cone. HC1 (3 drops) and H20 (4mL). The reaction was heated to reflux for three hours. Fe was removed by filtration. The filtrate was evaporated to give a solid. The solid was purified by column chromatography to give 4-amino-N-(2-methoxypyridin-4- yl)benzenesulfonamide (lOOmg, 23%). IH NMR (300Hz, DMSO-d6) δ ppm 7.88 (d, IH), 7.48 (d, 2H), 6.65 (d, IH), 6.59 (d, 2H), 6.36 (s, IH), 6.08 (s, 2H), 3.78 (s, 3H). MS (ESI) m/z 280 [M+H]+.
Preparation of 4-Amino-N-(pyrimidin-4-yl)benzenesulfonamide
To a solution of pyrimidin-4-amine (200mg, 2.10305mmol) in pyridine (4mL) was added 4-nitrobenzene-l-sulfonyl chloride (923mg, 4.206 lmmol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give 4-nitro-N-(pyrimidin-4- yl)benzenesulfonamide (290mg, 49%). MS (ESI) m z 279 [M-H]".
To a solution of 4-nitro-N-(pyrimidin-4-yl)benzenesulfonamide (150mg, 0.5352mmol) in EtOH (3ml) was added Fe (180mg, 3.2113mmol) followed by cone. HC1 (2 drops) and H20 (1.5mL). The reaction was heated to reflux for three hours. Fe was removed by filtration. The filtrate was evaporated to give a solid. The solid was purified by column chromatography to give 4-amino-N-(pyrimidin-4-yl)benzenesulfonamide
(62mg). 1H NMR (300Hz, DMSO-d6) δ ppm 8.61 (s, 1H), 8.33 (d, 1H), 7.56 (d, 2H), 6.95 (d, 1H), 6.57 (d, 2H), 6.00 (s, 2H). MS (ESI) m/z 249 [M-H]".
Preparation of 4-Amino-N-( 6-methylpyrimidin-4-yl)benzenesulfonamide
To a solution of 6-methylpyrimidin-4-amine (l .Og, 4.58mmol) in pyridine (15mL) was added 4-nitrobenzene-l-sulfonyl chloride (4g, 9.16mmol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give N-(6-methylpyrimidin-4-yl)-4- nitrobenzenesulfonamide (829mg, 26%). MS (ESI) m/z 293 [M-H]".
To a solution of N-(6-methylpyrimidin-4-yl)-4-nitrobenzenesulfonamide (300mg, 1.0194mmol) in EtOH (6ml) was added Fe (345mg, 6.1164mmol) followed by cone. HC1 (3 drops) and H20 (3mL). The reaction was heated to reflux for three hours. Fe was removed by filtration. The filtrate was evaporated to give a solid. The solid was purified by column chromatography to give 4-amino-N-(6-methylpyrimidin-4- yl)benzenesulfonamide (60 mg, 22%). 1H NMR (300Hz, DMSO-d6) δ ppm 8.48 (s, 1H), 7.56 (d, 2H), 6.81 (s, 1H), 6.56 (d, 2H), 5.99 (s, 2H), 2.29 (s, 3H). MS (ESI) m/z 265 [M+H]+.
Preparation of 4-Amino-N-( 6-phenylpyrimidin-4-yl)benzenesulfonamide
To a solution of 6-phenylpyrimidin-4-amine (170mg, 0.993mmol) in pyridine (3mL) was added 4-nitrobenzene-l-sulfonyl chloride (440mg, 1.99mol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid. The solid was purified by column chromatography to give 4-nitro-N-(6- phenylpyrimidin-4-yl)benzenesulfonamide (240mg, 68%). MS (ESI) m/z 354 [M-H]".
To a solution of 4-nitro-N-(6-phenylpyrimidin-4-yl)benzenesulfonamide (240mg, 0.67348mmol) in EtOH (4.8ml) was added Fe (230mg, 4.04088mmol) followed by cone. HCl (3 drops) and H20 (2.4mL). The reaction was heated to reflux for three hours. Fe was removed by filtration. The filtrate was evaporated to give a solid. The solid was purified by column chromatography to give 4-amino-N-(6-phenylpyrimidin-4- yl)benzenesulfonamide (263mg, 100%). 1H NMR (300Hz, DMSO-d6) δ ppm 11.55 (s, 1H), 8.75 (s, 1H), 7.97 (s, 2H), 7.64 (d, 2H), 7.54 (s, 3H), 7.42 (s, 1H), 6.58 (d, 2H), 6.08 (s, 2H). MS (ESI) m/z 325.3 [M-H]".
Preparation of 4-Amino-N-(5-methoxypyridin-2-yl)benzenesulfonamide
To a solution of 5-methoxypyridin-2-amine (200mg, 1.611 lmmol) in pyridine
(4mL) was added 4-nitrobenzene-l-sulfonyl chloride (428mg, 1.9333mmol). The mixture was stirred at RT for two hours. The solvent was removed under reduced pressure to give a solid (260 mg, 52%). The solid was purified by column chromatography to give N-(5- methoxypyridin-2-yl)-4-nitrobenzenesulfonamide. MS (ESI) m/z 308.3 [M-H]".
Determining the PD-1 Activity of Sulfonamides
The specificity of the effects of sulfamonomethoxine and sulfamethizole were assessed by comparing responses of wild type, PD-1C, and PD-1"7" T cells. The effects of sulfamonomethoxine and sulfamethizole were evaluated over a range of compound concentrations (dilution series from 16 nM to 80 μΜ) and analyzed their effects on T cell proliferation and cytokine production. The 2D structure and data from the primary screen are shown in Figure 2. A secondary screen demonstrated the specificity of
sulfamonomethoxine and sulfamethizole by the rescue of PD-1 mediated inhibition in PD-1 Tg cells only when PD-L2 was present. Furthermore, there was no effect on PD-1 KO cells (Figure 3). Specific effects of sulfamonomethoxine and sulfamethizole are seen above 400
nM in rescuing PD-1 mediated inhibition of IFN-γ production. It can be concluded that both sulfonamides conferred some PD-1 -pathway specific rescue.
More detail regarding experimental procedures is provided below.
Obtaining T-Cells. To obtain T cells the mice were sacrificed. The spleen was harvested from each type of mouse, and processed by crushing the organ through a 10 μΜ screen filter with the plunger of a syringe. The CD4 T cells were then separated from the rest of the lymphocytes using Miltenyi Biotec LS columns (Cat # 130-042-401) with CD4 (L3T4) Microbeads (Cat # 130-049-201). The LS columns are composed of ferromagnetic spheres which are coated with a cell friendly plastic coating. The columns have a capacity of up to 1 x 108 magnetically labeled cells from up to 2 109 total cells. The CD4 (L3T4) Microbeads are antibodies specific for the CD4 receptor conjugated with a magnetic bead. The lymphocytes from the PD and the PD-1 KO mice are respectively labeled with the CD4 microbeads. The LS column is attached to a strong magnet while the lymphocyte/CD4 microbeads combination is passed through the column. This process allows for positive selection of the CD4 T cells. These cells are then used for the various assays. The table below outlines this procedure.
10 Add cells to the column
11 Wash LS columns
Wash 3X with 3 mis of MACs buffer
12 Remove column from Magnetic holder
Elute column with 5mls of MACs buffer
13 Add 5mls of MACs buffer and Count Cells
14 Wash cells 2X in RPMI with 10% fetal bovine serum (FBS), 1M Hepes buffer, 1% Antibiotic, 1% L-Glutamine and 0.1M of β-mercaptoethanol (RPMI with these components will be referred to as CR10 media)
15 Resuspend cells in CR10 media at appropriate concentration
T Cell Culture Assay. T cells were added to tissue culture wells coated with plate- bound anti-CD3 (8 μ§/ηι1) plus either 3 μg/ml PD-L2Ig or control Ig fusion protein. Cells were added at 1 x 105 cells/well in 100 of media. Drug or media control was added in 100 μί. Plates were incubated for up to 96 hours. Supernatants were harvested at various times for cytokine analyses. In some experiments, T cells were labeled with CFSE to assess T cell proliferation, as will be discussed below.
Cytokine Detection Assay. BD Biosciences' Cytometric Bead Array (CBA): Mouse Thl/Th2 Cytokine Kit (Cat #551287) was used to measure Interleukin-2 (IL-2), Interleukin- 4 (IL-4), Interleukin-5 (IL-5), Interferon-γ (IFN-γ), and Tumor Necrosis Factor (TNF). This kit makes use of fluorescence detection by flow cytometry to allow for detection of multiple analytes. 5 beads population with distinct fluorescent intensities are coated with specific antibodies for the cytokines. These beads are then mixed with a PE-conjugated detection reagent. The beads are incubated with the sample (supernatant from PD Tg or PD-1 KO CD4 T cell culture) or a standard curve. The concentration of the unknown samples can then be extrapolated from the standard curve for each cytokine. The table below outlines this procedure.
3 Prepare beads
Vortex each tube of bead gently but thoroughly
Take 4 μΐ. of each of the 5 beads (IL-2, IL-4, IL-5, IFN-γ, & TNF) for each sample and standard being measured and mix them into a tube for a "bead mixture"
4 Prepare samples
Take 50 μΐ^ of supernatant from CD4 T cell cultures and transfer into a 96 well V-bottom plate
5 Reaction
Add 20 μΐ^ of the bead mixture and 25 μΐ^ of the detection reagent into the 50 μΐ^ of supernatant in the V-bottom plate
Incubate @ RT for 2 hrs
6 Wash 3X with Wash buffer flicking out the wash buffer from the plate each time
7 Add at least 50 μΐ, of Wash buffer to the plate (more volume if not using HTS Flow cytometer)
8 Analyze samples using flow cytometer
9 Setting up the Flow Cytometer
Prepare 3 tubes of setup beads A, B,C
Add 50 μΐ, of FITC positive control to tube B
Add 50 μΐ, of PE positive control to tube C
Leave tube A for negative control
Incubate tubes A, B, & C @ RT for 30 min
10 Open CBA Setup template on Flow Cytometer
Follow instructions of template for adjusting gain and compensation controls
1 1 Switch to CBA Acquistion Template on Flow Cytometer
Run standards and sample
12 Analysis
Use CBA analysis template to analyze data
Analysis of T Cell Expansion by CFSE Dye Dilution Assay. The CFSE Proliferation assay uses a fluorescent dye to measure proliferation of cells. In this assay cells are stained with CFSE (Carboxyfiuorescein succinimidyl ester). Each time a cell proliferates, the CFSE will be diluted among the daughter cells. Since the fluorescent intensity will be halved in
each daughter cell, this method can be used to determine the number of times the cell population proliferates. PD-1 Tg and PD-1 KO cells can be stained to determine proliferation of the CD4 T cells with anti-CD3 stimulation and inhibited by PD-L2Ig under different drug conditions. The table below outlines this procedure.
IFN-y Detection Assays. The Mouse IFN-γ Flex Set Assay is a kit from BD Biosciences (Cat #558296). Using the same principles described in Cytometric Bead Array
(CBA): Mouse Thl/Th2 Cytokine Kit, this kit denoted by the "Flex Set" label is more focused on one analyte. In this case it is the measurement of IFN-γ. Biolegend's version of this assay was also used. The assays were compared to ensure continuity of data and Biolegend's protocol was adjusted to provide the same low level of background seen in the BD Biosciences Flex Set kit. The table below outlines this procedure.
In each of these assays the goal was to measure the amount of IFN-γ that was present in the supernatant of CD4 T cells following incubation with drug or controls. These assays were used for both the large high-throughput screen of compounds and the follow up validation experiments.
IFN-y ELISA Assay. The IFN-γ ELISA is a sandwich ELISA based on an R& D systems IFN-γ kit. The kit included the capture and biotinylated detection antibody. A secondary antibody was still required for measurement of the levels of IFN-γ cytokine. This assay used an anti-IFN-γ as the capture antibody. The IFN-γ in the supernatant of T cells (PD- 1 or PD- 1 KO) incubated with and without drug would be incubated with the capture antibody. Then a detection antibody, anti-IFN-γ conjugated with biotin would be added to bind to the IFN-γ. Streptavidin conjugated to IR 800 Dye was used to visualize the
interaction. Biotin on the detection antibody would bind to the streptavidin on the dye conjugate. The IR 800 Dye could then be detected by a plate reader.
INCORPORATION BY REFERENCE
The following references correspond to the numbers above in parenthesis. All of these references are incorporated by reference in their entirety. In addition, all of the U.S. patents and U.S. published patent applications cited herein are hereby incorporated by reference.
1. Zajac, A. J., J.N. Blattman, K. Murali-Krishna, D.J. Sourdive, M. Suresh, J.D. Altman, and R. Ahmed. 1998. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 188:2205-2213.
2. Matloubian, M., R.J. Concepcion, and R. Ahmed. 1994. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol 68:8056-8063.
3. Wherry, E.J., and R. Ahmed. 2004. Memory CD8 T-cell differentiation during viral infection. J Virol 78:5535-5545.
4. Wherry, E.J., J.N. Blattman, K. Murali-Krishna, R. van der Most, and R. Ahmed. 2003. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 77:4911-4927.
5. Berts, M.R., M.C. Nason, S.M. West, S.C. De Rosa, S.A. Migueles, J. Abraham, M.M. Lederman, J.M. Benito, P.A. Goepfert, M. Connors, M. Roederer, and R.A. Koup.
2006. HIV nonprogressors preferentially maintain highly functional HlV-specific CD8+ T cells. Blood 107:4781-4789.
6. Berts, M.R., B. Exley, D.A. Price, A. Bansal, Z.T. Camacho, V. Teaberry, S.M. West, D.R. Ambrozak, G. Tomaras, M. Roederer, J.M. Kilby, J. Tartaglia, R. Belshe, F. Gao, D.C. Douek, K.J. Weinhold, R.A. Koup, P. Goepfert, and G. Ferrari. 2005.
Characterization of functional and phenotypic changes in anti-Gag vaccine-induced T cell responses and their role in protection after HIV-1 infection. Proc Natl Acad Sci USA 102:4512-4517.
7. Klenerman, P., and A. Hill. 2005. T cells and viral persistence: lessons from diverse infections. Nat Immunol 6:873-879.
8. Pentcheva-Hoang, T., E. Corse, and J.P. Allison. 2009. Negative regulators of T- cell activation: potential targets for therapeutic intervention in cancer, autoimmune disease, and persistent infections. Immunol Rev 229:67-87.
9. Nurieva, R.I., X. Liu, and C. Dong. 2009. Yin- Yang of costimulation: crucial controls of immune tolerance and function. Immunol Rev 229:88-100.
10. Sharpe, A.H. 2009. Mechanisms of costimulation. Immunol Rev 229:5-11.
11. Sharpe, A.H., E.J. Wherry, R. Ahmed, and G.J. Freeman. 2007. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat
Immunol 8:239-245.
12. Okazaki, T., and T. Honjo. 2007. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 19:813-824.
13. Keir, M.E., M.J. Butte, G.J. Freeman, and A.H. Sharpe. 2008. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677-704.
14. Barber, D.L., E.J. Wherry, D. Masopust, B. Zhu, J.P. Allison, A.H. Sharpe, G.J. Freeman, and R. Ahmed. 2006. Restoring function in exhausted CD 8 T cells during chronic viral infection. Nature 439:682-687.
15. Ha, S.J., S.N. Mueller, E.J. Wherry, D.L. Barber, R.D. Aubert, A.H. Sharpe, G.J. Freeman, and R. Ahmed. 2008. Enhancing therapeutic vaccination by blocking PD-1- mediated inhibitory signals during chronic infection. J Exp Med 205:543-555.
16. Day, C.L., D.E. Kaufmann, P. Kiepiela, J. A. Brown, E.S. Moodley, S. Reddy, E.W. Mackey, J.D. Miller, A.J. Leslie, C. DePierres, Z. Mncube, J. Duraiswamy, B. Zhu, Q. Eichbaum, M. Altfeld, E.J. Wherry, H.M. Coovadia, P.J. Goulder, P. Klenerman, R. Ahmed, G.J. Freeman, and B.D. Walker. 2006. PD-1 expression on HlV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443:350-354.
17. Urbani, S., B. Amadei, D. Tola, M. Massari, S. Schivazappa, G. Missale, and C. Ferrari. 2006. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol 80: 11398-11403.
18. Boettler, T., E. Panther, B. Bengsch, N. Nazarova, H.C. Spangenberg, H.E.
Blum, and R. Thimme. 2006. Expression of the interleukin-7 receptor alpha chain (CD 127) on virus-specific CD 8+ T cells identifies functionally and phenotypically defined memory T cells during acute resolving hepatitis B virus infection. J Virol 80:3532-3540.
19. Trautmann, L., L. Janbazian, N. Chomont, E.A. Said, S. Gimmig, B. Bessette, M.R. Boulassel, E. Delwart, H. Sepulveda, R.S. Balderas, J.P. Routy, E.K. Haddad, and R.P. Sekaly. 2006. Upregulation of PD-1 expression on HlV-specific CD8(+) T cells leads to reversible immune dysfunction. Nat Med 12: 1198-1202.
20. Petrovas, C, J.P. Casazza, J.M. Brenchley, D.A. Price, E. Gostick, W.C. Adams, M . Precopio, T. Schacker, M. Roederer, D.C. Douek, and R.A. Koup. 2006. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med 203:2281- 2292.
21. Radziewicz, H., C.C. Ibegbu, M.L. Fernandez, K.A. Workowski, K. Obideen,
M. Wehbi, H.L. Hanson, J.P. Steinberg, D. Masopust, E.J. Wherry, J.D. Altman, B.T.
Rouse, G.J. Freeman, R. Ahmed, and A. Grakoui. 2007. Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J Virol 81 :2545-2553.
22. Freeman, G.J., E.J. Wherry, R. Ahmed, and A.H. Sharpe. 2006. Reinvigorating exhausted HIV-specific T cells via PD-l-PD-1 ligand blockade. J Exp Med 203:2223-2227.
23. Boni, C, P. Fisicaro, C. Valdatta, B. Amadei, P. Di Vincenzo, T. Giuberti, D. Laccabue, A. Zerbini, A. Cavalli, G. Missale, A. Bertoletti, and C. Ferrari. 2007.
Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol 81 :4215-4225.
24. Chen, L., Z. Zhang, W. Chen, Z. Zhang, Y. Li, M. Shi, J. Zhang, L. Chen, S. Wang, and F.S. Wang. 2007. B7-H1 up-regulation on myeloid dendritic cells significantly suppresses T cell immune function in patients with chronic hepatitis B. J Immunol
178:6634-6641.
25. Zhang, J.Y., Z. Zhang, X. Wang, J.L. Fu, J. Yao, Y. Jiao, L. Chen, H. Zhang, J.
Wei, L. Jin, M. Shi, G.F. Gao, H. Wu, and F.S. Wang. 2007. PD-1 up-regulation is correlated with HIV-specific memory CD 8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors. Blood 109:4671-4678.
26. Yao, Z.Q., E. King, D. Prayther, D. Yin, and J. Moorman. 2007. T cell dysfunction by hepatitis C virus core protein involves PD-l/PDL-1 signaling. Viral
Immunol 20:276-287.
27. Jeong, H.Y., Y.J. Lee, S.K. Seo, S.W. Lee, S.J. Park, J.N. Lee, H.S. Sohn, S. Yao, L. Chen, and I. Choi. 2008. Blocking of monocyte-associated B7-H1 (CD274) enhances HCV-specific T cell immunity in chronic hepatitis C infection. J Leukoc Biol 83:755-764.
28. Geng, L., G. Jiang, Y. Fang, S. Dong, H. Xie, Y. Chen, M. Shen, and S. Zheng. 2006. B7-H1 expression is upregulated in peripheral blood CD 14+ monocytes of patients
with chronic hepatitis B virus infection, which correlates with higher serum IL-10 levels. J Viral Hepat 13:725-733.
29. Trabattoni, D., M. Saresella, M. Biasin, A. Boasso, L. Piacentini, P. Ferrante, H. Dong, R. Maserati, G.M. Shearer, L. Chen, and M. Clerici. 2003. B7-H1 is up-regulated in HIV infection and is a novel surrogate marker of disease progression. Blood 101 :2514- 2520.
30. Velu, V., S. Kannanganat, C. Ibegbu, L. Chennareddi, F. Villinger, G.J.
Freeman, R. Ahmed, and R.R. Amara. 2007. Elevated expression levels of inhibitory receptor programmed death 1 on simian immunodeficiency virus-specific CD8 T cells during chronic infection but not after vaccination. J Virol 81 :5819-5828.
31. Velu, V., K. Titanji, B. Zhu, S. Husain, A. Pladevega, L. Lai, T.H. Vanderford, L. Chennareddi, G. Silvestri, G.J. Freeman, R. Ahmed, and R.R. Amara. 2009. Enhancing SlV-specific immunity in vivo by PD-1 blockade. Nature 458:206-210.
32. Beswick, E.J., I.V. Pinchuk, S. Das, D.W. Powell, and V.E. Reyes. 2007.
Expression of the programmed death ligand 1, B7-H1, on gastric epithelial cells after
Helicobacter pylori exposure promotes development of CD4+ CD25+ FoxP3+ regulatory T cells. Infect Immun 75:4334-4341.
33. Das, S., G. Suarez, E.J. Beswick, J.C. Sierra, D.Y. Graham, and V.E. Reyes. 2006. Expression of B7-H1 on gastric epithelial cells: its potential role in regulating T cells during Helicobacter pylori infection. J Immunol 176:3000-3009.
34. Sheppard, K.A., L.J. Fitz, J.M. Lee, C. Benander, J.A. George, J. Wooters, Y. Qiu, J.M. Jussif, L.L. Carter, C.R. Wood, and D. Chaudhary. 2004. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett 574:37-41.
35. Parry, R.V., J.M. Chemnitz, K.A. Frauwirth, A.R. Lanfranco, I. Braunstein, S.V.
Kobayashi, P.S. Linsley, C.B. Thompson, and J.L. Riley. 2005. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25:9543-9553.
36. Latchman, Y., C.R. Wood, T. Chernova, D. Chaudhary, M. Borde, I. Chernova,
Y. Iwai, A.J. Long, J.A. Brown, R. Nunes, E.A. Greenfield, K. Bourque, V.A. Boussiotis, L.L. Carter, B.M. Carreno, N. Malenkovich, H. Nishimura, T. Okazaki, T. Honjo, A.H.
Sharpe, and G.J. Freeman. 2001. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2:261-268.
37. Freeman, G.J., A.J. Long, Y. Iwai, K. Bourque, T. Chernova, H. Nishimura, L.J. Fitz, N. Malenkovich, T. Okazaki, M.C. Byrne, H.F. Horton, L. Fouser, L. Carter, V. Ling, M.R. Bowman, B.M. Carreno, M. Collins, C.R. Wood, and T. Honjo. 2000. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192: 1027-1034.
38. Riley, J.L. 2009. PD-1 signaling in primary T cells. Immunol Rev 229: 114-125.
39. Chemnitz, J.M., R.V. Parry, K.E. Nichols, C.H. June, and J.L. Riley. 2004. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 173:945-954.
40. Keir, M.E., S.C. Liang, I. Guleria, Y.E. Latchman, A. Qipo, L.A. Albacker, M. Koulmanda, G.J. Freeman, M.H. Sayegh, and A.H. Sharpe. 2006. Tissue expression of PD- Ll mediates peripheral T cell tolerance. J Exp Med 203:883-895.
41. Carter, L., L.A. Fouser, J. Jussif, L. Fitz, B. Deng, C.R. Wood, M. Collins, T. Honjo, G.J. Freeman, and B.M. Carreno. 2002. PD-1 :PD-L inhibitory pathway affects both
CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol 32:634-643.
42. Wherry, E.J., J.N. Blattman, and R. Ahmed. 2005. Low CD8 T-cell proliferative potential and high viral load limit the effectiveness of therapeutic vaccination. J Virol 79:8960-8968.
43. Keir, M.E., Y.E. Latchman, G.J. Freeman, and A.H. Sharpe. 2005. Programmed death-1 (PD-l):PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes. J Immunol 175:7372-7379.
44. Keir, M.E., G.J. Freeman, and A. Sharpe. 2007. PD-1 regulates self-reactive CD8+ T cell responses to antigen in lymph nodes and tissues. Journal of Immunology 179:5064-5070.
45. Ansari, M.J.I. , Salama, A.D., Chitnis, T., Smith, R.N., Yagita, H., Akiba, H., Yamazaki, T., Azuma, M., Iwai, J., Khoury, S.J., Auchincloss Jr, H., & Sayegh, M.H. (2003). The programmed death-1 (PD-1) pathway regulated automimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med, 198(1), 63-69.
46. Zhang, L., T. F. Gajewskil, and J. Kline (2009). PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood, 114(8), 1545-1552; and references to solid tumors cited therein.
47. Hirata S, Senju S, Matsuyoshi H, Fukuma D, Uemura Y, Nishimura Y. 2005. Prevention of experimental autoimmune encephalomyelitis by transfer of embryonic stem cell-derived dendritic cells expressing myelin oligodendrocyte glycoprotein peptide along with TRAIL or programmed death-1 ligand. J Immunol 174: 1888-97
EQUIVALENTS
While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or
modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present invention.
Claims
We claim:
I
or a pharmaceutically acceptable salt, solvate, enantiomer or stereoisomer thereof, wherein independently for each occurrence,
A is aryl, heteroaryl or biaryl;
B is aryl, heteroaryl or biaryl;
X is -N(R)-, -C(R)2-, -O- or -S-;
R is hydrogen or alkyl; and
Y is -S(=0)2-, -S(=0)- or -C(=0)-.
2. The compound of claim 1, wherein X is -N(R)-.
3. The compound of claim 1, wherein X is -N(H)-.
4. The compound of claim 1, wherein X is -N(CH3)-.
5. The compound of claim 1, wherein X is -C(H)2-.
6. The compound of claim 1, wherein X is -0-.
7. The compound of claim 1, wherein X is -S-.
8. The compound of any one of claims 1-7, wherein Y is -S(=0)2-.
9. The compound of any one of claims 1-7, wherein Y is -S(=0)-.
10. The compound of any one of claims 1-7, wherein Y is -C(=0)-.
11. The compound of claim 1 , wherein X is -N(R)-; and Y is -S(=0)2-.
12. The compound of claim 1, wherein X is -N(R)-; and Y is -C(=0)2-.
13. The compound of any one of claims 1-12, wherein A is heteroaryl, arylheteroaryl or heteroarylheteroaryl.
14 The compound of any one < of claims 1 -12, wherein A is
or ; R1 to R5 are independently selected from the group consisting of hydrogen, alkyl, heterocyclyl, aryl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl, halo, haloalkyl, cyano, nitro, -N(R12)R13, -CH2N(R12)R13, -CH2CH2N(R12)R13, -CH2CH2CH2N(R12)R13, -OR12, -CH2OR12, -CH2CH2OR12 and -CH2CH2CH2OR12 ; R12 is hydrogen, alkyl, haloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl, formyl, alkylcarbonyl, haloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heterocyclylalkylcarbonyl, aralkylcarbonyl, heteroaralkylcarbonyl, alkyloxycarbonyl, haloalkyloxycarbonyl,
heterocyclyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl,
heteroaryloxycarbonyl, heterocyclylalkyloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl and amido; and R13 is hydrogen or alkyl.
15. The compound of claim 14, wherein R1 is hydrogen.
16. The compound of claim 14 or 15, wherein R2 is hydrogen.
17. The compound of any one of claims 14-16, wherein R3 is hydrogen.
18. The compound of any one of claims 14-17, wherein R4 is hydrogen.
19. The compound of any one of claims 14-17, wherein R4 is hydrogen, methyl, phenyl or methoxy.
20. The compound of any one of claims 14-20, wherein R5 is hydrogen.
21. The compound of any one of claims 14-20, wherein R12 is hydrogen.
22. The compound of any one of claims 14-20, wherein R12 is alkyl.
23. The compound of any one of claims 14-20, wherein R12 is methyl.
24. The compound of any one of claims 14-23, wherein R13 is hydrogen.
25. The compound of any one of claims 14-23, wherein R13 is alkyl.
26. The compound of any one of claims 14-23, wherein R13 is methyl.
27. The compound of any one of claims 1-12, wherein A is
,
R2 R2
R5 R4 or R4 ; R1 to R5 are independently selected from the group consisting of hydrogen, alkyl, aryl, -OR12, -CH2OR12, -CH2CH2OR12 and
-CH2CH2CH2OR12; and R12 is hydrogen or alkyl.
R2 R2
R5 R4 or R4 ; R1, R2, R3 and R5 are hydrogen; R4 is hydrogen, alkyl, aryl, -OR12, -CH2OR12, -CH2CH2OR12 and -CH2CH2CH2OR12; and R12 is hydrogen or alkyl.
R2 R2
R5 R4 or R4 ; R1, R2, R3 and R5 are hydrogen; R4 is hydrogen, methyl, phenyl or methoxy.
30. h O ,
31.
heterocyclyl, aryl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl, halo, haloalkyl, cyano, nitro, -N(R12)R13, -CH2N(R12)R13, -CH2CH2N(R12)R13,
-CH2CH2CH2N(R12)R13, -OR12, -CH2OR12, -CH2CH2OR12 and -CH2CH2CH2OR12 ; R10 is hydrogen or alkyl; R12 is hydrogen, alkyl, haloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl, formyl, alkylcarbonyl, haloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heterocyclylalkylcarbonyl, aralkylcarbonyl,
heteroaralkylcarbonyl, alkyloxycarbonyl, haloalkyloxycarbonyl,
heterocyclyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl,
heteroaryloxycarbonyl, heterocyclylalkyloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl and amido; and R13 is hydrogen or alkyl.
32. The compound of claim 31 , wherein W is -S-.
33. The compound of claim 31 , wherein W is -CH2-.
34. The compound of claim 31 , wherein W is -0-.
35. The compound of claim 31 , wherein W is -N(R)-.
36. The compound of claim 31 , wherein W is -N(H)-.
37. The compound of claim 31 , wherein W is -N(CH3)-.
38. The compound of any one of claims 31-37, wherein R12 is hydrogen.
39. The compound of any one of claims 31-37, wherein R12 is alkyl.
40. The compound of any one of claims 31-37, wherein R12 is methyl.
41. The compound of any one of claims 31-40, wherein R13 is hydrogen.
42. The compound of any one of claims 31-40, wherein R13 is alkyl.
43. The compound of any one of claims 31-40, wherein R13 is methyl.
e group consisting of hydrogen, alkyl, alkyloxy, alkyloxyalkyl and aryl.
x xx wxxx w xxxxU wx cxxxj wxx wx iaiiiio x - x ^, vv xx x xxx ^ x x ; W lS -S-; and
R7 is hydrogen, alkyl, aryl, -OR12, -CH2OR12, -CH2CH2OR12 or -CH2CH2CH2OR12; and R is hydrogen or alkyl.
The compound of any one of claims 1-46, wherein B is aryl.
The compound of any one of claims 1-46, wherein B is substituted phenyl.
The compound of any one of claims 1-46, wherein B is
; R1 to R5 are independently selected from the group consisting of hydrogen, alkyl, heterocyclyl, aryl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl, halo, haloalkyl, cyano, nitro, -N(R12)R13, -CH2N(R12)R13, -CH2CH2N(R12)R13, -CH2CH2CH2N(R12)R13, -OR12, -CH2OR12, -CH2CH2OR12 and -CH2CH2CH2OR12 ; R10 is hydrogen or alkyl; R12 is hydrogen, alkyl, haloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl,
heterocyclylalkyl, aralkyl, heteroaralkyl, formyl, alkylcarbonyl, haloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heterocyclylalkylcarbonyl, aralkylcarbonyl, heteroaralkylcarbonyl,
alkyloxycarbonyl, haloalkyloxycarbonyl, heterocyclyloxycarbonyl,
aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl,
heterocyclylalkyloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl and amido; and R13 is hydrogen or alkyl.
50. The compound of claim 49, wherein R1 is hydrogen.
51. The compound of claim 49 or 50, wherein R2 is hydrogen.
52. The compound of any one of claims 49-51 , wherein R3 is hydrogen.
53. The compound of any one of claims 49-51, wherein R3 is -N(R12)R13,
-CH2N(R12)R13, -CH2CH2N(R12)R13 or -CH2CH2CH2N(R12)R13.
54. The compound of any one of claims 49-51 , wherein R3 is -N(R12)R13.
55. The compound of any one of claims 49-51, R3 is -OR12, -CH2OR12, -CH2CH2OR or -CH2CH2CH2OR12.
56. The compound of any one of claims 49-51 , wherein R3 is -OR12.
57. The compound of any one of claims 49-56, wherein R4 is hydrogen.
58. The compound of any one of claims 49-57, wherein R5 is hydrogen.
59. The compound of any one of claims 49-58, wherein R12 is hydrogen, alkyl,
alkylcarbonyl, alkoxycarbonyl or amido.
60. The compound of any one of claims 49-58, wherein R12 is hydrogen.
61. The compound of any one of claims 49-58, wherein R12 is alkyl.
62. The compound of any one of claims 49-58, wherein R12 is methyl.
63. The compound of any one of claims 49-58, wherein R12 is methylcarbonyl.
64. The compound of any one of claims 49-58, wherein R12 is methyoxycarbonyl.
65. The compound of any one of claims 49-58, wherein R12 is methylaminocarbonyl. 66. The compound of any one of claims 49-65, wherein R13 is hydrogen.
67. The compound of any one of claims 49-65, wherein R13 is alkyl.
68. The compound of any one of claims 49-65, wherein R13 is methyl.
69. The compound of any one of claims 49-58, wherein R12 is hydrogen; and R13 is hydrogen.
70. The compound of any one of claims 49-58, wherein R12 is methyl; and R13 is hydrogen.
71. The compound of any one of claims 1-46, wherein B is
R1, R2, R4 and R5 are hydrogen; R3 is hydrogen, alkyl, heterocyclyl, aryl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl, halo, haloalkyl, cyano, nitro, -N(R12)R13, -CH2N(R12)R13, -CH2CH2N(R12)R13, -CH2CH2CH2N(R12)R13, -OR12, -CH2OR12,
-CH2CH2OR12 and -CH2CH2CH2OR12 ; R10 is hydrogen or alkyl; R12 is hydrogen,
alkyl, haloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heterocyclylalkyl, aralkyl, heteroaralkyl, formyl, alkylcarbonyl, haloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heterocyclylalkylcarbonyl, aralkylcarbonyl, heteroaralkylcarbonyl, alkyloxycarbonyl, haloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl,
heteroaryloxycarbonyl, heterocyclylalkyloxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl and amido; and R13 is hydrogen or alkyl.
The compound of any one of claims 1-46, wherein B is
R1, R2, R4 and R 5 are hydrogen; R 3 is 12 13 12 13
-N(R )R or -OR ; and R is hydrogen or methyl.
The compound of any one of claims 1-46, wherein B is
R1, R2, R4 and R are hydrogen; R3 is -N(R12)R13 or -OR12; R12 is hydrogen, alkylcarbonyl, alkyloxycarbonyl or amido; and R13 is hydrogen or methyl.
A compound, or a pharmaceutically acceptable salt, solvate, enantiomer or
The compound of any one of claims 1-75, wherein the compound is a PD-1 agonist. The compound of any one of claims 1-75, wherein the compound is a selective inhibitor of the PD-1 :PD-L1 pathway.
79. A pharmacutical composition comprising a compound of any one of claims 1-78, and a pharmacutically acceptable excipient.
80. A method of treating or preventing a disease in a subject comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-78, or a pharmaceutical composition of claim 79, to the subject.
81. The method of claim 80, wherein the disorder is an infectious disease.
82. The method of claim 81, wherein the infectious disease is a chronic infection.
83. The method of claim 81 or 82, wherein the infectious disease is a viral infection.
84. The method of any one of claims 81-83, wherein the infectious disease is selected from the group consisting of HIV, HBV, HCV, H. pylori and Herpes simplex virus.
85. The method of claim 80, wherein the disorder is cancer.
86. The method of claim 85, wherein the cancer is selected from the group consisting of melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer.
87. The method of claim 80, wherein the disorder is an immune disorder
88. The method of claim 87, wherein the immune disorder is selected from the group consisting of an autoimmune disorder, an immune response to a graft, and an allergic reaction.
89. The method of claim 87, wherein the immune disorder selected from the group
consisting of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease,
Crohn's disease, systemic lupus erythematosis, type I diabetes, transplant rejection, graft-versus-host disease and hyperproliferative immune disorders.
90. A method for suppressing, treating, or preventing graft rejection accompanying the transplantation of an organ, or a portion thereof, or a tissue in a subject, the method comprising administering a therapeutically effective amount of a compound of any one of claims 1-78, or a pharmaceutical composition of claim 79, to the subject.
91. The method of claim 90, wherein the transplantation is allotransplantation.
92. The method of claim 90, wherein the transplantation is xenotransplantation.
93. The method of claim 90, wherein the organ is the liver, heart, kidney, lung,
pancreas.
94. The method of claim 90, wherein the tissue is the skin, cornea, or bone tissue.
95. A method of enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) the antigen; and (ii) a compound of any one of
claims 1-78, or a pharmaceutical composition of claim 79, such that an immune response to the antigen in the subject is enhanced.
The method of claim 95, wherein the antigen is a tumor antigen, a microbial antig or an antigen from a pathogen.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/519,621 US20130022629A1 (en) | 2010-01-04 | 2011-01-03 | Modulators of Immunoinhibitory Receptor PD-1, and Methods of Use Thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US29202010P | 2010-01-04 | 2010-01-04 | |
US61/292,020 | 2010-01-04 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2011082400A2 true WO2011082400A2 (en) | 2011-07-07 |
WO2011082400A3 WO2011082400A3 (en) | 2011-11-03 |
Family
ID=44227175
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2011/020046 WO2011082400A2 (en) | 2010-01-04 | 2011-01-03 | Modulators of immunoinhibitory receptor pd-1, and methods of use thereof |
Country Status (2)
Country | Link |
---|---|
US (1) | US20130022629A1 (en) |
WO (1) | WO2011082400A2 (en) |
Cited By (251)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2403499A2 (en) * | 2009-03-02 | 2012-01-11 | Stemsynergy Therapeutics, Inc | Methods and compositions useful in treating cancer and reducing wnt mediated effects in a cell |
WO2013132317A1 (en) | 2012-03-07 | 2013-09-12 | Aurigene Discovery Technologies Limited | Peptidomimetic compounds as immunomodulators |
WO2014036412A2 (en) | 2012-08-30 | 2014-03-06 | Amgen Inc. | A method for treating melanoma using a herpes simplex virus and an immune checkpoint inhibitor |
US8829195B2 (en) | 2012-05-15 | 2014-09-09 | Novartis Ag | Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1 |
US8841487B2 (en) | 2010-07-16 | 2014-09-23 | Abbvie Inc. | Phosphine ligands for catalytic reactions |
US8895737B2 (en) | 2010-07-16 | 2014-11-25 | Shashank Shekhar | Process for preparing antiviral compounds |
US8975443B2 (en) | 2010-07-16 | 2015-03-10 | Abbvie Inc. | Phosphine ligands for catalytic reactions |
WO2015160641A3 (en) * | 2014-04-14 | 2015-12-23 | Bristol-Myers Squibb Company | Compounds useful as immunomodulators |
US9255074B2 (en) | 2010-07-16 | 2016-02-09 | Abbvie Inc. | Process for preparing antiviral compounds |
US9278981B2 (en) | 2012-05-15 | 2016-03-08 | Novartis Ag | Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1 |
US9315489B2 (en) | 2012-05-15 | 2016-04-19 | Novartis Ag | Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1 |
US9340537B2 (en) | 2012-05-15 | 2016-05-17 | Novatis Ag | Benzamide derivatives for inhibiting the activity of ABL1, ABL2 and BCR-ABL1 |
WO2016081854A1 (en) | 2014-11-20 | 2016-05-26 | Promega Corporation | Systems and methods for assessing modulators of immune checkpoints |
CN105705489A (en) * | 2013-09-04 | 2016-06-22 | 百时美施贵宝公司 | Compounds useful as immunomodulators |
WO2016100364A1 (en) | 2014-12-18 | 2016-06-23 | Amgen Inc. | Stable frozen herpes simplex virus formulation |
US9505728B2 (en) | 2012-03-09 | 2016-11-29 | Inception 2, Inc. | Triazolone compounds and uses thereof |
WO2017009842A2 (en) | 2015-07-16 | 2017-01-19 | Biokine Therapeutics Ltd. | Compositions and methods for treating cancer |
WO2017032867A1 (en) | 2015-08-27 | 2017-03-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of patients suffering from a lung cancer |
WO2017055324A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of cells of monocytic origin in a tissue sample |
WO2017055327A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of endothelial cells in a tissue sample |
WO2017055484A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for determining the metabolic status of lymphomas |
WO2017055321A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of fibroblasts in a tissue sample |
WO2017055322A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of neutrophils in a tissue sample |
WO2017059224A2 (en) | 2015-10-01 | 2017-04-06 | Gilead Sciences, Inc. | Combination of a btk inhibitor and a checkpoint inhibitor for treating cancers |
WO2017055326A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of myeloid dendritic cells in a tissue sample |
WO2017055320A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of cytotoxic lymphocytes in a tissue sample |
WO2017055319A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of b cells in a tissue sample |
WO2017055325A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of nk cells in a tissue sample |
WO2017060397A1 (en) | 2015-10-09 | 2017-04-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of subjects suffering from melanoma metastases |
CN106565616A (en) * | 2016-11-14 | 2017-04-19 | 杭州洪晟生物技术股份有限公司 | Preparation method of antibacterial veterinary drug sulfamonomethoxine sodium |
US9676754B2 (en) | 2012-12-20 | 2017-06-13 | Inception 2, Inc. | Triazolone compounds and uses thereof |
WO2017106634A1 (en) * | 2015-12-17 | 2017-06-22 | Incyte Corporation | N-phenyl-pyridine-2-carboxamide derivatives and their use as pd-1/pd-l1 protein/protein interaction modulators |
WO2017118634A1 (en) | 2016-01-04 | 2017-07-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of pd-1 and tim-3 as a measure for cd8+ cells in predicting and treating renal cell carcinoma |
WO2017129790A1 (en) | 2016-01-28 | 2017-08-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical composition for the treatment of cancer |
WO2017129769A1 (en) | 2016-01-28 | 2017-08-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for enhancing the potency of the immune checkpoint inhibitors |
WO2017129763A1 (en) | 2016-01-28 | 2017-08-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of signet ring cell gastric cancer |
WO2017144668A1 (en) | 2016-02-26 | 2017-08-31 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Antibodies having specificity for btla and uses thereof |
US9776976B2 (en) | 2013-09-06 | 2017-10-03 | Inception 2, Inc. | Triazolone compounds and uses thereof |
WO2017202949A1 (en) | 2016-05-25 | 2017-11-30 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cancers |
WO2017202962A1 (en) | 2016-05-24 | 2017-11-30 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of non small cell lung cancer (nsclc) that coexists with chronic obstructive pulmonary disease (copd) |
WO2017223422A1 (en) | 2016-06-24 | 2017-12-28 | Infinity Pharmaceuticals, Inc. | Combination therapies |
WO2018011166A2 (en) | 2016-07-12 | 2018-01-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of myeloid dendritic cells in a tissue sample |
WO2018029336A1 (en) | 2016-08-12 | 2018-02-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for determining whether a subject was administered with an activator of the ppar beta/delta pathway. |
WO2018033135A1 (en) | 2016-08-19 | 2018-02-22 | Beigene, Ltd. | Use of a combination comprising a btk inhibitor for treating cancers |
WO2018044783A1 (en) * | 2016-08-29 | 2018-03-08 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
WO2018046736A1 (en) | 2016-09-12 | 2018-03-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of patients suffering from cancer |
WO2018046738A1 (en) | 2016-09-12 | 2018-03-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of patients suffering from cancer |
WO2018055080A1 (en) | 2016-09-22 | 2018-03-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for reprograming immune environment in a subject in need thereof |
US9938254B2 (en) | 2016-01-08 | 2018-04-10 | Celgene Corporation | Antiproliferative compounds, and their pharmaceutical compositions and uses |
US9951069B1 (en) | 2017-01-11 | 2018-04-24 | Rodin Therapeutics, Inc. | Bicyclic inhibitors of histone deacetylase |
WO2018075447A1 (en) | 2016-10-19 | 2018-04-26 | The Trustees Of Columbia University In The City Of New York | Combination of braf inhibitor, talimogene laherparepvec, and immune checkpoint inhibitor for use in the treatment cancer (melanoma) |
WO2018087391A1 (en) | 2016-11-14 | 2018-05-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for modulating stem cells proliferation or differentiation |
WO2018119286A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Bicyclic heteroaromatic compounds as immunomodulators |
WO2018119266A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Benzooxazole derivatives as immunomodulators |
WO2018119224A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Tetrahydro imidazo[4,5-c]pyridine derivatives as pd-l1 internalization inducers |
WO2018119221A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Pyridine derivatives as immunomodulators |
WO2018119263A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Heterocyclic compounds derivatives as pd-l1 internalization inducers |
WO2018115458A1 (en) | 2016-12-23 | 2018-06-28 | Virttu Biologics Limited | Treatment of cancer |
WO2018122249A1 (en) | 2016-12-28 | 2018-07-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of patients suffering from a microsatellite stable colorectal cancer |
WO2018122245A1 (en) | 2016-12-28 | 2018-07-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of predicting the survival time of patients suffering from cms3 colorectal cancer |
WO2018140671A1 (en) | 2017-01-27 | 2018-08-02 | Celgene Corporation | 3-(1-oxo-4-((4-((3-oxomorpholino) methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dione and isotopologues thereof |
CN108368090A (en) * | 2015-10-15 | 2018-08-03 | 百时美施贵宝公司 | Compound as immunomodulator |
WO2018146128A1 (en) | 2017-02-07 | 2018-08-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Detection of kit polymorphism for predicting the response to checkpoint blockade cancer immunotherapy |
WO2018146148A1 (en) | 2017-02-07 | 2018-08-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A method for predicting the response to checkpoint blockade cancer immunotherapy |
US10052315B2 (en) | 2016-01-08 | 2018-08-21 | Celgene Corporation | Formulations of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide |
WO2018170133A1 (en) | 2017-03-15 | 2018-09-20 | Amgen Inc. | Use of oncolytic viruses, alone or in combination with a checkpoint inhibitor, for the treatment of cancer |
WO2018172508A1 (en) | 2017-03-24 | 2018-09-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2018195321A1 (en) * | 2017-04-20 | 2018-10-25 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
WO2018234367A1 (en) | 2017-06-20 | 2018-12-27 | Institut Curie | Inhibitor of suv39h1 histone methyltransferase for use in cancer combination therapy |
WO2019014100A1 (en) | 2017-07-10 | 2019-01-17 | Celgene Corporation | Antiproliferative compounds and methods of use thereof |
JP2019501944A (en) * | 2016-01-14 | 2019-01-24 | リサーチ・コオペレイション・ファウンデイション・オブ・ユンナム・ユニヴァーシティResearch Cooperation Foundation Of Yeungnam University | Pyridinol derivative or pharmaceutically acceptable salt thereof and pharmaceutical composition containing this as an active ingredient |
US10189808B2 (en) | 2016-01-08 | 2019-01-29 | Celgene Corporation | Solid forms of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide, and their pharmaceutical compositions and uses |
WO2019020593A1 (en) | 2017-07-25 | 2019-01-31 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for modulating monocytopoiesis |
EP3267984A4 (en) * | 2015-03-10 | 2019-03-13 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators |
WO2019057744A1 (en) | 2017-09-19 | 2019-03-28 | Institut Curie | Agonist of aryl hydrocarbon receptor for use in cancer combination therapy |
US10266530B2 (en) | 2016-09-09 | 2019-04-23 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
US10280164B2 (en) | 2016-09-09 | 2019-05-07 | Incyte Corporation | Pyrazolopyridone compounds and uses thereof |
WO2019094268A1 (en) | 2017-11-10 | 2019-05-16 | Armo Biosciences, Inc. | Compositions and methods of use of interleukin-10 in combination with immune checkpoint pathway inhibitors |
WO2019101956A1 (en) | 2017-11-24 | 2019-05-31 | Institut National De La Santé Et De La Recherche Médicale (Inserm) | Methods and compositions for treating cancers |
WO2019134946A1 (en) | 2018-01-04 | 2019-07-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma resistant |
WO2019160882A1 (en) * | 2018-02-13 | 2019-08-22 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
WO2019162325A1 (en) | 2018-02-21 | 2019-08-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of sk1 as biomarker for predicting response to immunecheckpoint inhibitors |
WO2019170727A1 (en) | 2018-03-06 | 2019-09-12 | Institut Curie | Inhibitor of setdb1 histone methyltransferase for use in cancer combination therapy |
US10421756B2 (en) | 2015-07-06 | 2019-09-24 | Rodin Therapeutics, Inc. | Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase |
WO2019185792A1 (en) | 2018-03-29 | 2019-10-03 | Philogen S.P.A | Cancer treatment using immunoconjugates and immune check-point inhibitors |
US10450273B2 (en) | 2016-08-29 | 2019-10-22 | Novartis Ag | N-(pyridin-2-yl)pyridine-sulfonamide derivatives and their use in the treatment of disease |
WO2019207030A1 (en) | 2018-04-26 | 2019-10-31 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting a response with an immune checkpoint inhibitor in a patient suffering from a lung cancer |
WO2019226761A1 (en) | 2018-05-23 | 2019-11-28 | Celgene Corporation | Antiproliferative compounds and bispecific antibody against bcma and cd3 for combined use |
WO2019245817A1 (en) | 2018-06-19 | 2019-12-26 | Armo Biosciences, Inc. | Compositions and methods of use of il-10 agents in conjunction with chimeric antigen receptor cell therapy |
WO2020030634A1 (en) | 2018-08-06 | 2020-02-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cancers |
US10590093B2 (en) | 2013-09-06 | 2020-03-17 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole derivatives as immunomodulators |
US10618916B2 (en) | 2018-05-11 | 2020-04-14 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
WO2020079164A1 (en) | 2018-10-18 | 2020-04-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Combination of a big-h3 antagonist and an immune checkpoint inhibitor for the treatment of solid tumor |
WO2020104479A1 (en) | 2018-11-20 | 2020-05-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cancers and resistant cancers with anti transferrin receptor 1 antibodies |
WO2020104496A1 (en) | 2018-11-20 | 2020-05-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Bispecific antibody targeting transferrin receptor 1 and soluble antigen |
US10669271B2 (en) | 2018-03-30 | 2020-06-02 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
WO2020115261A1 (en) | 2018-12-07 | 2020-06-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2020120592A1 (en) | 2018-12-12 | 2020-06-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for predicting and treating melanoma |
WO2020127411A1 (en) | 2018-12-19 | 2020-06-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cancers by immuno-modulation using antibodies against cathespin-d |
WO2020127885A1 (en) | 2018-12-21 | 2020-06-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Compositions for treating cancers and resistant cancers |
WO2020140012A1 (en) | 2018-12-27 | 2020-07-02 | Amgen Inc. | Lyophilized virus formulations |
WO2020141199A1 (en) | 2019-01-03 | 2020-07-09 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for enhancing cd8+ t cell-dependent immune responses in subjects suffering from cancer |
CN111407767A (en) * | 2020-03-28 | 2020-07-14 | 中山大学 | Application of sulfamonomethoxine derivative in preparation of antitumor drugs |
WO2020146440A1 (en) | 2019-01-09 | 2020-07-16 | Celgene Corporation | Antiproliferative compounds and second active agents for use in treating multiple myeloma |
WO2020146463A1 (en) | 2019-01-09 | 2020-07-16 | Celgene Corporation | Solid forms comprising (s)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl) benzyl)piperazin-1-yl)-3-fluorobenzonitrile and salts thereof, and compositions comprising and methods of using the same |
WO2020146441A1 (en) | 2019-01-09 | 2020-07-16 | Celgene Corporation | Pharmaceutical compositions comprising (s)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl) benzyl)piperazin-1-yl)-3-fluorobenzonitrile and methods of using the same |
US10722495B2 (en) | 2017-09-08 | 2020-07-28 | Incyte Corporation | Cyanoindazole compounds and uses thereof |
WO2020157131A1 (en) | 2019-01-30 | 2020-08-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for identifying whether a subject suffering from a cancer will achieve a response with an immune-checkpoint inhibitor |
WO2020161083A1 (en) | 2019-02-04 | 2020-08-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for modulating blood-brain barrier |
US10745388B2 (en) | 2018-02-20 | 2020-08-18 | Incyte Corporation | Indazole compounds and uses thereof |
WO2020168178A1 (en) | 2019-02-15 | 2020-08-20 | Incyte Corporation | Cyclin-dependent kinase 2 biomarkers and uses thereof |
WO2020165370A1 (en) | 2019-02-13 | 2020-08-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for selecting a cancer treatment in a subject suffering from cancer |
WO2020168197A1 (en) | 2019-02-15 | 2020-08-20 | Incyte Corporation | Pyrrolo[2,3-d]pyrimidinone compounds as cdk2 inhibitors |
US10752635B2 (en) | 2018-02-20 | 2020-08-25 | Incyte Corporation | Indazole compounds and uses thereof |
WO2020180864A1 (en) | 2019-03-05 | 2020-09-10 | Amgen Inc. | Use of oncolytic viruses for the treatment of cancer |
WO2020180959A1 (en) | 2019-03-05 | 2020-09-10 | Incyte Corporation | Pyrazolyl pyrimidinylamine compounds as cdk2 inhibitors |
US10774071B2 (en) | 2018-07-13 | 2020-09-15 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
US10793565B2 (en) | 2016-12-22 | 2020-10-06 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
WO2020205412A1 (en) | 2019-03-29 | 2020-10-08 | Amgen Inc. | Use of oncolytic viruses in the neoadjuvant therapy of cancer |
US10800761B2 (en) | 2018-02-20 | 2020-10-13 | Incyte Corporation | Carboxamide compounds and uses thereof |
WO2020221796A1 (en) | 2019-04-30 | 2020-11-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2020226633A1 (en) | 2019-05-07 | 2020-11-12 | Immunicom, Inc. | Increasing responses to checkpoint inhibitors by extracorporeal apheresis |
WO2021003432A1 (en) | 2019-07-02 | 2021-01-07 | Fred Hutchinson Cancer Research Center | Recombinant ad35 vectors and related gene therapy improvements |
WO2021007269A1 (en) | 2019-07-09 | 2021-01-14 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
US10899735B2 (en) | 2018-04-19 | 2021-01-26 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
US10899755B2 (en) | 2018-08-08 | 2021-01-26 | Incyte Corporation | Benzothiazole compounds and uses thereof |
WO2021024020A1 (en) | 2019-08-06 | 2021-02-11 | Astellas Pharma Inc. | Combination therapy involving antibodies against claudin 18.2 and immune checkpoint inhibitors for treatment of cancer |
US10919902B2 (en) | 2015-07-06 | 2021-02-16 | Alkermes, Inc. | Hetero-halo inhibitors of histone deacetylase |
WO2021030537A1 (en) | 2019-08-14 | 2021-02-18 | Incyte Corporation | Imidazolyl pyrimidinylamine compounds as cdk2 inhibitors |
WO2021048292A1 (en) | 2019-09-11 | 2021-03-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
US10969381B2 (en) | 2018-05-23 | 2021-04-06 | Celgene Corporation | Methods for treating multiple myeloma and the use of companion biomarkers for 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile |
WO2021064180A1 (en) | 2019-10-03 | 2021-04-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for modulating macrophages polarization |
US10973822B2 (en) | 2015-07-02 | 2021-04-13 | Celgene Corporation | Combination therapy for treatment of hematological cancers and solid tumors |
WO2021072232A1 (en) | 2019-10-11 | 2021-04-15 | Incyte Corporation | Bicyclic amines as cdk2 inhibitors |
WO2021076602A1 (en) | 2019-10-14 | 2021-04-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
WO2021074391A1 (en) | 2019-10-17 | 2021-04-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for diagnosing nasal intestinal type adenocarcinomas |
EP3669872A4 (en) * | 2017-08-18 | 2021-05-05 | Shanghai Ennovabio Pharmaceuticals Co., Ltd. | Compound having pd-l1 inhibitory activity, preparation method therefor and use thereof |
WO2021083959A1 (en) | 2019-10-29 | 2021-05-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating uveal melanoma |
US11014923B2 (en) | 2015-02-20 | 2021-05-25 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US11014929B2 (en) | 2016-09-09 | 2021-05-25 | Incyte Corporation | Pyrazolopyrimidine compounds and uses thereof |
US11040948B2 (en) | 2017-09-29 | 2021-06-22 | Curis, Inc. | Crystal forms of immunomodulators |
WO2021123243A1 (en) | 2019-12-19 | 2021-06-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and vaccine compositions to treat cancers |
US11053246B2 (en) | 2012-06-13 | 2021-07-06 | Incyte Corporation | Substituted tricyclic compounds as FGFR inhibitors |
WO2021138512A1 (en) | 2020-01-03 | 2021-07-08 | Incyte Corporation | Combination therapy comprising a2a/a2b and pd-1/pd-l1 inhibitors |
US11066394B2 (en) | 2019-08-06 | 2021-07-20 | Incyte Corporation | Solid forms of an HPK1 inhibitor |
US11066404B2 (en) | 2018-10-11 | 2021-07-20 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
WO2021144426A1 (en) | 2020-01-17 | 2021-07-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2021156360A1 (en) | 2020-02-05 | 2021-08-12 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for discontinuing a treatment with a tyrosine kinase inhibitor (tki) |
US11096940B2 (en) | 2017-06-22 | 2021-08-24 | Celgene Corporation | Treatment of hepatocellular carcinoma characterized by hepatitis B virus infection |
WO2021170777A1 (en) | 2020-02-28 | 2021-09-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for diagnosing, prognosing and managing treatment of breast cancer |
US11111247B2 (en) | 2018-09-25 | 2021-09-07 | Incyte Corporation | Pyrazolopyrimidine compounds and uses thereof |
WO2021178779A1 (en) | 2020-03-06 | 2021-09-10 | Incyte Corporation | Combination therapy comprising axl/mer and pd-1/pd-l1 inhibitors |
WO2021183318A2 (en) | 2020-03-09 | 2021-09-16 | President And Fellows Of Harvard College | Methods and compositions relating to improved combination therapies |
US11136300B2 (en) | 2017-10-11 | 2021-10-05 | Aurigene Discovery Technologies Limited | Crystalline forms of 3-substituted 1,2,4-oxadiazole |
WO2021211864A1 (en) | 2020-04-16 | 2021-10-21 | Incyte Corporation | Fused tricyclic kras inhibitors |
US11173162B2 (en) | 2015-02-20 | 2021-11-16 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US11174257B2 (en) | 2018-05-04 | 2021-11-16 | Incyte Corporation | Salts of an FGFR inhibitor |
WO2021231526A1 (en) | 2020-05-13 | 2021-11-18 | Incyte Corporation | Fused pyrimidine compounds as kras inhibitors |
WO2021236771A1 (en) * | 2020-05-22 | 2021-11-25 | Aligos Therapeutics, Inc. | Methods and compositions for targeting pd-l1 |
WO2021242794A2 (en) | 2020-05-29 | 2021-12-02 | President And Fellows Of Harvard College | Living cells engineered with polyphenol-functionalized biologically active nanocomplexes |
WO2021262962A1 (en) | 2020-06-25 | 2021-12-30 | Celgene Corporation | Methods for treating cancer with combination therapies |
WO2021262969A1 (en) | 2020-06-24 | 2021-12-30 | The General Hospital Corporation | Materials and methods of treating cancer |
WO2022002873A1 (en) | 2020-06-30 | 2022-01-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the risk of recurrence and/or death of patients suffering from a solid cancer after preoperative adjuvant therapies |
WO2022002874A1 (en) | 2020-06-30 | 2022-01-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the risk of recurrence and/or death of patients suffering from a solid cancer after preoperative adjuvant therapy and radical surgery |
WO2022008519A1 (en) | 2020-07-07 | 2022-01-13 | BioNTech SE | Therapeutic rna for hpv-positive cancer |
WO2022010854A1 (en) | 2020-07-07 | 2022-01-13 | Celgene Corporation | Pharmaceutical compositions comprising (s)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)m ethyl) benzyl)piperazin-1-yl)-3-fluorobenzonitrile and methods of using the same |
US11225475B2 (en) | 2017-08-07 | 2022-01-18 | Alkermes, Inc. | Substituted pyridines as inhibitors of histone deacetylase |
US11236085B2 (en) | 2018-10-24 | 2022-02-01 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
WO2022023379A1 (en) | 2020-07-28 | 2022-02-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for preventing and treating a cancer |
US11242343B2 (en) | 2016-09-09 | 2022-02-08 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
WO2022047093A1 (en) | 2020-08-28 | 2022-03-03 | Incyte Corporation | Vinyl imidazole compounds as inhibitors of kras |
WO2022072783A1 (en) | 2020-10-02 | 2022-04-07 | Incyte Corporation | Bicyclic dione compounds as inhibitors of kras |
US11299473B2 (en) | 2018-04-13 | 2022-04-12 | Incyte Corporation | Benzimidazole and indole compounds and uses thereof |
WO2022084531A1 (en) | 2020-10-23 | 2022-04-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating glioma |
WO2022098972A1 (en) | 2020-11-08 | 2022-05-12 | Seagen Inc. | Combination-therapy antibody drug conjugate with immune cell inhibitor |
WO2022101484A1 (en) | 2020-11-16 | 2022-05-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for predicting and treating uveal melanoma |
WO2022101481A1 (en) | 2020-11-16 | 2022-05-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for predicting and treating uveal melanoma |
WO2022135666A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Treatment schedule for cytokine proteins |
WO2022136266A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Therapeutic rna for treating cancer |
WO2022135667A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Therapeutic rna for treating cancer |
WO2022147092A1 (en) | 2020-12-29 | 2022-07-07 | Incyte Corporation | Combination therapy comprising a2a/a2b inhibitors, pd-1/pd-l1 inhibitors, and anti-cd73 antibodies |
WO2022150788A2 (en) | 2021-01-11 | 2022-07-14 | Synthekine, Inc. | Compositions and methods related to receptor pairing |
TWI771305B (en) * | 2016-06-20 | 2022-07-21 | 美商英塞特公司 | Heterocyclic compounds as immunomodulators |
US11401279B2 (en) | 2019-09-30 | 2022-08-02 | Incyte Corporation | Pyrido[3,2-d]pyrimidine compounds as immunomodulators |
US11407750B2 (en) | 2019-12-04 | 2022-08-09 | Incyte Corporation | Derivatives of an FGFR inhibitor |
US11407749B2 (en) | 2015-10-19 | 2022-08-09 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11406624B2 (en) | 2017-02-15 | 2022-08-09 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
WO2022171121A1 (en) | 2021-02-10 | 2022-08-18 | 同润生物医药(上海)有限公司 | Method and combination for treating tumors |
US11440914B2 (en) | 2019-05-01 | 2022-09-13 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
US11447494B2 (en) | 2019-05-01 | 2022-09-20 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
WO2022194908A1 (en) | 2021-03-17 | 2022-09-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2022203090A1 (en) | 2021-03-25 | 2022-09-29 | Astellas Pharma Inc. | Combination therapy involving antibodies against claudin 18.2 for treatment of cancer |
US11466004B2 (en) | 2018-05-04 | 2022-10-11 | Incyte Corporation | Solid forms of an FGFR inhibitor and processes for preparing the same |
WO2022217026A1 (en) | 2021-04-09 | 2022-10-13 | Seagen Inc. | Methods of treating cancer with anti-tigit antibodies |
US11472801B2 (en) | 2017-05-26 | 2022-10-18 | Incyte Corporation | Crystalline forms of a FGFR inhibitor and processes for preparing the same |
WO2022221170A1 (en) | 2021-04-12 | 2022-10-20 | Incyte Corporation | Combination therapy comprising an fgfr inhibitor and a nectin-4 targeting agent |
WO2022226100A1 (en) | 2021-04-20 | 2022-10-27 | Seagen Inc. | Modulation of antibody-dependent cellular cytotoxicity |
WO2022223791A1 (en) | 2021-04-23 | 2022-10-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cell senescence accumulation related disease |
US11492346B2 (en) | 2019-06-18 | 2022-11-08 | Pfizer Inc. | Benzisoxazole sulfonamide derivatives |
US11497734B2 (en) | 2017-11-03 | 2022-11-15 | Aurigene Discovery Technologies Limited | Dual inhibitors of TIM-3 and PD-1 pathways |
US11497735B2 (en) | 2017-11-06 | 2022-11-15 | Aurigene Discovery Technologies Limited | Conjoint therapies for immunomodulation |
WO2022261160A1 (en) | 2021-06-09 | 2022-12-15 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
WO2022261159A1 (en) | 2021-06-09 | 2022-12-15 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
US11530214B2 (en) | 2013-04-19 | 2022-12-20 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11535615B2 (en) | 2015-12-22 | 2022-12-27 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
WO2023283213A1 (en) | 2021-07-07 | 2023-01-12 | Incyte Corporation | Tricyclic compounds as inhibitors of kras |
WO2023285552A1 (en) | 2021-07-13 | 2023-01-19 | BioNTech SE | Multispecific binding agents against cd40 and cd137 in combination therapy for cancer |
WO2023287896A1 (en) | 2021-07-14 | 2023-01-19 | Incyte Corporation | Tricyclic compounds as inhibitors of kras |
US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11572366B2 (en) | 2015-11-19 | 2023-02-07 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
WO2023034290A1 (en) | 2021-08-31 | 2023-03-09 | Incyte Corporation | Naphthyridine compounds as inhibitors of kras |
US11608337B2 (en) | 2016-05-06 | 2023-03-21 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
WO2023049697A1 (en) | 2021-09-21 | 2023-03-30 | Incyte Corporation | Hetero-tricyclic compounds as inhibitors of kras |
WO2023052531A1 (en) | 2021-09-30 | 2023-04-06 | BioNTech SE | Treatment involving non-immunogenic rna for antigen vaccination and pd-1 axis binding antagonists |
WO2023056421A1 (en) | 2021-10-01 | 2023-04-06 | Incyte Corporation | Pyrazoloquinoline kras inhibitors |
WO2023057534A1 (en) | 2021-10-06 | 2023-04-13 | Genmab A/S | Multispecific binding agents against pd-l1 and cd137 in combination |
US11628162B2 (en) | 2019-03-08 | 2023-04-18 | Incyte Corporation | Methods of treating cancer with an FGFR inhibitor |
WO2023064857A1 (en) | 2021-10-14 | 2023-04-20 | Incyte Corporation | Quinoline compounds as inhibitors of kras |
WO2023061930A1 (en) | 2021-10-11 | 2023-04-20 | BioNTech SE | Therapeutic rna for lung cancer |
WO2023078900A1 (en) | 2021-11-03 | 2023-05-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating triple negative breast cancer (tnbc) |
WO2023083868A1 (en) | 2021-11-09 | 2023-05-19 | BioNTech SE | Tlr7 agonist and combinations for cancer treatment |
WO2023091746A1 (en) | 2021-11-22 | 2023-05-25 | Incyte Corporation | Combination therapy comprising an fgfr inhibitor and a kras inhibitor |
WO2023102184A1 (en) | 2021-12-03 | 2023-06-08 | Incyte Corporation | Bicyclic amine compounds as cdk12 inhibitors |
US11673883B2 (en) | 2016-05-26 | 2023-06-13 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11673894B2 (en) | 2018-02-27 | 2023-06-13 | Incyte Corporation | Imidazopyrimidines and triazolopyrimidines as A2A / A2B inhibitors |
WO2023107705A1 (en) | 2021-12-10 | 2023-06-15 | Incyte Corporation | Bicyclic amines as cdk12 inhibitors |
EP4201399A2 (en) | 2017-06-30 | 2023-06-28 | Celgene Corporation | Compositions and methods of use of 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl) -2,2-difluoroacetamide |
WO2023118165A1 (en) | 2021-12-21 | 2023-06-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2023122134A1 (en) | 2021-12-22 | 2023-06-29 | Incyte Corporation | Salts and solid forms of an fgfr inhibitor and processes of preparing thereof |
US11718605B2 (en) | 2016-07-14 | 2023-08-08 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11753406B2 (en) | 2019-08-09 | 2023-09-12 | Incyte Corporation | Salts of a PD-1/PD-L1 inhibitor |
WO2023172921A1 (en) | 2022-03-07 | 2023-09-14 | Incyte Corporation | Solid forms, salts, and processes of preparation of a cdk2 inhibitor |
US11760756B2 (en) | 2020-11-06 | 2023-09-19 | Incyte Corporation | Crystalline form of a PD-1/PD-L1 inhibitor |
US11780836B2 (en) | 2020-11-06 | 2023-10-10 | Incyte Corporation | Process of preparing a PD-1/PD-L1 inhibitor |
WO2023218046A1 (en) | 2022-05-12 | 2023-11-16 | Genmab A/S | Binding agents capable of binding to cd27 in combination therapy |
WO2023227949A1 (en) | 2022-05-27 | 2023-11-30 | Takeda Pharmaceutical Company Limited | Dosing of cd38-binding fusion protein |
WO2023239768A1 (en) | 2022-06-08 | 2023-12-14 | Incyte Corporation | Tricyclic triazolo compounds as dgk inhibitors |
WO2023250430A1 (en) | 2022-06-22 | 2023-12-28 | Incyte Corporation | Bicyclic amine cdk12 inhibitors |
US11859021B2 (en) | 2021-03-19 | 2024-01-02 | Icahn School Of Medicine At Mount Sinai | Compounds for regulating trained immunity, and their methods of use |
US11866434B2 (en) | 2020-11-06 | 2024-01-09 | Incyte Corporation | Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof |
US11866451B2 (en) | 2019-11-11 | 2024-01-09 | Incyte Corporation | Salts and crystalline forms of a PD-1/PD-L1 inhibitor |
US11866429B2 (en) | 2019-10-16 | 2024-01-09 | Chemocentryx, Inc. | Heteroaryl-biphenyl amines for the treatment of PD-L1 diseases |
US11873304B2 (en) | 2018-05-18 | 2024-01-16 | Incyte Corporation | Fused pyrimidine derivatives as A2A/A2B inhibitors |
WO2024015731A1 (en) | 2022-07-11 | 2024-01-18 | Incyte Corporation | Fused tricyclic compounds as inhibitors of kras g12v mutants |
US11884665B2 (en) | 2019-01-29 | 2024-01-30 | Incyte Corporation | Pyrazolopyridines and triazolopyridines as A2A / A2B inhibitors |
US11897891B2 (en) | 2019-12-04 | 2024-02-13 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
WO2024033400A1 (en) | 2022-08-10 | 2024-02-15 | Institut National de la Santé et de la Recherche Médicale | Sk2 inhibitor for the treatment of pancreatic cancer |
WO2024033399A1 (en) | 2022-08-10 | 2024-02-15 | Institut National de la Santé et de la Recherche Médicale | Sigmar1 ligand for the treatment of pancreatic cancer |
US11911372B2 (en) | 2018-06-28 | 2024-02-27 | Ctxt Pty Ltd | Compounds |
US11919904B2 (en) | 2019-03-29 | 2024-03-05 | Incyte Corporation | Sulfonylamide compounds as CDK2 inhibitors |
WO2024056716A1 (en) | 2022-09-14 | 2024-03-21 | Institut National de la Santé et de la Recherche Médicale | Methods and pharmaceutical compositions for the treatment of dilated cardiomyopathy |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013022091A1 (en) * | 2011-08-11 | 2013-02-14 | 小野薬品工業株式会社 | Therapeutic agent for autoimmune diseases comprising pd-1 agonist |
CN113967253A (en) * | 2012-05-15 | 2022-01-25 | 百时美施贵宝公司 | Immunotherapy by disrupting PD-1/PD-L1 signaling |
DK3054936T5 (en) | 2013-10-10 | 2024-03-18 | Eastern Virginia Medical School | 4-((2-HYDROXY-3-METHOXYBENZYL)AMINO) BENZENESULFONAMIDE DERIVATIVES AS 12-LIPOXYGENASE INHIBITORS |
EP3140298A1 (en) | 2014-05-07 | 2017-03-15 | Pfizer Inc. | Tropomyosin-related kinase inhibitors |
JP2018504143A (en) * | 2015-01-26 | 2018-02-15 | セレクティスCellectis | Anti-HSP70-specific chimeric antigen receptor (CAR) for cancer immunotherapy |
CA2979161A1 (en) * | 2015-03-10 | 2016-09-15 | Aurigene Discovery Technologies Limited | 3-substituted-1,2,4-oxadiazole and thiadiazole compounds as immunomodulators |
CN108136025B (en) | 2015-07-16 | 2022-09-06 | 比奥克斯塞尔医疗股份有限公司 | A novel method of treating cancer using immunomodulation |
AU2017305399A1 (en) * | 2016-08-03 | 2019-01-31 | Arising International, Inc. | Symmetric or semi-symmetric compounds useful as immunomodulators |
AU2017370002B2 (en) | 2016-12-02 | 2022-04-21 | Augusta University Research Institute, Inc. | Compositions for modulating PD-1 signal transduction |
TWI804572B (en) | 2018-02-09 | 2023-06-11 | 日商小野藥品工業股份有限公司 | Bispecific antibody |
CN114507227A (en) * | 2020-11-17 | 2022-05-17 | 中国医学科学院药物研究所 | Benzisothiazole compound, preparation method thereof, pharmaceutical composition and application |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007140222A2 (en) * | 2006-05-26 | 2007-12-06 | Novartis Ag | Pyrrolopyrimidine compounds and their uses |
WO2007147883A1 (en) * | 2006-06-23 | 2007-12-27 | Laboratorios Del Dr. Esteve, S.A. | Combination of a cholinesterase inhibitor and a compound with 5-ht6 receptor affinity |
-
2011
- 2011-01-03 US US13/519,621 patent/US20130022629A1/en not_active Abandoned
- 2011-01-03 WO PCT/US2011/020046 patent/WO2011082400A2/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007140222A2 (en) * | 2006-05-26 | 2007-12-06 | Novartis Ag | Pyrrolopyrimidine compounds and their uses |
WO2007147883A1 (en) * | 2006-06-23 | 2007-12-27 | Laboratorios Del Dr. Esteve, S.A. | Combination of a cholinesterase inhibitor and a compound with 5-ht6 receptor affinity |
Non-Patent Citations (1)
Title |
---|
DATABASE PUBCHEM COMPOUND [Online] NCBI Database accession no. 231303 & DATABASE PUBCHEM COMPOUND [Online] 'Cid 13515015, 13076233' Database accession no. 313718 * |
Cited By (375)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3626240A1 (en) * | 2009-03-02 | 2020-03-25 | StemSynergy Therapeutics, Inc. | Process of preparation of a n-aryl benzyl sulfonamide substituted with an amido group |
US9862714B2 (en) | 2009-03-02 | 2018-01-09 | Stemsynergy Therapeutics, Inc. | Methods and compositions useful in treating cancer and reducing Wnt mediated effects in a cell |
US11834446B2 (en) | 2009-03-02 | 2023-12-05 | Stemsynergy Therapeutics, Inc. | Methods and compositions useful in treating cancer and reducing Wnt mediated effects in a cell |
EP2403499A2 (en) * | 2009-03-02 | 2012-01-11 | Stemsynergy Therapeutics, Inc | Methods and compositions useful in treating cancer and reducing wnt mediated effects in a cell |
US11512081B2 (en) | 2009-03-02 | 2022-11-29 | Stemsynergy Therapeutics, Inc. | Methods and compositions useful in treating cancer and reducing WNT mediated effects in a cell |
US10975067B2 (en) | 2009-03-02 | 2021-04-13 | Stemsynergy Therapeutics, Inc. | Methods and compositions useful in treating cancer and reducing Wnt mediated effects in a cell |
EP2403499A4 (en) * | 2009-03-02 | 2012-09-12 | Stemsynergy Therapeutics Inc | Methods and compositions useful in treating cancer and reducing wnt mediated effects in a cell |
US9732045B2 (en) | 2010-07-16 | 2017-08-15 | Abbvie Inc. | Process for preparing antiviral compounds |
US8975443B2 (en) | 2010-07-16 | 2015-03-10 | Abbvie Inc. | Phosphine ligands for catalytic reactions |
US9669399B2 (en) | 2010-07-16 | 2017-06-06 | Abbvie Inc. | Phosphine ligands for catalytic reactions |
US9266913B2 (en) | 2010-07-16 | 2016-02-23 | Abbvie Inc. | Phosphine ligands for catalytic reactions |
US9381508B2 (en) | 2010-07-16 | 2016-07-05 | Abbvie Inc. | Phosphine ligands for catalytic reactions |
US8895737B2 (en) | 2010-07-16 | 2014-11-25 | Shashank Shekhar | Process for preparing antiviral compounds |
US8841487B2 (en) | 2010-07-16 | 2014-09-23 | Abbvie Inc. | Phosphine ligands for catalytic reactions |
US9255074B2 (en) | 2010-07-16 | 2016-02-09 | Abbvie Inc. | Process for preparing antiviral compounds |
US9434698B2 (en) | 2010-07-16 | 2016-09-06 | Abbvie Inc. | Process for preparing antiviral compounds |
US9200021B2 (en) | 2010-07-16 | 2015-12-01 | Abbvie Inc. | Phosphine ligands for catalytic reactions |
WO2013132317A1 (en) | 2012-03-07 | 2013-09-12 | Aurigene Discovery Technologies Limited | Peptidomimetic compounds as immunomodulators |
US9505728B2 (en) | 2012-03-09 | 2016-11-29 | Inception 2, Inc. | Triazolone compounds and uses thereof |
US9896444B2 (en) | 2012-05-15 | 2018-02-20 | Novartis Ag | Benzamide derivatives for inhibiting the activity of ABL1, ABL2 and BCR-ABL1 |
US9458112B2 (en) | 2012-05-15 | 2016-10-04 | Novartis Ag | Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1 |
US9340537B2 (en) | 2012-05-15 | 2016-05-17 | Novatis Ag | Benzamide derivatives for inhibiting the activity of ABL1, ABL2 and BCR-ABL1 |
US9315489B2 (en) | 2012-05-15 | 2016-04-19 | Novartis Ag | Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1 |
US9278981B2 (en) | 2012-05-15 | 2016-03-08 | Novartis Ag | Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1 |
US8829195B2 (en) | 2012-05-15 | 2014-09-09 | Novartis Ag | Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1 |
US11840534B2 (en) | 2012-06-13 | 2023-12-12 | Incyte Corporation | Substituted tricyclic compounds as FGFR inhibitors |
US11053246B2 (en) | 2012-06-13 | 2021-07-06 | Incyte Corporation | Substituted tricyclic compounds as FGFR inhibitors |
EP3981791A1 (en) | 2012-08-30 | 2022-04-13 | Amgen Inc. | A method for treating melanoma using a herpes simplex virus and an immune checkpoint inhibitor |
EP3381942A1 (en) | 2012-08-30 | 2018-10-03 | Amgen Inc. | A method for treating melanoma using a herpes simplex virus and an immune checkpoint inhibitor |
WO2014036412A2 (en) | 2012-08-30 | 2014-03-06 | Amgen Inc. | A method for treating melanoma using a herpes simplex virus and an immune checkpoint inhibitor |
US10034938B2 (en) | 2012-08-30 | 2018-07-31 | Amgen Inc. | Method for treating melanoma using a herpes simplex virus and an immune checkpoint inhibitor |
US10568871B2 (en) | 2012-12-20 | 2020-02-25 | Tempest Therapeutics, Inc. | Triazolone compounds and uses thereof |
US11666557B2 (en) | 2012-12-20 | 2023-06-06 | Tempest Therapeutics, Inc. | Triazolone compounds and uses thereof |
US9676754B2 (en) | 2012-12-20 | 2017-06-13 | Inception 2, Inc. | Triazolone compounds and uses thereof |
US11530214B2 (en) | 2013-04-19 | 2022-12-20 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
CN105705489A (en) * | 2013-09-04 | 2016-06-22 | 百时美施贵宝公司 | Compounds useful as immunomodulators |
CN105705489B (en) * | 2013-09-04 | 2019-04-26 | 百时美施贵宝公司 | Compound as immunomodulator |
US9776976B2 (en) | 2013-09-06 | 2017-10-03 | Inception 2, Inc. | Triazolone compounds and uses thereof |
US10961205B2 (en) | 2013-09-06 | 2021-03-30 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole derivatives as immunomodulators |
US11512060B2 (en) | 2013-09-06 | 2022-11-29 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole derivatives as immunomodulators |
US10590093B2 (en) | 2013-09-06 | 2020-03-17 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole derivatives as immunomodulators |
WO2015160641A3 (en) * | 2014-04-14 | 2015-12-23 | Bristol-Myers Squibb Company | Compounds useful as immunomodulators |
JP2017518961A (en) * | 2014-04-14 | 2017-07-13 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Compounds useful as immunomodulators |
CN106536515B (en) * | 2014-04-14 | 2019-08-16 | 百时美施贵宝公司 | Compound as immunomodulator |
EA030811B1 (en) * | 2014-04-14 | 2018-09-28 | Бристол-Майерс Сквибб Компани | Compounds useful as immunomodulators |
CN106536515A (en) * | 2014-04-14 | 2017-03-22 | 百时美施贵宝公司 | Compounds useful as immunomodulators |
EP3984542A1 (en) | 2014-11-20 | 2022-04-20 | Promega Corporation | Systems and methods for assessing modulators of immune checkpoints |
WO2016081854A1 (en) | 2014-11-20 | 2016-05-26 | Promega Corporation | Systems and methods for assessing modulators of immune checkpoints |
WO2016100364A1 (en) | 2014-12-18 | 2016-06-23 | Amgen Inc. | Stable frozen herpes simplex virus formulation |
US11014923B2 (en) | 2015-02-20 | 2021-05-25 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US11173162B2 (en) | 2015-02-20 | 2021-11-16 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US11667635B2 (en) | 2015-02-20 | 2023-06-06 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
EP3267984A4 (en) * | 2015-03-10 | 2019-03-13 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators |
US10781189B2 (en) | 2015-03-10 | 2020-09-22 | Aurigene Discovery Technologies Limited | 1,2,4-Oxadiazole and thiadiazole compounds as immunomodulators |
US11465976B2 (en) | 2015-03-10 | 2022-10-11 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators |
EP4023645A1 (en) * | 2015-03-10 | 2022-07-06 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators |
US10973822B2 (en) | 2015-07-02 | 2021-04-13 | Celgene Corporation | Combination therapy for treatment of hematological cancers and solid tumors |
US11858939B2 (en) | 2015-07-06 | 2024-01-02 | Alkermes, Inc. | Hetero-halo inhibitors of histone deacetylase |
US10919902B2 (en) | 2015-07-06 | 2021-02-16 | Alkermes, Inc. | Hetero-halo inhibitors of histone deacetylase |
US10421756B2 (en) | 2015-07-06 | 2019-09-24 | Rodin Therapeutics, Inc. | Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase |
EP3943098A2 (en) | 2015-07-16 | 2022-01-26 | Biokine Therapeutics Ltd. | Compositions and methods for treating cancer |
WO2017009842A2 (en) | 2015-07-16 | 2017-01-19 | Biokine Therapeutics Ltd. | Compositions and methods for treating cancer |
EP3744340A2 (en) | 2015-07-16 | 2020-12-02 | Biokine Therapeutics Ltd. | Compositions and methods for treating cancer |
WO2017032867A1 (en) | 2015-08-27 | 2017-03-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of patients suffering from a lung cancer |
WO2017055326A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of myeloid dendritic cells in a tissue sample |
WO2017055484A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for determining the metabolic status of lymphomas |
WO2017055324A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of cells of monocytic origin in a tissue sample |
WO2017055325A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of nk cells in a tissue sample |
WO2017055319A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of b cells in a tissue sample |
WO2017055320A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of cytotoxic lymphocytes in a tissue sample |
WO2017055327A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of endothelial cells in a tissue sample |
WO2017055321A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of fibroblasts in a tissue sample |
WO2017055322A1 (en) | 2015-09-29 | 2017-04-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of neutrophils in a tissue sample |
WO2017059224A2 (en) | 2015-10-01 | 2017-04-06 | Gilead Sciences, Inc. | Combination of a btk inhibitor and a checkpoint inhibitor for treating cancers |
WO2017060397A1 (en) | 2015-10-09 | 2017-04-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of subjects suffering from melanoma metastases |
CN108368090A (en) * | 2015-10-15 | 2018-08-03 | 百时美施贵宝公司 | Compound as immunomodulator |
CN108368090B (en) * | 2015-10-15 | 2022-04-12 | 百时美施贵宝公司 | Compounds as immunomodulators |
US11407749B2 (en) | 2015-10-19 | 2022-08-09 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11572366B2 (en) | 2015-11-19 | 2023-02-07 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
WO2017106634A1 (en) * | 2015-12-17 | 2017-06-22 | Incyte Corporation | N-phenyl-pyridine-2-carboxamide derivatives and their use as pd-1/pd-l1 protein/protein interaction modulators |
US11535615B2 (en) | 2015-12-22 | 2022-12-27 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11866435B2 (en) | 2015-12-22 | 2024-01-09 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
WO2017118634A1 (en) | 2016-01-04 | 2017-07-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of pd-1 and tim-3 as a measure for cd8+ cells in predicting and treating renal cell carcinoma |
US11883389B2 (en) | 2016-01-08 | 2024-01-30 | Celgene Corporation | Formulations of 2-(4-chlorophenyl)-N-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide |
EP3808346A1 (en) | 2016-01-08 | 2021-04-21 | Celgene Corporation | Antiproliferative compounds for use in the treatment of leukemia |
US10618883B2 (en) | 2016-01-08 | 2020-04-14 | Celgene Corporation | Antiproliferative compounds, and their pharmaceutical compositions and uses |
US10189808B2 (en) | 2016-01-08 | 2019-01-29 | Celgene Corporation | Solid forms of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide, and their pharmaceutical compositions and uses |
US10449187B2 (en) | 2016-01-08 | 2019-10-22 | Celgene Corporation | Formulations of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide |
US10227325B2 (en) | 2016-01-08 | 2019-03-12 | Celgene Corporation | Antiproliferative compounds, and their pharmaceutical compositions and uses |
US10626101B2 (en) | 2016-01-08 | 2020-04-21 | Celgene Corporation | Solid forms of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide, and their pharmaceutical compositions and uses |
US10052315B2 (en) | 2016-01-08 | 2018-08-21 | Celgene Corporation | Formulations of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide |
US11365184B2 (en) | 2016-01-08 | 2022-06-21 | Celgene Corporation | Antiproliferative compounds, and their pharmaceutical compositions and uses |
US11401257B2 (en) | 2016-01-08 | 2022-08-02 | Celgene Corporation | Solid forms of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide, and their pharmaceutical compositions and uses |
US11129821B2 (en) | 2016-01-08 | 2021-09-28 | Celgene Corporation | Formulations of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide |
US9938254B2 (en) | 2016-01-08 | 2018-04-10 | Celgene Corporation | Antiproliferative compounds, and their pharmaceutical compositions and uses |
EP4275707A2 (en) | 2016-01-08 | 2023-11-15 | Celgene Corporation | Formulations of 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide |
JP2019501944A (en) * | 2016-01-14 | 2019-01-24 | リサーチ・コオペレイション・ファウンデイション・オブ・ユンナム・ユニヴァーシティResearch Cooperation Foundation Of Yeungnam University | Pyridinol derivative or pharmaceutically acceptable salt thereof and pharmaceutical composition containing this as an active ingredient |
EP4035681A1 (en) | 2016-01-28 | 2022-08-03 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Methods and pharmaceutical composition for the treatment of cancer |
WO2017129769A1 (en) | 2016-01-28 | 2017-08-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for enhancing the potency of the immune checkpoint inhibitors |
WO2017129763A1 (en) | 2016-01-28 | 2017-08-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of signet ring cell gastric cancer |
WO2017129790A1 (en) | 2016-01-28 | 2017-08-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical composition for the treatment of cancer |
WO2017144668A1 (en) | 2016-02-26 | 2017-08-31 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Antibodies having specificity for btla and uses thereof |
US11608337B2 (en) | 2016-05-06 | 2023-03-21 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
WO2017202962A1 (en) | 2016-05-24 | 2017-11-30 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of non small cell lung cancer (nsclc) that coexists with chronic obstructive pulmonary disease (copd) |
WO2017202949A1 (en) | 2016-05-25 | 2017-11-30 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cancers |
US11673883B2 (en) | 2016-05-26 | 2023-06-13 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
TWI771305B (en) * | 2016-06-20 | 2022-07-21 | 美商英塞特公司 | Heterocyclic compounds as immunomodulators |
US11873309B2 (en) | 2016-06-20 | 2024-01-16 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
WO2017223422A1 (en) | 2016-06-24 | 2017-12-28 | Infinity Pharmaceuticals, Inc. | Combination therapies |
WO2018011166A2 (en) | 2016-07-12 | 2018-01-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for quantifying the population of myeloid dendritic cells in a tissue sample |
US11718605B2 (en) | 2016-07-14 | 2023-08-08 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
WO2018029336A1 (en) | 2016-08-12 | 2018-02-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for determining whether a subject was administered with an activator of the ppar beta/delta pathway. |
WO2018033135A1 (en) | 2016-08-19 | 2018-02-22 | Beigene, Ltd. | Use of a combination comprising a btk inhibitor for treating cancers |
EP4353747A2 (en) | 2016-08-19 | 2024-04-17 | BeiGene Switzerland GmbH | Combination of zanubrutinib with an anti-cd20 or an anti-pd-1 antibody for use in treating cancer |
US11066369B2 (en) | 2016-08-29 | 2021-07-20 | Novartis Ag | N-(pyridin-2-yl)pyridine-sulfonamide derivatives and their use in the treatment of disease |
US10450273B2 (en) | 2016-08-29 | 2019-10-22 | Novartis Ag | N-(pyridin-2-yl)pyridine-sulfonamide derivatives and their use in the treatment of disease |
WO2018044783A1 (en) * | 2016-08-29 | 2018-03-08 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11613536B2 (en) | 2016-08-29 | 2023-03-28 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11014929B2 (en) | 2016-09-09 | 2021-05-25 | Incyte Corporation | Pyrazolopyrimidine compounds and uses thereof |
US11795166B2 (en) | 2016-09-09 | 2023-10-24 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
US11891388B2 (en) | 2016-09-09 | 2024-02-06 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
US10266530B2 (en) | 2016-09-09 | 2019-04-23 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
US10280164B2 (en) | 2016-09-09 | 2019-05-07 | Incyte Corporation | Pyrazolopyridone compounds and uses thereof |
US11542265B2 (en) | 2016-09-09 | 2023-01-03 | Incyte Corporation | Pyrazolopyrimidine compounds and uses thereof |
US11242343B2 (en) | 2016-09-09 | 2022-02-08 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
US10934288B2 (en) | 2016-09-09 | 2021-03-02 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
US10435405B2 (en) | 2016-09-09 | 2019-10-08 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
WO2018046738A1 (en) | 2016-09-12 | 2018-03-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of patients suffering from cancer |
WO2018046736A1 (en) | 2016-09-12 | 2018-03-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of patients suffering from cancer |
WO2018055080A1 (en) | 2016-09-22 | 2018-03-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for reprograming immune environment in a subject in need thereof |
WO2018075447A1 (en) | 2016-10-19 | 2018-04-26 | The Trustees Of Columbia University In The City Of New York | Combination of braf inhibitor, talimogene laherparepvec, and immune checkpoint inhibitor for use in the treatment cancer (melanoma) |
WO2018087391A1 (en) | 2016-11-14 | 2018-05-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for modulating stem cells proliferation or differentiation |
CN106565616A (en) * | 2016-11-14 | 2017-04-19 | 杭州洪晟生物技术股份有限公司 | Preparation method of antibacterial veterinary drug sulfamonomethoxine sodium |
US10308644B2 (en) | 2016-12-22 | 2019-06-04 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
WO2018119286A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Bicyclic heteroaromatic compounds as immunomodulators |
JP2020504739A (en) * | 2016-12-22 | 2020-02-13 | インサイト・コーポレイションIncyte Corporation | Tetrahydroimidazo [4,5-C] pyridine derivative as PD-L1 internalization inducer |
KR102641030B1 (en) | 2016-12-22 | 2024-02-29 | 인사이트 코포레이션 | Tetrahydroimidazo[4,5-C]pyridine derivatives as inducers of PD-L1 internalization. |
US11465981B2 (en) | 2016-12-22 | 2022-10-11 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11566026B2 (en) | 2016-12-22 | 2023-01-31 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
CN110267953A (en) * | 2016-12-22 | 2019-09-20 | 因赛特公司 | Imidazolidine simultaneously [4,5-C] pyridine derivate as PD-L1 internalization inducer |
JP7149276B2 (en) | 2016-12-22 | 2022-10-06 | インサイト・コーポレイション | Tetrahydroimidazo[4,5-C]pyridine derivatives as PD-L1 internalization inducers |
KR20190112265A (en) * | 2016-12-22 | 2019-10-04 | 인사이트 코포레이션 | Tetrahydro imidazo [4,5-C] pyridine derivatives as PD-L1 internalization inducers |
WO2018119263A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Heterocyclic compounds derivatives as pd-l1 internalization inducers |
CN110267953B (en) * | 2016-12-22 | 2022-12-20 | 因赛特公司 | Tetrahydroimidazo [4,5-C ] pyridine derivatives as inducers of PD-L1 internalization |
WO2018119221A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Pyridine derivatives as immunomodulators |
TWI798192B (en) * | 2016-12-22 | 2023-04-11 | 美商英塞特公司 | Immunomodulator compounds and methods of use |
TWI808955B (en) * | 2016-12-22 | 2023-07-21 | 美商英塞特公司 | Heterocyclic compounds as immunomodulators |
WO2018119224A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Tetrahydro imidazo[4,5-c]pyridine derivatives as pd-l1 internalization inducers |
US11787793B2 (en) | 2016-12-22 | 2023-10-17 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
AU2017382870B2 (en) * | 2016-12-22 | 2022-03-24 | Incyte Corporation | Benzooxazole derivatives as immunomodulators |
JP2020504737A (en) * | 2016-12-22 | 2020-02-13 | インサイト・コーポレイションIncyte Corporation | Heterocyclic compounds as immunomodulators |
AU2017382258B2 (en) * | 2016-12-22 | 2022-07-28 | Incyte Corporation | Tetrahydro imidazo(4,5-c)pyridine derivatives as PD-L1 internalization inducers |
US11339149B2 (en) | 2016-12-22 | 2022-05-24 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US10793565B2 (en) | 2016-12-22 | 2020-10-06 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
WO2018119266A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Benzooxazole derivatives as immunomodulators |
US10800768B2 (en) | 2016-12-22 | 2020-10-13 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
JP7101678B2 (en) | 2016-12-22 | 2022-07-15 | インサイト・コーポレイション | Heterocyclic compounds as immunomodulators |
US10806785B2 (en) | 2016-12-22 | 2020-10-20 | Incyte Corporation | Immunomodulator compounds and methods of use |
EP4223369A1 (en) * | 2016-12-22 | 2023-08-09 | Incyte Corporation | Immunomodulator compounds and methods of use |
WO2018115458A1 (en) | 2016-12-23 | 2018-06-28 | Virttu Biologics Limited | Treatment of cancer |
WO2018122249A1 (en) | 2016-12-28 | 2018-07-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the survival time of patients suffering from a microsatellite stable colorectal cancer |
WO2018122245A1 (en) | 2016-12-28 | 2018-07-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of predicting the survival time of patients suffering from cms3 colorectal cancer |
US11225479B2 (en) | 2017-01-11 | 2022-01-18 | Alkermes, Inc. | Bicyclic inhibitors of histone deacetylase |
US10519149B2 (en) | 2017-01-11 | 2019-12-31 | Rodin Therapeutics, Inc. | Bicyclic inhibitors of histone deacetylase |
US9951069B1 (en) | 2017-01-11 | 2018-04-24 | Rodin Therapeutics, Inc. | Bicyclic inhibitors of histone deacetylase |
US10793567B2 (en) | 2017-01-11 | 2020-10-06 | Rodin Therapeutics, Inc. | Bicyclic inhibitors of histone deacetylase |
US10696673B2 (en) | 2017-01-11 | 2020-06-30 | Rodin Therapeutics, Inc. | Bicyclic inhibitors of histone deacetylase |
US11286256B2 (en) | 2017-01-11 | 2022-03-29 | Alkermes, Inc. | Bicyclic inhibitors of histone deacetylase |
WO2018140671A1 (en) | 2017-01-27 | 2018-08-02 | Celgene Corporation | 3-(1-oxo-4-((4-((3-oxomorpholino) methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dione and isotopologues thereof |
WO2018146148A1 (en) | 2017-02-07 | 2018-08-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A method for predicting the response to checkpoint blockade cancer immunotherapy |
WO2018146128A1 (en) | 2017-02-07 | 2018-08-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Detection of kit polymorphism for predicting the response to checkpoint blockade cancer immunotherapy |
US11406624B2 (en) | 2017-02-15 | 2022-08-09 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
WO2018170133A1 (en) | 2017-03-15 | 2018-09-20 | Amgen Inc. | Use of oncolytic viruses, alone or in combination with a checkpoint inhibitor, for the treatment of cancer |
WO2018172508A1 (en) | 2017-03-24 | 2018-09-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
EP4026835A3 (en) * | 2017-04-20 | 2022-09-21 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
WO2018195321A1 (en) * | 2017-04-20 | 2018-10-25 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
JP7161491B2 (en) | 2017-04-20 | 2022-10-26 | ギリアード サイエンシーズ, インコーポレイテッド | PD-1/PD-L1 inhibitor |
JP2020518561A (en) * | 2017-04-20 | 2020-06-25 | ギリアード サイエンシーズ, インコーポレイテッド | PD-1/PD-L1 inhibitor |
US11472801B2 (en) | 2017-05-26 | 2022-10-18 | Incyte Corporation | Crystalline forms of a FGFR inhibitor and processes for preparing the same |
WO2018234367A1 (en) | 2017-06-20 | 2018-12-27 | Institut Curie | Inhibitor of suv39h1 histone methyltransferase for use in cancer combination therapy |
US11096940B2 (en) | 2017-06-22 | 2021-08-24 | Celgene Corporation | Treatment of hepatocellular carcinoma characterized by hepatitis B virus infection |
EP4201399A2 (en) | 2017-06-30 | 2023-06-28 | Celgene Corporation | Compositions and methods of use of 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl) -2,2-difluoroacetamide |
WO2019014100A1 (en) | 2017-07-10 | 2019-01-17 | Celgene Corporation | Antiproliferative compounds and methods of use thereof |
WO2019020593A1 (en) | 2017-07-25 | 2019-01-31 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for modulating monocytopoiesis |
US11225475B2 (en) | 2017-08-07 | 2022-01-18 | Alkermes, Inc. | Substituted pyridines as inhibitors of histone deacetylase |
US11912702B2 (en) | 2017-08-07 | 2024-02-27 | Alkermes, Inc. | Substituted pyridines as inhibitors of histone deacetylase |
EP3669872A4 (en) * | 2017-08-18 | 2021-05-05 | Shanghai Ennovabio Pharmaceuticals Co., Ltd. | Compound having pd-l1 inhibitory activity, preparation method therefor and use thereof |
US10722495B2 (en) | 2017-09-08 | 2020-07-28 | Incyte Corporation | Cyanoindazole compounds and uses thereof |
WO2019057744A1 (en) | 2017-09-19 | 2019-03-28 | Institut Curie | Agonist of aryl hydrocarbon receptor for use in cancer combination therapy |
US11939306B2 (en) | 2017-09-29 | 2024-03-26 | Curis, Inc. | Crystal forms of immunomodulators |
US11040948B2 (en) | 2017-09-29 | 2021-06-22 | Curis, Inc. | Crystal forms of immunomodulators |
US11643401B2 (en) | 2017-09-29 | 2023-05-09 | Curis, Inc. | Crystal forms of immunomodulators |
US11136300B2 (en) | 2017-10-11 | 2021-10-05 | Aurigene Discovery Technologies Limited | Crystalline forms of 3-substituted 1,2,4-oxadiazole |
US11680051B2 (en) | 2017-10-11 | 2023-06-20 | Aurigene Discovery Technologies Limited | Crystalline forms of 3-substituted 1,2,4-oxadiazole |
US11497734B2 (en) | 2017-11-03 | 2022-11-15 | Aurigene Discovery Technologies Limited | Dual inhibitors of TIM-3 and PD-1 pathways |
US11497735B2 (en) | 2017-11-06 | 2022-11-15 | Aurigene Discovery Technologies Limited | Conjoint therapies for immunomodulation |
WO2019094268A1 (en) | 2017-11-10 | 2019-05-16 | Armo Biosciences, Inc. | Compositions and methods of use of interleukin-10 in combination with immune checkpoint pathway inhibitors |
WO2019101956A1 (en) | 2017-11-24 | 2019-05-31 | Institut National De La Santé Et De La Recherche Médicale (Inserm) | Methods and compositions for treating cancers |
WO2019134946A1 (en) | 2018-01-04 | 2019-07-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma resistant |
AU2021204222B2 (en) * | 2018-02-13 | 2023-02-16 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
AU2019222644B2 (en) * | 2018-02-13 | 2021-04-01 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
US11555029B2 (en) | 2018-02-13 | 2023-01-17 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
KR20200121323A (en) * | 2018-02-13 | 2020-10-23 | 길리애드 사이언시즈, 인코포레이티드 | PD-1/PD-L1 inhibitor |
EP4227302A1 (en) * | 2018-02-13 | 2023-08-16 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
JP7062792B2 (en) | 2018-02-13 | 2022-05-06 | ギリアード サイエンシーズ, インコーポレイテッド | PD-1 / PD-L1 inhibitor |
JP2021513561A (en) * | 2018-02-13 | 2021-05-27 | ギリアード サイエンシーズ, インコーポレイテッド | PD-1 / PD-L1 inhibitor |
US10710986B2 (en) | 2018-02-13 | 2020-07-14 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
WO2019160882A1 (en) * | 2018-02-13 | 2019-08-22 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
KR102445054B1 (en) | 2018-02-13 | 2022-09-22 | 길리애드 사이언시즈, 인코포레이티드 | PD-1/PD-L1 inhibitors |
CN111712494A (en) * | 2018-02-13 | 2020-09-25 | 吉利德科学公司 | PD-1/PD-L1 inhibitors |
US10745388B2 (en) | 2018-02-20 | 2020-08-18 | Incyte Corporation | Indazole compounds and uses thereof |
US10800761B2 (en) | 2018-02-20 | 2020-10-13 | Incyte Corporation | Carboxamide compounds and uses thereof |
US11492354B2 (en) | 2018-02-20 | 2022-11-08 | Incyte Corporation | Indazole compounds and uses thereof |
US11731958B2 (en) | 2018-02-20 | 2023-08-22 | Incyte Corporation | Carboxamide compounds and uses thereof |
US10752635B2 (en) | 2018-02-20 | 2020-08-25 | Incyte Corporation | Indazole compounds and uses thereof |
WO2019162325A1 (en) | 2018-02-21 | 2019-08-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of sk1 as biomarker for predicting response to immunecheckpoint inhibitors |
US11673894B2 (en) | 2018-02-27 | 2023-06-13 | Incyte Corporation | Imidazopyrimidines and triazolopyrimidines as A2A / A2B inhibitors |
WO2019170727A1 (en) | 2018-03-06 | 2019-09-12 | Institut Curie | Inhibitor of setdb1 histone methyltransferase for use in cancer combination therapy |
WO2019185792A1 (en) | 2018-03-29 | 2019-10-03 | Philogen S.P.A | Cancer treatment using immunoconjugates and immune check-point inhibitors |
US11124511B2 (en) | 2018-03-30 | 2021-09-21 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US10669271B2 (en) | 2018-03-30 | 2020-06-02 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11299473B2 (en) | 2018-04-13 | 2022-04-12 | Incyte Corporation | Benzimidazole and indole compounds and uses thereof |
US10899735B2 (en) | 2018-04-19 | 2021-01-26 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
WO2019207030A1 (en) | 2018-04-26 | 2019-10-31 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting a response with an immune checkpoint inhibitor in a patient suffering from a lung cancer |
US11466004B2 (en) | 2018-05-04 | 2022-10-11 | Incyte Corporation | Solid forms of an FGFR inhibitor and processes for preparing the same |
US11174257B2 (en) | 2018-05-04 | 2021-11-16 | Incyte Corporation | Salts of an FGFR inhibitor |
US10906920B2 (en) | 2018-05-11 | 2021-02-02 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11414433B2 (en) | 2018-05-11 | 2022-08-16 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US10618916B2 (en) | 2018-05-11 | 2020-04-14 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11873304B2 (en) | 2018-05-18 | 2024-01-16 | Incyte Corporation | Fused pyrimidine derivatives as A2A/A2B inhibitors |
US11726080B2 (en) | 2018-05-23 | 2023-08-15 | Celgene Corporation | Methods for treating multiple myeloma and the use of companion biomarkers for 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile |
US10969381B2 (en) | 2018-05-23 | 2021-04-06 | Celgene Corporation | Methods for treating multiple myeloma and the use of companion biomarkers for 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile |
EP4218762A2 (en) | 2018-05-23 | 2023-08-02 | Celgene Corporation | Antiproliferative compounds and bispecific antibody against bcma and cd3 for combined use |
WO2019226761A1 (en) | 2018-05-23 | 2019-11-28 | Celgene Corporation | Antiproliferative compounds and bispecific antibody against bcma and cd3 for combined use |
WO2019245817A1 (en) | 2018-06-19 | 2019-12-26 | Armo Biosciences, Inc. | Compositions and methods of use of il-10 agents in conjunction with chimeric antigen receptor cell therapy |
US11911372B2 (en) | 2018-06-28 | 2024-02-27 | Ctxt Pty Ltd | Compounds |
US10774071B2 (en) | 2018-07-13 | 2020-09-15 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
WO2020030634A1 (en) | 2018-08-06 | 2020-02-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cancers |
US10899755B2 (en) | 2018-08-08 | 2021-01-26 | Incyte Corporation | Benzothiazole compounds and uses thereof |
US11866426B2 (en) | 2018-08-08 | 2024-01-09 | Incyte Corporation | Benzothiazole compounds and uses thereof |
US11111247B2 (en) | 2018-09-25 | 2021-09-07 | Incyte Corporation | Pyrazolopyrimidine compounds and uses thereof |
US11066404B2 (en) | 2018-10-11 | 2021-07-20 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
US11866432B2 (en) | 2018-10-11 | 2024-01-09 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
WO2020079164A1 (en) | 2018-10-18 | 2020-04-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Combination of a big-h3 antagonist and an immune checkpoint inhibitor for the treatment of solid tumor |
US11236085B2 (en) | 2018-10-24 | 2022-02-01 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
WO2020104479A1 (en) | 2018-11-20 | 2020-05-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cancers and resistant cancers with anti transferrin receptor 1 antibodies |
WO2020104496A1 (en) | 2018-11-20 | 2020-05-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Bispecific antibody targeting transferrin receptor 1 and soluble antigen |
WO2020115261A1 (en) | 2018-12-07 | 2020-06-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2020120592A1 (en) | 2018-12-12 | 2020-06-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for predicting and treating melanoma |
WO2020127411A1 (en) | 2018-12-19 | 2020-06-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cancers by immuno-modulation using antibodies against cathespin-d |
WO2020127885A1 (en) | 2018-12-21 | 2020-06-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Compositions for treating cancers and resistant cancers |
WO2020140012A1 (en) | 2018-12-27 | 2020-07-02 | Amgen Inc. | Lyophilized virus formulations |
WO2020141199A1 (en) | 2019-01-03 | 2020-07-09 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for enhancing cd8+ t cell-dependent immune responses in subjects suffering from cancer |
EP4059569A1 (en) | 2019-01-03 | 2022-09-21 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Methods and pharmaceutical compositions for enhancing cd8+ t cell-dependent immune responses in subjects suffering from cancer |
WO2020146463A1 (en) | 2019-01-09 | 2020-07-16 | Celgene Corporation | Solid forms comprising (s)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl) benzyl)piperazin-1-yl)-3-fluorobenzonitrile and salts thereof, and compositions comprising and methods of using the same |
WO2020146440A1 (en) | 2019-01-09 | 2020-07-16 | Celgene Corporation | Antiproliferative compounds and second active agents for use in treating multiple myeloma |
WO2020146441A1 (en) | 2019-01-09 | 2020-07-16 | Celgene Corporation | Pharmaceutical compositions comprising (s)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl) benzyl)piperazin-1-yl)-3-fluorobenzonitrile and methods of using the same |
US11884665B2 (en) | 2019-01-29 | 2024-01-30 | Incyte Corporation | Pyrazolopyridines and triazolopyridines as A2A / A2B inhibitors |
WO2020157131A1 (en) | 2019-01-30 | 2020-08-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for identifying whether a subject suffering from a cancer will achieve a response with an immune-checkpoint inhibitor |
WO2020161083A1 (en) | 2019-02-04 | 2020-08-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for modulating blood-brain barrier |
WO2020165370A1 (en) | 2019-02-13 | 2020-08-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for selecting a cancer treatment in a subject suffering from cancer |
WO2020168178A1 (en) | 2019-02-15 | 2020-08-20 | Incyte Corporation | Cyclin-dependent kinase 2 biomarkers and uses thereof |
US11384083B2 (en) | 2019-02-15 | 2022-07-12 | Incyte Corporation | Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors |
WO2020168197A1 (en) | 2019-02-15 | 2020-08-20 | Incyte Corporation | Pyrrolo[2,3-d]pyrimidinone compounds as cdk2 inhibitors |
US11472791B2 (en) | 2019-03-05 | 2022-10-18 | Incyte Corporation | Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors |
WO2020180864A1 (en) | 2019-03-05 | 2020-09-10 | Amgen Inc. | Use of oncolytic viruses for the treatment of cancer |
WO2020180959A1 (en) | 2019-03-05 | 2020-09-10 | Incyte Corporation | Pyrazolyl pyrimidinylamine compounds as cdk2 inhibitors |
US11628162B2 (en) | 2019-03-08 | 2023-04-18 | Incyte Corporation | Methods of treating cancer with an FGFR inhibitor |
WO2020205412A1 (en) | 2019-03-29 | 2020-10-08 | Amgen Inc. | Use of oncolytic viruses in the neoadjuvant therapy of cancer |
US11919904B2 (en) | 2019-03-29 | 2024-03-05 | Incyte Corporation | Sulfonylamide compounds as CDK2 inhibitors |
WO2020221796A1 (en) | 2019-04-30 | 2020-11-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
US11447494B2 (en) | 2019-05-01 | 2022-09-20 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
US11440914B2 (en) | 2019-05-01 | 2022-09-13 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
WO2020226633A1 (en) | 2019-05-07 | 2020-11-12 | Immunicom, Inc. | Increasing responses to checkpoint inhibitors by extracorporeal apheresis |
US11492346B2 (en) | 2019-06-18 | 2022-11-08 | Pfizer Inc. | Benzisoxazole sulfonamide derivatives |
WO2021003432A1 (en) | 2019-07-02 | 2021-01-07 | Fred Hutchinson Cancer Research Center | Recombinant ad35 vectors and related gene therapy improvements |
WO2021007269A1 (en) | 2019-07-09 | 2021-01-14 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
WO2021025177A1 (en) | 2019-08-06 | 2021-02-11 | Astellas Pharma Inc. | Combination therapy involving antibodies against claudin 18.2 and immune checkpoint inhibitors for treatment of cancer |
WO2021024020A1 (en) | 2019-08-06 | 2021-02-11 | Astellas Pharma Inc. | Combination therapy involving antibodies against claudin 18.2 and immune checkpoint inhibitors for treatment of cancer |
US11066394B2 (en) | 2019-08-06 | 2021-07-20 | Incyte Corporation | Solid forms of an HPK1 inhibitor |
US11787784B2 (en) | 2019-08-06 | 2023-10-17 | Incyte Corporation | Solid forms of an HPK1 inhibitor |
US11753406B2 (en) | 2019-08-09 | 2023-09-12 | Incyte Corporation | Salts of a PD-1/PD-L1 inhibitor |
WO2021030537A1 (en) | 2019-08-14 | 2021-02-18 | Incyte Corporation | Imidazolyl pyrimidinylamine compounds as cdk2 inhibitors |
US11427567B2 (en) | 2019-08-14 | 2022-08-30 | Incyte Corporation | Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors |
WO2021048292A1 (en) | 2019-09-11 | 2021-03-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
US11401279B2 (en) | 2019-09-30 | 2022-08-02 | Incyte Corporation | Pyrido[3,2-d]pyrimidine compounds as immunomodulators |
WO2021064180A1 (en) | 2019-10-03 | 2021-04-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for modulating macrophages polarization |
WO2021072232A1 (en) | 2019-10-11 | 2021-04-15 | Incyte Corporation | Bicyclic amines as cdk2 inhibitors |
US11851426B2 (en) | 2019-10-11 | 2023-12-26 | Incyte Corporation | Bicyclic amines as CDK2 inhibitors |
WO2021076602A1 (en) | 2019-10-14 | 2021-04-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
US11607416B2 (en) | 2019-10-14 | 2023-03-21 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11866429B2 (en) | 2019-10-16 | 2024-01-09 | Chemocentryx, Inc. | Heteroaryl-biphenyl amines for the treatment of PD-L1 diseases |
US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
WO2021074391A1 (en) | 2019-10-17 | 2021-04-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for diagnosing nasal intestinal type adenocarcinomas |
WO2021083959A1 (en) | 2019-10-29 | 2021-05-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating uveal melanoma |
US11866451B2 (en) | 2019-11-11 | 2024-01-09 | Incyte Corporation | Salts and crystalline forms of a PD-1/PD-L1 inhibitor |
US11407750B2 (en) | 2019-12-04 | 2022-08-09 | Incyte Corporation | Derivatives of an FGFR inhibitor |
US11897891B2 (en) | 2019-12-04 | 2024-02-13 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
WO2021123243A1 (en) | 2019-12-19 | 2021-06-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and vaccine compositions to treat cancers |
WO2021138512A1 (en) | 2020-01-03 | 2021-07-08 | Incyte Corporation | Combination therapy comprising a2a/a2b and pd-1/pd-l1 inhibitors |
WO2021144426A1 (en) | 2020-01-17 | 2021-07-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2021156360A1 (en) | 2020-02-05 | 2021-08-12 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for discontinuing a treatment with a tyrosine kinase inhibitor (tki) |
WO2021170777A1 (en) | 2020-02-28 | 2021-09-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for diagnosing, prognosing and managing treatment of breast cancer |
WO2021178779A1 (en) | 2020-03-06 | 2021-09-10 | Incyte Corporation | Combination therapy comprising axl/mer and pd-1/pd-l1 inhibitors |
WO2021183318A2 (en) | 2020-03-09 | 2021-09-16 | President And Fellows Of Harvard College | Methods and compositions relating to improved combination therapies |
CN111407767B (en) * | 2020-03-28 | 2021-05-25 | 中山大学 | Application of sulfamonomethoxine derivative in preparation of antitumor drugs |
CN111407767A (en) * | 2020-03-28 | 2020-07-14 | 中山大学 | Application of sulfamonomethoxine derivative in preparation of antitumor drugs |
WO2021211864A1 (en) | 2020-04-16 | 2021-10-21 | Incyte Corporation | Fused tricyclic kras inhibitors |
WO2021231526A1 (en) | 2020-05-13 | 2021-11-18 | Incyte Corporation | Fused pyrimidine compounds as kras inhibitors |
WO2021236771A1 (en) * | 2020-05-22 | 2021-11-25 | Aligos Therapeutics, Inc. | Methods and compositions for targeting pd-l1 |
US11760764B2 (en) | 2020-05-22 | 2023-09-19 | Aligos Therapeutics, Inc. | Methods and compositions for targeting PD-L1 |
WO2021242794A2 (en) | 2020-05-29 | 2021-12-02 | President And Fellows Of Harvard College | Living cells engineered with polyphenol-functionalized biologically active nanocomplexes |
WO2021262969A1 (en) | 2020-06-24 | 2021-12-30 | The General Hospital Corporation | Materials and methods of treating cancer |
WO2021262962A1 (en) | 2020-06-25 | 2021-12-30 | Celgene Corporation | Methods for treating cancer with combination therapies |
WO2022002873A1 (en) | 2020-06-30 | 2022-01-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the risk of recurrence and/or death of patients suffering from a solid cancer after preoperative adjuvant therapies |
WO2022002874A1 (en) | 2020-06-30 | 2022-01-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the risk of recurrence and/or death of patients suffering from a solid cancer after preoperative adjuvant therapy and radical surgery |
WO2022008519A1 (en) | 2020-07-07 | 2022-01-13 | BioNTech SE | Therapeutic rna for hpv-positive cancer |
WO2022010854A1 (en) | 2020-07-07 | 2022-01-13 | Celgene Corporation | Pharmaceutical compositions comprising (s)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)m ethyl) benzyl)piperazin-1-yl)-3-fluorobenzonitrile and methods of using the same |
WO2022023379A1 (en) | 2020-07-28 | 2022-02-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for preventing and treating a cancer |
WO2022047093A1 (en) | 2020-08-28 | 2022-03-03 | Incyte Corporation | Vinyl imidazole compounds as inhibitors of kras |
WO2022072783A1 (en) | 2020-10-02 | 2022-04-07 | Incyte Corporation | Bicyclic dione compounds as inhibitors of kras |
WO2022084531A1 (en) | 2020-10-23 | 2022-04-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating glioma |
US11760756B2 (en) | 2020-11-06 | 2023-09-19 | Incyte Corporation | Crystalline form of a PD-1/PD-L1 inhibitor |
US11866434B2 (en) | 2020-11-06 | 2024-01-09 | Incyte Corporation | Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof |
US11780836B2 (en) | 2020-11-06 | 2023-10-10 | Incyte Corporation | Process of preparing a PD-1/PD-L1 inhibitor |
WO2022098972A1 (en) | 2020-11-08 | 2022-05-12 | Seagen Inc. | Combination-therapy antibody drug conjugate with immune cell inhibitor |
WO2022101481A1 (en) | 2020-11-16 | 2022-05-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for predicting and treating uveal melanoma |
WO2022101484A1 (en) | 2020-11-16 | 2022-05-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for predicting and treating uveal melanoma |
WO2022136257A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Therapeutic rna for treating cancer |
WO2022135666A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Treatment schedule for cytokine proteins |
WO2022136266A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Therapeutic rna for treating cancer |
WO2022135667A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Therapeutic rna for treating cancer |
WO2022136255A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Treatment schedule for cytokine proteins |
WO2022147092A1 (en) | 2020-12-29 | 2022-07-07 | Incyte Corporation | Combination therapy comprising a2a/a2b inhibitors, pd-1/pd-l1 inhibitors, and anti-cd73 antibodies |
WO2022150788A2 (en) | 2021-01-11 | 2022-07-14 | Synthekine, Inc. | Compositions and methods related to receptor pairing |
WO2022171121A1 (en) | 2021-02-10 | 2022-08-18 | 同润生物医药(上海)有限公司 | Method and combination for treating tumors |
WO2022194908A1 (en) | 2021-03-17 | 2022-09-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
US11859021B2 (en) | 2021-03-19 | 2024-01-02 | Icahn School Of Medicine At Mount Sinai | Compounds for regulating trained immunity, and their methods of use |
WO2022203090A1 (en) | 2021-03-25 | 2022-09-29 | Astellas Pharma Inc. | Combination therapy involving antibodies against claudin 18.2 for treatment of cancer |
WO2022217026A1 (en) | 2021-04-09 | 2022-10-13 | Seagen Inc. | Methods of treating cancer with anti-tigit antibodies |
WO2022221170A1 (en) | 2021-04-12 | 2022-10-20 | Incyte Corporation | Combination therapy comprising an fgfr inhibitor and a nectin-4 targeting agent |
WO2022226100A1 (en) | 2021-04-20 | 2022-10-27 | Seagen Inc. | Modulation of antibody-dependent cellular cytotoxicity |
WO2022223791A1 (en) | 2021-04-23 | 2022-10-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating cell senescence accumulation related disease |
WO2022261159A1 (en) | 2021-06-09 | 2022-12-15 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
WO2022261160A1 (en) | 2021-06-09 | 2022-12-15 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
US11939331B2 (en) | 2021-06-09 | 2024-03-26 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
WO2023283213A1 (en) | 2021-07-07 | 2023-01-12 | Incyte Corporation | Tricyclic compounds as inhibitors of kras |
WO2023285552A1 (en) | 2021-07-13 | 2023-01-19 | BioNTech SE | Multispecific binding agents against cd40 and cd137 in combination therapy for cancer |
WO2023287896A1 (en) | 2021-07-14 | 2023-01-19 | Incyte Corporation | Tricyclic compounds as inhibitors of kras |
WO2023034290A1 (en) | 2021-08-31 | 2023-03-09 | Incyte Corporation | Naphthyridine compounds as inhibitors of kras |
WO2023049697A1 (en) | 2021-09-21 | 2023-03-30 | Incyte Corporation | Hetero-tricyclic compounds as inhibitors of kras |
WO2023052531A1 (en) | 2021-09-30 | 2023-04-06 | BioNTech SE | Treatment involving non-immunogenic rna for antigen vaccination and pd-1 axis binding antagonists |
WO2023051926A1 (en) | 2021-09-30 | 2023-04-06 | BioNTech SE | Treatment involving non-immunogenic rna for antigen vaccination and pd-1 axis binding antagonists |
WO2023056421A1 (en) | 2021-10-01 | 2023-04-06 | Incyte Corporation | Pyrazoloquinoline kras inhibitors |
WO2023057534A1 (en) | 2021-10-06 | 2023-04-13 | Genmab A/S | Multispecific binding agents against pd-l1 and cd137 in combination |
WO2023061930A1 (en) | 2021-10-11 | 2023-04-20 | BioNTech SE | Therapeutic rna for lung cancer |
WO2023064857A1 (en) | 2021-10-14 | 2023-04-20 | Incyte Corporation | Quinoline compounds as inhibitors of kras |
WO2023078900A1 (en) | 2021-11-03 | 2023-05-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating triple negative breast cancer (tnbc) |
WO2023083868A1 (en) | 2021-11-09 | 2023-05-19 | BioNTech SE | Tlr7 agonist and combinations for cancer treatment |
WO2023083439A1 (en) | 2021-11-09 | 2023-05-19 | BioNTech SE | Tlr7 agonist and combinations for cancer treatment |
WO2023091746A1 (en) | 2021-11-22 | 2023-05-25 | Incyte Corporation | Combination therapy comprising an fgfr inhibitor and a kras inhibitor |
WO2023102184A1 (en) | 2021-12-03 | 2023-06-08 | Incyte Corporation | Bicyclic amine compounds as cdk12 inhibitors |
WO2023107705A1 (en) | 2021-12-10 | 2023-06-15 | Incyte Corporation | Bicyclic amines as cdk12 inhibitors |
WO2023118165A1 (en) | 2021-12-21 | 2023-06-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for treating melanoma |
WO2023122134A1 (en) | 2021-12-22 | 2023-06-29 | Incyte Corporation | Salts and solid forms of an fgfr inhibitor and processes of preparing thereof |
WO2023172921A1 (en) | 2022-03-07 | 2023-09-14 | Incyte Corporation | Solid forms, salts, and processes of preparation of a cdk2 inhibitor |
WO2023218046A1 (en) | 2022-05-12 | 2023-11-16 | Genmab A/S | Binding agents capable of binding to cd27 in combination therapy |
WO2023227949A1 (en) | 2022-05-27 | 2023-11-30 | Takeda Pharmaceutical Company Limited | Dosing of cd38-binding fusion protein |
WO2023239768A1 (en) | 2022-06-08 | 2023-12-14 | Incyte Corporation | Tricyclic triazolo compounds as dgk inhibitors |
WO2023250430A1 (en) | 2022-06-22 | 2023-12-28 | Incyte Corporation | Bicyclic amine cdk12 inhibitors |
WO2024015731A1 (en) | 2022-07-11 | 2024-01-18 | Incyte Corporation | Fused tricyclic compounds as inhibitors of kras g12v mutants |
WO2024033400A1 (en) | 2022-08-10 | 2024-02-15 | Institut National de la Santé et de la Recherche Médicale | Sk2 inhibitor for the treatment of pancreatic cancer |
WO2024033399A1 (en) | 2022-08-10 | 2024-02-15 | Institut National de la Santé et de la Recherche Médicale | Sigmar1 ligand for the treatment of pancreatic cancer |
WO2024056716A1 (en) | 2022-09-14 | 2024-03-21 | Institut National de la Santé et de la Recherche Médicale | Methods and pharmaceutical compositions for the treatment of dilated cardiomyopathy |
Also Published As
Publication number | Publication date |
---|---|
US20130022629A1 (en) | 2013-01-24 |
WO2011082400A3 (en) | 2011-11-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2011082400A2 (en) | Modulators of immunoinhibitory receptor pd-1, and methods of use thereof | |
JP7106572B2 (en) | Compounds Useful as Immunomodulators | |
JP6636673B2 (en) | Benzo [b] thiophene compounds as STING agonists | |
JP6911031B2 (en) | Heterocyclic compounds as immunomodulators | |
JP6762299B2 (en) | Immunomodulator | |
CA2726588C (en) | Compounds and methods for treating inflammatory and fibrotic disorders | |
JP2023500395A (en) | Salts and Crystal Forms of PD-1/PD-L1 Inhibitors | |
KR20220119088A (en) | KRAS mutant protein inhibitor | |
JP2020203887A (en) | Modified cyclic dinucleotide compounds | |
KR20200085836A (en) | Pyrimidine derivatives as PD1/PD-L1 activation inhibitors | |
TW201726623A (en) | Heterocyclic compounds as immunomodulators | |
WO2020025030A1 (en) | Preparation and application of aromatic compound having immunoregulatory function | |
JP2008514658A (en) | Thermodynamically stable form of BAY 43-9006 tosylate | |
AU2016238437B2 (en) | Particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2- oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide | |
BR112013005523B1 (en) | compound as c-met kinase inhibitor | |
WO2012125544A2 (en) | Necroptosis inhibitors and methods of use therefor | |
KR20140038443A (en) | Piperidine derivatives and compositions for the inhibition of nicotinamide phosphoribosyltransferase (nampt) | |
CA3162992A1 (en) | Substituted quinolinonyl piperazine compounds useful as t cell activators | |
CN101243085A (en) | Process for preparing triazole substituted azaindoleoxoacetic piperazine derivatives and novel salt forms produced therein | |
JP4805166B2 (en) | Aroylfuran and aroylthiophene | |
JP2021532077A (en) | A dimeric immunomodulatory compound that opposes the cereblon mechanism | |
KR20150068484A (en) | Inhibitors of syk | |
AU2018327414A1 (en) | Substituted imidazoquinolines | |
ES2352748T3 (en) | PHENYLAMINOPIRIDINS AND PHENYLAMINOPIRACINES. | |
CA3095934A1 (en) | Aryl hydrocarbon receptor modulators and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11728548 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13519621 Country of ref document: US |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 11728548 Country of ref document: EP Kind code of ref document: A2 |